<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01670877</url>
  </required_header>
  <id_info>
    <org_study_id>201209135</org_study_id>
    <nct_id>NCT01670877</nct_id>
  </id_info>
  <brief_title>Neratinib +/- Fulvestrant in Metastatic HER2 Non-amplified But HER2 Mutant Breast Cancer</brief_title>
  <official_title>A Phase II Study of Neratinib Alone and in Combination With Fulvestrant in Metastatic HER2 Non-amplified But HER2 Mutant Breast Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Washington University School of Medicine</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Puma Biotechnology, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>United States Department of Defense</agency>
      <agency_class>U.S. Fed</agency_class>
    </collaborator>
  </sponsors>
  <source>Washington University School of Medicine</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase II study will test cancer to see if it has a HER2 mutation and, if so, see how&#xD;
      HER2 mutated cancer responds to treatment with neratinib.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Overexpression of HER2 due to gene amplification is an established therapeutic target in&#xD;
      breast cancer for which multiple HER2 targeted drugs are now available. However, the majority&#xD;
      of breast cancers are without HER2 overexpression/non-amplified and not currently eligible to&#xD;
      receive HER2 targeted drugs. Advances in tumor genome sequencing technology led to the&#xD;
      identification of recurrent HER2 mutations (HER2mut) in approximately 2% of HER2&#xD;
      non-amplified primary breast cancers, and 3-5% of metastatic tumors. Importantly, tumor cells&#xD;
      harboring HER2mut are sensitive to the anti-tumor effects of HER2-targeted agents in&#xD;
      preclinical models, especially neratinib, a potent irreversible pan-HER inhibitor. However,&#xD;
      neratinib monotherapy has demonstrated only modest single agent activity in HER2mut,,&#xD;
      non-amplified metastatic breast cancer (MBC). Based on the hypothesis that the combination of&#xD;
      neratinib and fulvestrant will be more effective than neratinib alone in ER+/HER2mut,&#xD;
      non-amplified MBC the investigators conducted a single arm phase II study of neratinib plus&#xD;
      fulvestrant with 2 cohorts, fulvestrant (FUL)-treated and FUL-naïve, for patients with&#xD;
      ER+/HER2mut, non-amplified MBC to assess the anti-tumor effects of this combination. An&#xD;
      exploratory ER-negative (ER-) HER2mut cohort was also included for the efficacy of neratinib&#xD;
      monotherapy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 11, 2012</start_date>
  <completion_date type="Actual">March 11, 2021</completion_date>
  <primary_completion_date type="Actual">February 11, 2021</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Part I Only: Clinical Benefit Rate (CR+PR+SD≥6months) of Patients Who Received Neratinib Alone</measure>
    <time_frame>Through completion of treatment (median treatment time of 90 days, full range 54-716 days)</time_frame>
    <description>Imaging for clinical benefit rate occurred at baseline (for an initial comparison scan) and every 2 cycles (28 day length) thereafter.&#xD;
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.&#xD;
Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.&#xD;
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have had stable disease for at least 6 months.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part II ER-cohort Only: Clinical Benefit Rate (CR+PR+SD≥6months) of Neratinib in Patients With Metastatic HER2-, ER- Breast Cancer That Carry HER2 Mutation</measure>
    <time_frame>Through completion of treatment (median treatment time of 62 days, full range 56-413 days)</time_frame>
    <description>Imaging for clinical benefit rate occurred at baseline (for an initial comparison scan) and every 2 cycles (28 day length) thereafter.&#xD;
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.&#xD;
Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.&#xD;
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have had stable disease for at least 6 months.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part II Fulvestrant-naive ER+ Cohort Only: Clinical Benefit (CR+PR+SD≥6 Months) of Neratinib + Fulvestrant in Patients With Metastatic HER2- ER+ Fulvestrant-naive Breast Cancer That Carry HER2 Mutation</measure>
    <time_frame>Through completion of treatment (median treatment time of 140.5 days, full range 48-770 days)</time_frame>
    <description>Imaging for clinical benefit rate occurred at baseline (for an initial comparison scan) and every 2 cycles (28 day length) thereafter.&#xD;
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.&#xD;
Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.&#xD;
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have had stable disease for at least 6 months.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Part II Fulvestrant-treated ER+ Cohort Only: Clinical Benefit Rate (CR+PR+SD≥6months) of Neratinib + Fulvestrant in Patients With Metastatic HER2- ER+ Fulvestrant-treated Breast Cancer That Carry HER2 Mutation</measure>
    <time_frame>Through completion of treatment (median treatment time of 168 days, full range 28-671 days)</time_frame>
    <description>Imaging for clinical benefit rate occurred at baseline (for an initial comparison scan) and every 2 cycles (28 day length) thereafter.&#xD;
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.&#xD;
Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.&#xD;
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have had stable disease for at least 6 months.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression-free Survival (PFS) of Patients Treated With Neratinib Alone in Patients With Metastatic HER2- But HER2 Mutated Breast Cancer by ER Status and by HER2 Mutations (Activating Versus Unknown Significance)</measure>
    <time_frame>Through completion of follow-up; follow-up was through 30 days following completion of treatment (median follow-up of 92 days, full range 86 days-443 days)</time_frame>
    <description>Participants were followed for progressive disease from start of treatment until completion of follow-up.&#xD;
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With HER2 Mutation Subtype and Histology Subtype</measure>
    <time_frame>At the time of enrollment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With HER2 Mutation Subtype and Tumor Grade</measure>
    <time_frame>A time of enrollment</time_frame>
    <description>-Cancer cells are graded when they are removed from the breast. The grade is based on how much the cancer cells look like normal cells.&#xD;
A low grade number (grade 1) usually means the cancer is slower-growing and less likely to spread.&#xD;
An intermediate grade number (grade 2) means the cancer is growing faster than a grade 1 cancer but slower than a grade 3 cancer.&#xD;
A high grade number (grade 3) means a faster-growing cancer that's more likely to spread.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlate the Presence of HER2 Mutation Subtype With Tumor Staging at Initial Diagnosis</measure>
    <time_frame>At time of enrollment</time_frame>
    <description>Staging occurred at initial diagnosis after physical exam, mammogram, and other diagnostic imaging tests. The staging also takes into account pathology reports from the breast biopsy or surgery.&#xD;
Stage I has a better outcome than Stage IV.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlate the Presence of HER2 Mutation Subtype With Progression-free Survival</measure>
    <time_frame>Through completion of follow-up; follow-up was through 30 days following completion of treatment (median follow-up of 142 days, full range 54-800 days)</time_frame>
    <description>Progression-free survival is defined as the number of weeks from start of treatment until disease progression or death.&#xD;
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part II ER-cohort Only: Progression-free Survival (PFS)</measure>
    <time_frame>Through completion of treatment (median treatment time of 62 days, full range 56-413 days)</time_frame>
    <description>Progression-free survival is defined as the number of weeks from start of treatment until disease progression or death.&#xD;
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part II Fulvestrant-naive ER+ Cohort Only: Progression-free Survival (PFS)</measure>
    <time_frame>Through completion of treatment (median treatment time of 140.5 days, full range 48-770 days)</time_frame>
    <description>Progression-free survival is defined as the number of weeks from start of treatment until disease progression or death.&#xD;
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part II Fulvestrant-treated ER+ Cohort Only: Progression-free Survival (PFS)</measure>
    <time_frame>Through completion of treatment (median treatment time of 168 days, full range 28-671 days)</time_frame>
    <description>Progression-free survival is defined as the number of weeks from start of treatment until disease progression or death.&#xD;
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety and Tolerability of Neratinib in Combination With Fulvestrant in Patients With HER2- ER+ HER2 Mutated Breast Cancer as Measured by Number of Participants With Related Adverse Events</measure>
    <time_frame>Through completion of follow-up; follow-up was through 28 days following completion of treatment (median follow-up of 140 days, full range 52-798 days)</time_frame>
    <description>-CTCAE v 4.0 will be used to record adverse events. Related includes those possibly, probably, or definitely related to the treatment regimen.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part II Fulvestrant-naive ER+ Cohort Only: Response Rate (RR)</measure>
    <time_frame>Through completion of treatment (median treatment time of 140.5 days, full range 48-770 days)</time_frame>
    <description>RR is defined as number of participants with complete response or partial response as best response.&#xD;
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.&#xD;
Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Part II Fulvestrant-treated ER+ Cohort Only: Response Rate (RR)</measure>
    <time_frame>Through completion of treatment (median treatment time of 168 days, full range 28-671 days)</time_frame>
    <description>RR is defined as number of participants with complete response or partial response as best response.&#xD;
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.&#xD;
Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.</description>
  </secondary_outcome>
  <number_of_arms>6</number_of_arms>
  <enrollment type="Actual">56</enrollment>
  <condition>Breast Neoplasms</condition>
  <arm_group>
    <arm_group_label>Part I: Neratinib Only</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part II: Neratinib Only (ER-)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part II: Neratinib + Fulvestrant (ER+, fulvestrant-naive)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part II: Neratinib + Fulvestrant (ER+. prior fulvestrant-tx)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Crossover: Neratinib + Trastuzumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Crossover: Neratinib + Fulvestrant + Trastuzumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Neratinib</intervention_name>
    <arm_group_label>Crossover: Neratinib + Fulvestrant + Trastuzumab</arm_group_label>
    <arm_group_label>Crossover: Neratinib + Trastuzumab</arm_group_label>
    <arm_group_label>Part I: Neratinib Only</arm_group_label>
    <arm_group_label>Part II: Neratinib + Fulvestrant (ER+, fulvestrant-naive)</arm_group_label>
    <arm_group_label>Part II: Neratinib + Fulvestrant (ER+. prior fulvestrant-tx)</arm_group_label>
    <arm_group_label>Part II: Neratinib Only (ER-)</arm_group_label>
    <other_name>PF-05208767</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fulvestrant</intervention_name>
    <arm_group_label>Crossover: Neratinib + Fulvestrant + Trastuzumab</arm_group_label>
    <arm_group_label>Part II: Neratinib + Fulvestrant (ER+, fulvestrant-naive)</arm_group_label>
    <arm_group_label>Part II: Neratinib + Fulvestrant (ER+. prior fulvestrant-tx)</arm_group_label>
    <other_name>Faslodex</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Trastuzumab</intervention_name>
    <arm_group_label>Crossover: Neratinib + Fulvestrant + Trastuzumab</arm_group_label>
    <arm_group_label>Crossover: Neratinib + Trastuzumab</arm_group_label>
    <other_name>Herceptin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Tumor biopsy</intervention_name>
    <description>-Optional at baseline and disease progression</description>
    <arm_group_label>Crossover: Neratinib + Fulvestrant + Trastuzumab</arm_group_label>
    <arm_group_label>Crossover: Neratinib + Trastuzumab</arm_group_label>
    <arm_group_label>Part I: Neratinib Only</arm_group_label>
    <arm_group_label>Part II: Neratinib + Fulvestrant (ER+, fulvestrant-naive)</arm_group_label>
    <arm_group_label>Part II: Neratinib + Fulvestrant (ER+. prior fulvestrant-tx)</arm_group_label>
    <arm_group_label>Part II: Neratinib Only (ER-)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Research blood sample</intervention_name>
    <description>-Baseline, cycle 1 day 15, cycle 2 day 1, cycle 3 day 1, day 1 of each odd cycle, end of treatment (progression)</description>
    <arm_group_label>Crossover: Neratinib + Fulvestrant + Trastuzumab</arm_group_label>
    <arm_group_label>Crossover: Neratinib + Trastuzumab</arm_group_label>
    <arm_group_label>Part I: Neratinib Only</arm_group_label>
    <arm_group_label>Part II: Neratinib + Fulvestrant (ER+, fulvestrant-naive)</arm_group_label>
    <arm_group_label>Part II: Neratinib + Fulvestrant (ER+. prior fulvestrant-tx)</arm_group_label>
    <arm_group_label>Part II: Neratinib Only (ER-)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria for Pre-registration (for patients with unknown HER2 mutation status to&#xD;
        have tumor tissue screened centrally by Washington University GPS laboratory):&#xD;
&#xD;
          -  Histologically or cytologically confirmed HER2-negative (0 or 1+ by IHC or&#xD;
             non-amplified by FISH) breast cancer that is stage IV.&#xD;
&#xD;
          -  Agree to provide archival tumor material for research&#xD;
&#xD;
          -  There is no limitation on the number of prior lines of systemic therapy.&#xD;
&#xD;
          -  Presence of measurable or non-measurable disease by RECIST 1.1 is acceptable, except&#xD;
             to be eligible for the Part II fulvestrant-naive ER+ cohort, at least one measurable&#xD;
             disease by RECIST 1.1 is required.&#xD;
&#xD;
          -  At least 18 years of age.&#xD;
&#xD;
          -  ECOG performance status ≤ 2&#xD;
&#xD;
          -  Adequate organ function as defined below within 8 weeks of pre-registration:&#xD;
&#xD;
               -  Serum creatinine ≤1.5 x ULN&#xD;
&#xD;
               -  Chil-Pugh class A if with liver disease&#xD;
&#xD;
          -  Able to understand and willing to sign an IRB approved written informed consent&#xD;
             document.&#xD;
&#xD;
        Note: HER2 mutation testing may be performed while the patient is receiving active systemic&#xD;
        therapy for metastatic breast cancer so that the result can be used to determine&#xD;
        eligibility for study drug therapy in the future.&#xD;
&#xD;
        Exclusion Criteria for Pre-registration:&#xD;
&#xD;
          -  Testing for LVEF is not required for pre-registration, but patient must not have a&#xD;
             recent LVEF &lt; LLN or have symptoms of congestive heart failure.&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social&#xD;
             situations that would limit compliance with study requirements.&#xD;
&#xD;
          -  Acute or currently active hepatic or biliary disease requiring antiviral therapy (with&#xD;
             the exception of Gilbert's syndrome, asymptomatic gallstones, liver metastases, or&#xD;
             stable chronic liver disease per investigator assessment).&#xD;
&#xD;
          -  History of significant cardiac disease, cardiac risk factors, or uncontrolled&#xD;
             arrhythmias.&#xD;
&#xD;
          -  Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs&#xD;
             resulting in dyspnea at rest.&#xD;
&#xD;
        Inclusion Criteria for Registration (for patients initially pre-registered and with HER2&#xD;
        mutation identified by Washington University GPS laboratory)&#xD;
&#xD;
          -  Tumor tissue tested positive for HER2 mutation. HER2 mutations detected by Guardant360&#xD;
             are also eligible.&#xD;
&#xD;
          -  Agree to provide archival tumor material for research&#xD;
&#xD;
          -  ECOG performance status ≤2&#xD;
&#xD;
          -  Adequate organ function as defined below within 2 weeks of registration:&#xD;
&#xD;
               -  ANC ≥1.5 x 10^9/L&#xD;
&#xD;
               -  Platelet count ≥100 x 10^9/L&#xD;
&#xD;
               -  Serum creatinine ≤1.5 x ULN&#xD;
&#xD;
               -  Child-Pugh class A if with liver disease&#xD;
&#xD;
          -  The patient must have completed radiation therapy and be at least 1 week from the last&#xD;
             systemic chemotherapy administration, with adequate recovery of bone marrow and organ&#xD;
             functions, before starting neratinib.&#xD;
&#xD;
          -  Presence of disease progression on the most recent disease evaluation.&#xD;
&#xD;
          -  Patients with known brain metastasis are eligible, but must have received radiation&#xD;
             and be off steroids and stable (without evidence of disease progression by imaging or&#xD;
             exam) for 3 months.&#xD;
&#xD;
          -  QTc interval ≤450 msec for men or &lt; or ≤ 470 msec for women within 2 weeks of&#xD;
             registration.&#xD;
&#xD;
          -  LVEF &gt; or = institutional ILLN within 4 weeks of registration.&#xD;
&#xD;
          -  Women of childbearing potential and men must agree to use adequate contraception&#xD;
             (hormonal or barrier method of birth control, abstinence) prior to study entry and for&#xD;
             the duration of study participation. Should a woman become pregnant or suspect she is&#xD;
             pregnant while participating in this study, she must inform her treating physician&#xD;
             immediately. Men must agree and commit to use a barrier method of contraception while&#xD;
             on treatment and for 3 months after the last dose of the investigational product.&#xD;
&#xD;
          -  Able to understand and willing to sign an IRB approved written informed consent&#xD;
             document.&#xD;
&#xD;
          -  There is no limitation on the number of prior lines of systemic therapy.&#xD;
&#xD;
          -  To be eligible for the Part II fulvestrant-naive ER+ cohort, prior treatment with&#xD;
             fulvestrant is not allowed. In addition, ER and/or PR positivity by institutional&#xD;
             standard is required on pathology from the most recent tumor specimen if biopsy was&#xD;
             done unless the tissue source (for example, pleural effusion or ascites or bone&#xD;
             biopsy) may yield false negative ER and/or PR result, in which case the pathology from&#xD;
             an earlier time point could be used and a discussion with the study chair is required.&#xD;
&#xD;
          -  To be eligible for the Part II fulvestrant-treated ER+ cohort, prior disease&#xD;
             progression on fulvestrant is required. In addition, ER and/or PR positivity by&#xD;
             institutional standard is required on pathology from the most recent tumor specimen&#xD;
             unless the tissue source (for example, pleural effusion or ascites or bone biopsy) may&#xD;
             yield false negative ER and/or PR result, in which case the pathology form an earlier&#xD;
             time point could be used and a discussion with the study chair is required.&#xD;
&#xD;
        Inclusion Criteria for Registration (for patients with HER2 mutation identified at an&#xD;
        outside CLIA certified location):&#xD;
&#xD;
          -  Histologically or cytologically confirmed HER2-negative (0 or 1+ by IHC or&#xD;
             non-amplified by FISH) breast cancer that is stage IV.&#xD;
&#xD;
          -  Tumor tissue or circulating tumor DNA tested positive for HER2 mutation. Mutations&#xD;
             outside the list will be assessed on a case-by-case basis by the study team to&#xD;
             determine eligibility.&#xD;
&#xD;
          -  Presence of measurable or non-measurable disease by RECIST 1.1 is acceptable, except&#xD;
             to be eligible for the Part II fulvestrant-naïve ER+ cohort, at least one measurable&#xD;
             disease by RECIST 1.1 is required.&#xD;
&#xD;
          -  At least 18 years of age.&#xD;
&#xD;
          -  ECOG performance status &lt; 2 (see Appendix A).&#xD;
&#xD;
          -  Adequate organ function as defined below within 2 weeks of registration:&#xD;
&#xD;
               -  Absolute neutrophil count: ≥1.5 × 109/L (1500/mm3)&#xD;
&#xD;
               -  Platelet count: ≥100 × 109/L (100,000/mm3)&#xD;
&#xD;
               -  Serum creatinine: ≤1.5 x ULN&#xD;
&#xD;
               -  Child-Pugh class A if with liver disease&#xD;
&#xD;
          -  The patient must have completed radiation therapy and be at least 1 week from the last&#xD;
             systemic therapy administration, with adequate recovery of bone marrow and organ&#xD;
             functions, before starting neratinib.&#xD;
&#xD;
          -  Presence of disease progression on the most recent disease evaluation.&#xD;
&#xD;
          -  Patients with known treated brain metastasis are eligible, but must have received&#xD;
             radiation and be off steroids and stable (without evidence of disease progression by&#xD;
             imaging or exam) for 3 months.&#xD;
&#xD;
          -  QTc interval ≤ 450 msec for men or ≤ 470 msec for women within 2 weeks of&#xD;
             registration.&#xD;
&#xD;
          -  LVEF &gt; institutional LLN within 4 weeks of registration.&#xD;
&#xD;
          -  Women of childbearing potential and men must agree to use adequate contraception&#xD;
             (hormonal or barrier method of birth control, abstinence) prior to study entry and for&#xD;
             the duration of study participation. Should a woman become pregnant or suspect she is&#xD;
             pregnant while participating in this study, she must inform her treating physician&#xD;
             immediately. Men must agree and commit to use a barrier method of contraception while&#xD;
             on treatment and for 3 months after the last dose of the investigational product&#xD;
&#xD;
          -  Able to understand and willing to sign an IRB approved written informed consent&#xD;
             document.&#xD;
&#xD;
          -  There is no limitation on the number of prior lines of systemic therapy.&#xD;
&#xD;
          -  To be eligible for the Part II fulvestrant-naïve ER+ cohort, prior treatment with&#xD;
             fulvestrant is not allowed. In addition, ER and/or PR positivity by institutional&#xD;
             standard is required on pathology from the most recent tumor specimen if biopsy was&#xD;
             done unless the tissue source (for example, pleural effusion or ascites or bone&#xD;
             biopsy) may yield false negative ER and/or PR result, in which case the pathology from&#xD;
             an earlier time point could be used and a discussion with the study chair is required.&#xD;
&#xD;
          -  To be eligible for the Part II fulvestrant-treated ER+ cohort, prior disease&#xD;
             progression on fulvestrant is required. In addition, ER and/or PR positivity by&#xD;
             institutional standard is required on pathology from the most recent tumor specimen&#xD;
             unless the tissue source (for example, pleural effusion or ascites or bone biopsy) may&#xD;
             yield false negative ER and/or PR result, in which case the pathology from an earlier&#xD;
             time point could be used and a discussion with the study chair is required.&#xD;
&#xD;
        Exclusion Criteria for Registration:&#xD;
&#xD;
          -  Currently receiving any other investigational agents or systemic cancer therapy.&#xD;
&#xD;
          -  Currently taking medications and herbal or dietary supplements that are strong&#xD;
             cytochrome P450 (CYP) 3A4 inducers or inhibitors. The washout period must have been&#xD;
             completed prior to the start of neratinib if the patient was taking any of these&#xD;
             agents. If unavoidable, patients taking CYP3A4 inhibitors should be monitored closely.&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection symptomatic congestive heart failure, unstable angina pectoris, cardiac&#xD;
             arrhythmia, or psychiatric illness/social situations that would limit compliance with&#xD;
             study requirements.&#xD;
&#xD;
          -  Acute or currently active/requiring antiviral therapy hepatic or biliary disease (with&#xD;
             the exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver&#xD;
             metastases, or stable chronic liver disease per investigator assessment).&#xD;
&#xD;
          -  Pregnant and/or breastfeeding.&#xD;
&#xD;
          -  History of significant cardiac disease, cardiac risk factors, or uncontrolled&#xD;
             arrhythmias.&#xD;
&#xD;
          -  Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs&#xD;
             resulting in dyspnea at rest.&#xD;
&#xD;
          -  Experiencing grade 2 or greater diarrhea.&#xD;
&#xD;
          -  Prior treatment with neratinib&#xD;
&#xD;
          -  Child-Pugh class B or C liver dysfunction&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Cynthia Ma, M.D., Ph.D</last_name>
    <role>Principal Investigator</role>
    <affiliation>Washington University School of Medicine</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Alabama Cancer Center</name>
      <address>
        <city>Birmingham</city>
        <state>Alabama</state>
        <zip>35294</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic</name>
      <address>
        <city>Phoenix</city>
        <state>Arizona</state>
        <zip>85054</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Southern California Keck School of Medicine</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90033</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stanford Medicine Cancer Institute</name>
      <address>
        <city>Stanford</city>
        <state>California</state>
        <zip>94305</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Miami Hospital and Clinics</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33136</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Northwestern University - Feinberg School of Medicine</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60611</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rush University Medical Center</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dana-Farber Cancer Institute, Harvard University</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Michigan</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48109</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Luke's Cancer Institute</name>
      <address>
        <city>Kansas City</city>
        <state>Missouri</state>
        <zip>64111</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Washington University School of Medicine</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of North Carolina at Chapel Hill (Lineberger Comprehensive Cancer Center)</name>
      <address>
        <city>Chapel Hill</city>
        <state>North Carolina</state>
        <zip>27514</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Duke Cancer Institute at Duke University Medical Center</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27710</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Avera Cancer Institute</name>
      <address>
        <city>Sioux Falls</city>
        <state>South Dakota</state>
        <zip>57105</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Baylor College of Medicine</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>BC Cancer Agency</name>
      <address>
        <city>Vancouver</city>
        <state>British Columbia</state>
        <zip>V5Z 1L3</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Princess Margaret Cancer Centre</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G 2M9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.siteman.wustl.edu</url>
    <description>Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine</description>
  </link>
  <verification_date>April 2022</verification_date>
  <study_first_submitted>August 17, 2012</study_first_submitted>
  <study_first_submitted_qc>August 17, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 22, 2012</study_first_posted>
  <results_first_submitted>February 10, 2022</results_first_submitted>
  <results_first_submitted_qc>April 14, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">April 15, 2022</results_first_posted>
  <last_update_submitted>April 14, 2022</last_update_submitted>
  <last_update_submitted_qc>April 14, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">April 15, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Neratinib</keyword>
  <keyword>fulvestrant</keyword>
  <keyword>HER2 mutation</keyword>
  <keyword>metastatic breast cancer</keyword>
  <keyword>trastuzumab</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Trastuzumab</mesh_term>
    <mesh_term>Fulvestrant</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>March 16, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/77/NCT01670877/Prot_SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>January 14, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/77/NCT01670877/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Part I: Neratinib Only</title>
          <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
        </group>
        <group group_id="P2">
          <title>Part II: Neratinib Only (ER-)</title>
          <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
        </group>
        <group group_id="P3">
          <title>Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive)</title>
          <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
        </group>
        <group group_id="P4">
          <title>Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx)</title>
          <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
        </group>
        <group group_id="P5">
          <title>Crossover: Neratinib + Trastuzumab</title>
          <description>-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks.</description>
        </group>
        <group group_id="P6">
          <title>Crossover: Neratinib + Fulvestrant + Trastuzumab</title>
          <description>-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Part I and Part 2</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="16"/>
                <participants group_id="P2" count="5"/>
                <participants group_id="P3" count="11"/>
                <participants group_id="P4" count="24"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="16"/>
                <participants group_id="P2" count="4"/>
                <participants group_id="P3" count="10"/>
                <participants group_id="P4" count="21"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="1"/>
                <participants group_id="P4" count="3"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Grade 2 vomiting and progressive disease</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Grade 3 diarrhea and withdrawal</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Grade 2 vomiting</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="1"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Grade 3 dizziness and progressive disease</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="1"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Grade 3 diarrhea and duodenal ulcer</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="1"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Crossover</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="3"/>
                <participants group_id="P6" count="5"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="3"/>
                <participants group_id="P6" count="5"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
                <participants group_id="P5" count="0"/>
                <participants group_id="P6" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Part I: Neratinib Only</title>
          <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
        </group>
        <group group_id="B2">
          <title>Part II: Neratinib Only (ER-)</title>
          <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
        </group>
        <group group_id="B3">
          <title>Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive)</title>
          <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
        </group>
        <group group_id="B4">
          <title>Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx)</title>
          <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
        </group>
        <group group_id="B5">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="16"/>
            <count group_id="B2" value="5"/>
            <count group_id="B3" value="11"/>
            <count group_id="B4" value="24"/>
            <count group_id="B5" value="56"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="58" lower_limit="31" upper_limit="74"/>
                    <measurement group_id="B2" value="63" lower_limit="58" upper_limit="67"/>
                    <measurement group_id="B3" value="58" lower_limit="41" upper_limit="82"/>
                    <measurement group_id="B4" value="64" lower_limit="35" upper_limit="76"/>
                    <measurement group_id="B5" value="61" lower_limit="31" upper_limit="82"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="16"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="10"/>
                    <measurement group_id="B4" value="24"/>
                    <measurement group_id="B5" value="55"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="2"/>
                    <measurement group_id="B5" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="16"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="9"/>
                    <measurement group_id="B4" value="17"/>
                    <measurement group_id="B5" value="47"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="5"/>
                    <measurement group_id="B5" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="8"/>
                    <measurement group_id="B4" value="23"/>
                    <measurement group_id="B5" value="48"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Canada</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="11"/>
                    <measurement group_id="B4" value="24"/>
                    <measurement group_id="B5" value="56"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>HER2 Status</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Activating</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="11"/>
                    <measurement group_id="B4" value="24"/>
                    <measurement group_id="B5" value="55"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Novel</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Histology Subtype</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Ductal</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="7"/>
                    <measurement group_id="B4" value="10"/>
                    <measurement group_id="B5" value="30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Lobular</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="12"/>
                    <measurement group_id="B5" value="21"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Other</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="2"/>
                    <measurement group_id="B5" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Unknown</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Tumor Grade</title>
          <description>Cancer cells are graded when they are removed from the breast. The grade is based on how much the cancer cells look like normal cells.&#xD;
A low grade number (grade 1) usually means the cancer is slower-growing and less likely to spread.&#xD;
An intermediate grade number (grade 2) means the cancer is growing faster than a grade 1 cancer but slower than a grade 3 cancer.&#xD;
A high grade number (grade 3) means a faster-growing cancer that's more likely to spread.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>I/II</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="5"/>
                    <measurement group_id="B4" value="12"/>
                    <measurement group_id="B5" value="25"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>II</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="3"/>
                    <measurement group_id="B5" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>III</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="3"/>
                    <measurement group_id="B5" value="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Unknown</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="6"/>
                    <measurement group_id="B5" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Tumor Stage at Initial Diagnosis</title>
          <description>Staging occurred at initial diagnosis after physical exam, mammogram, and other diagnostic imaging tests. The staging also takes into account pathology reports from the breast biopsy or surgery.&#xD;
Stage I has a better outcome than Stage IV.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>I</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="4"/>
                    <measurement group_id="B5" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>II</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="9"/>
                    <measurement group_id="B5" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>IIA</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>IIB</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>III</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="4"/>
                    <measurement group_id="B5" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>IIIA</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="3"/>
                    <measurement group_id="B5" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>IIIC</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>IV</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Unknown</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="2"/>
                    <measurement group_id="B5" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Part I Only: Clinical Benefit Rate (CR+PR+SD≥6months) of Patients Who Received Neratinib Alone</title>
        <description>Imaging for clinical benefit rate occurred at baseline (for an initial comparison scan) and every 2 cycles (28 day length) thereafter.&#xD;
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.&#xD;
Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.&#xD;
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have had stable disease for at least 6 months.</description>
        <time_frame>Through completion of treatment (median treatment time of 90 days, full range 54-716 days)</time_frame>
        <population>Only Part I participants were evaluable for this outcome measure.</population>
        <group_list>
          <group group_id="O1">
            <title>Part I: Neratinib Only</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O2">
            <title>Part II: Neratinib Only (ER-)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O3">
            <title>Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O4">
            <title>Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O5">
            <title>Crossover: Neratinib + Trastuzumab</title>
            <description>-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks.</description>
          </group>
          <group group_id="O6">
            <title>Crossover: Neratinib + Fulvestrant + Trastuzumab</title>
            <description>-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Part I Only: Clinical Benefit Rate (CR+PR+SD≥6months) of Patients Who Received Neratinib Alone</title>
          <description>Imaging for clinical benefit rate occurred at baseline (for an initial comparison scan) and every 2 cycles (28 day length) thereafter.&#xD;
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.&#xD;
Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.&#xD;
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have had stable disease for at least 6 months.</description>
          <population>Only Part I participants were evaluable for this outcome measure.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
                <count group_id="O4" value="0"/>
                <count group_id="O5" value="0"/>
                <count group_id="O6" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Part II ER-cohort Only: Clinical Benefit Rate (CR+PR+SD≥6months) of Neratinib in Patients With Metastatic HER2-, ER- Breast Cancer That Carry HER2 Mutation</title>
        <description>Imaging for clinical benefit rate occurred at baseline (for an initial comparison scan) and every 2 cycles (28 day length) thereafter.&#xD;
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.&#xD;
Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.&#xD;
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have had stable disease for at least 6 months.</description>
        <time_frame>Through completion of treatment (median treatment time of 62 days, full range 56-413 days)</time_frame>
        <population>Only participants enrolled in the Part II ER-cohort are evaluable for this outcome measure. One participant was not evaluable in this cohort as the participant stopped treatment in cycle 1.</population>
        <group_list>
          <group group_id="O1">
            <title>Part I: Neratinib Only</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O2">
            <title>Part II: Neratinib Only (ER-)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O3">
            <title>Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O4">
            <title>Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O5">
            <title>Crossover: Neratinib + Trastuzumab</title>
            <description>-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks.</description>
          </group>
          <group group_id="O6">
            <title>Crossover: Neratinib + Fulvestrant + Trastuzumab</title>
            <description>-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Part II ER-cohort Only: Clinical Benefit Rate (CR+PR+SD≥6months) of Neratinib in Patients With Metastatic HER2-, ER- Breast Cancer That Carry HER2 Mutation</title>
          <description>Imaging for clinical benefit rate occurred at baseline (for an initial comparison scan) and every 2 cycles (28 day length) thereafter.&#xD;
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.&#xD;
Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.&#xD;
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have had stable disease for at least 6 months.</description>
          <population>Only participants enrolled in the Part II ER-cohort are evaluable for this outcome measure. One participant was not evaluable in this cohort as the participant stopped treatment in cycle 1.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="4"/>
                <count group_id="O3" value="0"/>
                <count group_id="O4" value="0"/>
                <count group_id="O5" value="0"/>
                <count group_id="O6" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Part II Fulvestrant-naive ER+ Cohort Only: Clinical Benefit (CR+PR+SD≥6 Months) of Neratinib + Fulvestrant in Patients With Metastatic HER2- ER+ Fulvestrant-naive Breast Cancer That Carry HER2 Mutation</title>
        <description>Imaging for clinical benefit rate occurred at baseline (for an initial comparison scan) and every 2 cycles (28 day length) thereafter.&#xD;
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.&#xD;
Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.&#xD;
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have had stable disease for at least 6 months.</description>
        <time_frame>Through completion of treatment (median treatment time of 140.5 days, full range 48-770 days)</time_frame>
        <population>Only participants enrolled in the Part II fulvestrant-naive ER+ cohort is evaluable for this outcome measure. One participant was not evaluable in this cohort as the participant stopped treatment in cycle 1.</population>
        <group_list>
          <group group_id="O1">
            <title>Part I: Neratinib Only</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O2">
            <title>Part II: Neratinib Only (ER-)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O3">
            <title>Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O4">
            <title>Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O5">
            <title>Crossover: Neratinib + Trastuzumab</title>
            <description>-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks.</description>
          </group>
          <group group_id="O6">
            <title>Crossover: Neratinib + Fulvestrant + Trastuzumab</title>
            <description>-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Part II Fulvestrant-naive ER+ Cohort Only: Clinical Benefit (CR+PR+SD≥6 Months) of Neratinib + Fulvestrant in Patients With Metastatic HER2- ER+ Fulvestrant-naive Breast Cancer That Carry HER2 Mutation</title>
          <description>Imaging for clinical benefit rate occurred at baseline (for an initial comparison scan) and every 2 cycles (28 day length) thereafter.&#xD;
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.&#xD;
Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.&#xD;
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have had stable disease for at least 6 months.</description>
          <population>Only participants enrolled in the Part II fulvestrant-naive ER+ cohort is evaluable for this outcome measure. One participant was not evaluable in this cohort as the participant stopped treatment in cycle 1.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="10"/>
                <count group_id="O4" value="0"/>
                <count group_id="O5" value="0"/>
                <count group_id="O6" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O3" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Part II Fulvestrant-treated ER+ Cohort Only: Clinical Benefit Rate (CR+PR+SD≥6months) of Neratinib + Fulvestrant in Patients With Metastatic HER2- ER+ Fulvestrant-treated Breast Cancer That Carry HER2 Mutation</title>
        <description>Imaging for clinical benefit rate occurred at baseline (for an initial comparison scan) and every 2 cycles (28 day length) thereafter.&#xD;
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.&#xD;
Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.&#xD;
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have had stable disease for at least 6 months.</description>
        <time_frame>Through completion of treatment (median treatment time of 168 days, full range 28-671 days)</time_frame>
        <population>Only participants enrolled in the fulvestrant-treated ER+ cohort are evaluable for this outcome measure. Three participants were not evaluable in this cohort as the participants stopped treatment in cycle 1.</population>
        <group_list>
          <group group_id="O1">
            <title>Part I: Neratinib Only</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O2">
            <title>Part II: Neratinib Only (ER-)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O3">
            <title>Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O4">
            <title>Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O5">
            <title>Crossover: Neratinib + Trastuzumab</title>
            <description>-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks.</description>
          </group>
          <group group_id="O6">
            <title>Crossover: Neratinib + Fulvestrant + Trastuzumab</title>
            <description>-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Part II Fulvestrant-treated ER+ Cohort Only: Clinical Benefit Rate (CR+PR+SD≥6months) of Neratinib + Fulvestrant in Patients With Metastatic HER2- ER+ Fulvestrant-treated Breast Cancer That Carry HER2 Mutation</title>
          <description>Imaging for clinical benefit rate occurred at baseline (for an initial comparison scan) and every 2 cycles (28 day length) thereafter.&#xD;
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.&#xD;
Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.&#xD;
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have had stable disease for at least 6 months.</description>
          <population>Only participants enrolled in the fulvestrant-treated ER+ cohort are evaluable for this outcome measure. Three participants were not evaluable in this cohort as the participants stopped treatment in cycle 1.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
                <count group_id="O4" value="21"/>
                <count group_id="O5" value="0"/>
                <count group_id="O6" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O4" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression-free Survival (PFS) of Patients Treated With Neratinib Alone in Patients With Metastatic HER2- But HER2 Mutated Breast Cancer by ER Status and by HER2 Mutations (Activating Versus Unknown Significance)</title>
        <description>Participants were followed for progressive disease from start of treatment until completion of follow-up.&#xD;
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.</description>
        <time_frame>Through completion of follow-up; follow-up was through 30 days following completion of treatment (median follow-up of 92 days, full range 86 days-443 days)</time_frame>
        <population>Only participants enrolled in the Part II ER-cohort are evaluable for this outcome measure. One participant was not evaluable in this cohort as the participant stopped treatment in cycle 1. The data represents exact number of weeks that each participant had progression-free survival. 2 participants with Activating mutation - S310F both had 8 weeks of PFS.</population>
        <group_list>
          <group group_id="O1">
            <title>Part I: Neratinib Only</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O2">
            <title>Part II: Neratinib Only (ER-)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O3">
            <title>Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O4">
            <title>Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O5">
            <title>Crossover: Neratinib + Trastuzumab</title>
            <description>-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks.</description>
          </group>
          <group group_id="O6">
            <title>Crossover: Neratinib + Fulvestrant + Trastuzumab</title>
            <description>-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Progression-free Survival (PFS) of Patients Treated With Neratinib Alone in Patients With Metastatic HER2- But HER2 Mutated Breast Cancer by ER Status and by HER2 Mutations (Activating Versus Unknown Significance)</title>
          <description>Participants were followed for progressive disease from start of treatment until completion of follow-up.&#xD;
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.</description>
          <population>Only participants enrolled in the Part II ER-cohort are evaluable for this outcome measure. One participant was not evaluable in this cohort as the participant stopped treatment in cycle 1. The data represents exact number of weeks that each participant had progression-free survival. 2 participants with Activating mutation - S310F both had 8 weeks of PFS.</population>
          <units>weeks</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="4"/>
                <count group_id="O3" value="0"/>
                <count group_id="O4" value="0"/>
                <count group_id="O5" value="0"/>
                <count group_id="O6" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Activating mutation - L7L755S</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="0"/>
                    <count group_id="O2" value="1"/>
                    <count group_id="O3" value="0"/>
                    <count group_id="O4" value="0"/>
                    <count group_id="O5" value="0"/>
                    <count group_id="O6" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O2" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Activating mutation - S310F</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="0"/>
                    <count group_id="O2" value="2"/>
                    <count group_id="O3" value="0"/>
                    <count group_id="O4" value="0"/>
                    <count group_id="O5" value="0"/>
                    <count group_id="O6" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O2" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Activating mutation - A775_G776insYVMA</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="0"/>
                    <count group_id="O2" value="1"/>
                    <count group_id="O3" value="0"/>
                    <count group_id="O4" value="0"/>
                    <count group_id="O5" value="0"/>
                    <count group_id="O6" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O2" value="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With HER2 Mutation Subtype and Histology Subtype</title>
        <time_frame>At the time of enrollment</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Part I: Neratinib Only</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O2">
            <title>Part II: Neratinib Only (ER-)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O3">
            <title>Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O4">
            <title>Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With HER2 Mutation Subtype and Histology Subtype</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="5"/>
                <count group_id="O3" value="11"/>
                <count group_id="O4" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>ECD mutation : Ductal histology</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ECD mutation : Other histology</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Exon 20 ins mutation : Ductal histology</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Exon 20 ins mutation : Other histology</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>KD mutation : Ductal histology</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="5"/>
                    <measurement group_id="O4" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>KD mutation : Other histology</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="3"/>
                    <measurement group_id="O4" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With HER2 Mutation Subtype and Tumor Grade</title>
        <description>-Cancer cells are graded when they are removed from the breast. The grade is based on how much the cancer cells look like normal cells.&#xD;
A low grade number (grade 1) usually means the cancer is slower-growing and less likely to spread.&#xD;
An intermediate grade number (grade 2) means the cancer is growing faster than a grade 1 cancer but slower than a grade 3 cancer.&#xD;
A high grade number (grade 3) means a faster-growing cancer that's more likely to spread.</description>
        <time_frame>A time of enrollment</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Part I: Neratinib Only</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O2">
            <title>Part II: Neratinib Only (ER-)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O3">
            <title>Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O4">
            <title>Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With HER2 Mutation Subtype and Tumor Grade</title>
          <description>-Cancer cells are graded when they are removed from the breast. The grade is based on how much the cancer cells look like normal cells.&#xD;
A low grade number (grade 1) usually means the cancer is slower-growing and less likely to spread.&#xD;
An intermediate grade number (grade 2) means the cancer is growing faster than a grade 1 cancer but slower than a grade 3 cancer.&#xD;
A high grade number (grade 3) means a faster-growing cancer that's more likely to spread.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="5"/>
                <count group_id="O3" value="11"/>
                <count group_id="O4" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>ECD mutation : Tumor grade I/II</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ECD mutation : Tumor grade III</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="3"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ECD mutation : Unknown</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Exon 20 ins mutation : Tumor grade I/II</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Exon 20 ins mutation : Tumor grade III</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Exon 20 ins mutation : Unknown</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>KD mutation : Tumor grade I/II</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="4"/>
                    <measurement group_id="O4" value="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>KD mutation : Tumor grade III</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="2"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>KD mutation : Unknown</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="3"/>
                    <measurement group_id="O4" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Correlate the Presence of HER2 Mutation Subtype With Tumor Staging at Initial Diagnosis</title>
        <description>Staging occurred at initial diagnosis after physical exam, mammogram, and other diagnostic imaging tests. The staging also takes into account pathology reports from the breast biopsy or surgery.&#xD;
Stage I has a better outcome than Stage IV.</description>
        <time_frame>At time of enrollment</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Part I: Neratinib Only</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O2">
            <title>Part II: Neratinib Only (ER-)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O3">
            <title>Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O4">
            <title>Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Correlate the Presence of HER2 Mutation Subtype With Tumor Staging at Initial Diagnosis</title>
          <description>Staging occurred at initial diagnosis after physical exam, mammogram, and other diagnostic imaging tests. The staging also takes into account pathology reports from the breast biopsy or surgery.&#xD;
Stage I has a better outcome than Stage IV.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="5"/>
                <count group_id="O3" value="11"/>
                <count group_id="O4" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>ECD mutation : Stage I</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ECD mutation : Stage II</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ECD mutation : Stage III</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ECD mutation : Stage IV</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>ECD mutation : Unknown</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Exon 20 ins mutation : Stage I</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Exon 20 ins mutation : Stage II</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Exon 20 ins mutation : Stage III</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Exon 20 ins mutation : Stage IV</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Exon 20 ins mutation : Unknown</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>KD mutation : Stage I</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="2"/>
                    <measurement group_id="O4" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>KD mutation : Stage II</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="2"/>
                    <measurement group_id="O4" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>KD mutation : Stage III</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>KD mutation : Stage IV</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="2"/>
                    <measurement group_id="O4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>KD mutation : Unknown</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="2"/>
                    <measurement group_id="O4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Correlate the Presence of HER2 Mutation Subtype With Progression-free Survival</title>
        <description>Progression-free survival is defined as the number of weeks from start of treatment until disease progression or death.&#xD;
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.</description>
        <time_frame>Through completion of follow-up; follow-up was through 30 days following completion of treatment (median follow-up of 142 days, full range 54-800 days)</time_frame>
        <population>The number analyzed for each row adds up to overall total number analyzed.</population>
        <group_list>
          <group group_id="O1">
            <title>Part I: Neratinib Only</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O2">
            <title>Part II: Neratinib Only (ER-)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O3">
            <title>Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O4">
            <title>Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
        </group_list>
        <measure>
          <title>Correlate the Presence of HER2 Mutation Subtype With Progression-free Survival</title>
          <description>Progression-free survival is defined as the number of weeks from start of treatment until disease progression or death.&#xD;
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.</description>
          <population>The number analyzed for each row adds up to overall total number analyzed.</population>
          <units>weeks</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="5"/>
                <count group_id="O3" value="11"/>
                <count group_id="O4" value="24"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>ECD mutation</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="3"/>
                    <count group_id="O2" value="2"/>
                    <count group_id="O3" value="2"/>
                    <count group_id="O4" value="3"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11.0000" lower_limit="9.0000" upper_limit="32.0000"/>
                    <measurement group_id="O2" value="8.0000" lower_limit="NA" upper_limit="NA">The sample size is too small to calculate the 95% confidence interval.</measurement>
                    <measurement group_id="O3" value="48.5000" lower_limit="16.0000" upper_limit="81.0000"/>
                    <measurement group_id="O4" value="3.0000" lower_limit="1.0000" upper_limit="24.0000"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Exon 20 ins mutation</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="4"/>
                    <count group_id="O2" value="1"/>
                    <count group_id="O3" value="1"/>
                    <count group_id="O4" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="26.0000" lower_limit="8.0000" upper_limit="75.0000"/>
                    <measurement group_id="O2" value="17.0000" lower_limit="NA" upper_limit="NA">The sample size is too small to calculate the 95% confidence interval.</measurement>
                    <measurement group_id="O3" value="26.000" lower_limit="NA" upper_limit="NA">The sample size is too small to calculate the 95% confidence interval.</measurement>
                    <measurement group_id="O4" value="36.5000" lower_limit="9.0000" upper_limit="68.0000"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>KD mutation</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="9"/>
                    <count group_id="O2" value="2"/>
                    <count group_id="O3" value="8"/>
                    <count group_id="O4" value="17"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9.0000" lower_limit="3.0000" upper_limit="31.0000"/>
                    <measurement group_id="O2" value="6.5000" lower_limit="4.0000" upper_limit="9.0000"/>
                    <measurement group_id="O3" value="8.0000" lower_limit="1.0000" upper_limit="24.0000"/>
                    <measurement group_id="O4" value="16.0000" lower_limit="9.0000" upper_limit="27.0000"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Part II ER-cohort Only: Progression-free Survival (PFS)</title>
        <description>Progression-free survival is defined as the number of weeks from start of treatment until disease progression or death.&#xD;
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.</description>
        <time_frame>Through completion of treatment (median treatment time of 62 days, full range 56-413 days)</time_frame>
        <population>Only participants enrolled in the Part II ER-cohort are evaluable for this outcome measure. One participant was not evaluable in this cohort as the participant stopped treatment in cycle 1.</population>
        <group_list>
          <group group_id="O1">
            <title>Part I: Neratinib Only</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O2">
            <title>Part II: Neratinib Only (ER-)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O3">
            <title>Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O4">
            <title>Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O5">
            <title>Crossover: Neratinib + Trastuzumab</title>
            <description>-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks.</description>
          </group>
          <group group_id="O6">
            <title>Crossover: Neratinib + Fulvestrant + Trastuzumab</title>
            <description>-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Part II ER-cohort Only: Progression-free Survival (PFS)</title>
          <description>Progression-free survival is defined as the number of weeks from start of treatment until disease progression or death.&#xD;
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.</description>
          <population>Only participants enrolled in the Part II ER-cohort are evaluable for this outcome measure. One participant was not evaluable in this cohort as the participant stopped treatment in cycle 1.</population>
          <units>weeks</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="4"/>
                <count group_id="O3" value="0"/>
                <count group_id="O4" value="0"/>
                <count group_id="O5" value="0"/>
                <count group_id="O6" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O2" value="8.5" lower_limit="8" upper_limit="NA">There were too few participants with an event to calculate the upper limit of the confidence interval.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Part II Fulvestrant-naive ER+ Cohort Only: Progression-free Survival (PFS)</title>
        <description>Progression-free survival is defined as the number of weeks from start of treatment until disease progression or death.&#xD;
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.</description>
        <time_frame>Through completion of treatment (median treatment time of 140.5 days, full range 48-770 days)</time_frame>
        <population>Only participants enrolled in the Part II fulvestrant-naive ER+ cohort is evaluable for this outcome measure. One participant was not evaluable in this cohort as the participant stopped treatment in cycle 1.</population>
        <group_list>
          <group group_id="O1">
            <title>Part I: Neratinib Only</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O2">
            <title>Part II: Neratinib Only (ER-)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O3">
            <title>Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O4">
            <title>Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O5">
            <title>Crossover: Neratinib + Trastuzumab</title>
            <description>-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks.</description>
          </group>
          <group group_id="O6">
            <title>Crossover: Neratinib + Fulvestrant + Trastuzumab</title>
            <description>-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Part II Fulvestrant-naive ER+ Cohort Only: Progression-free Survival (PFS)</title>
          <description>Progression-free survival is defined as the number of weeks from start of treatment until disease progression or death.&#xD;
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.</description>
          <population>Only participants enrolled in the Part II fulvestrant-naive ER+ cohort is evaluable for this outcome measure. One participant was not evaluable in this cohort as the participant stopped treatment in cycle 1.</population>
          <units>weeks</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="10"/>
                <count group_id="O4" value="0"/>
                <count group_id="O5" value="0"/>
                <count group_id="O6" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O3" value="20" lower_limit="8" upper_limit="NA">There were too few participants with an event to calculate the upper limit of the confidence interval.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Part II Fulvestrant-treated ER+ Cohort Only: Progression-free Survival (PFS)</title>
        <description>Progression-free survival is defined as the number of weeks from start of treatment until disease progression or death.&#xD;
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.</description>
        <time_frame>Through completion of treatment (median treatment time of 168 days, full range 28-671 days)</time_frame>
        <population>Only participants enrolled in the fulvestrant-treated ER+ cohort are evaluable for this outcome measure. Three participants were not evaluable in this cohort as the participants stopped treatment in cycle 1.</population>
        <group_list>
          <group group_id="O1">
            <title>Part I: Neratinib Only</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O2">
            <title>Part II: Neratinib Only (ER-)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O3">
            <title>Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O4">
            <title>Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O5">
            <title>Crossover: Neratinib + Trastuzumab</title>
            <description>-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks.</description>
          </group>
          <group group_id="O6">
            <title>Crossover: Neratinib + Fulvestrant + Trastuzumab</title>
            <description>-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Part II Fulvestrant-treated ER+ Cohort Only: Progression-free Survival (PFS)</title>
          <description>Progression-free survival is defined as the number of weeks from start of treatment until disease progression or death.&#xD;
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.</description>
          <population>Only participants enrolled in the fulvestrant-treated ER+ cohort are evaluable for this outcome measure. Three participants were not evaluable in this cohort as the participants stopped treatment in cycle 1.</population>
          <units>weeks</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
                <count group_id="O4" value="21"/>
                <count group_id="O5" value="0"/>
                <count group_id="O6" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O4" value="24" lower_limit="15.7" upper_limit="31"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Safety and Tolerability of Neratinib in Combination With Fulvestrant in Patients With HER2- ER+ HER2 Mutated Breast Cancer as Measured by Number of Participants With Related Adverse Events</title>
        <description>-CTCAE v 4.0 will be used to record adverse events. Related includes those possibly, probably, or definitely related to the treatment regimen.</description>
        <time_frame>Through completion of follow-up; follow-up was through 28 days following completion of treatment (median follow-up of 140 days, full range 52-798 days)</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Part I: Neratinib Only</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O2">
            <title>Part II: Neratinib Only (ER-)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O3">
            <title>Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O4">
            <title>Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O5">
            <title>Crossover: Neratinib + Trastuzumab</title>
            <description>-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks.</description>
          </group>
          <group group_id="O6">
            <title>Crossover: Neratinib + Fulvestrant + Trastuzumab</title>
            <description>-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Safety and Tolerability of Neratinib in Combination With Fulvestrant in Patients With HER2- ER+ HER2 Mutated Breast Cancer as Measured by Number of Participants With Related Adverse Events</title>
          <description>-CTCAE v 4.0 will be used to record adverse events. Related includes those possibly, probably, or definitely related to the treatment regimen.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="5"/>
                <count group_id="O3" value="11"/>
                <count group_id="O4" value="24"/>
                <count group_id="O5" value="3"/>
                <count group_id="O6" value="5"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Anemia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="4"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>LVEF Decrease</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="1"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Heart failure with preserved ejection fraction</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Tinnitus</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Dry eye</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Abdominal cramping</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Abdominal pain</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="2"/>
                    <measurement group_id="O4" value="3"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Bloating</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="2"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Constipation</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="2"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Diarrhea</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="15"/>
                    <measurement group_id="O2" value="5"/>
                    <measurement group_id="O3" value="8"/>
                    <measurement group_id="O4" value="20"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Dry mouth</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="4"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Dyspepsia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="6"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Flatulence</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Mucositis oral</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="2"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Nausea</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9"/>
                    <measurement group_id="O2" value="3"/>
                    <measurement group_id="O3" value="4"/>
                    <measurement group_id="O4" value="11"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Stomach pain</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Stomatitis</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Vomiting</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="6"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Fatigue</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="5"/>
                    <measurement group_id="O4" value="12"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Fever</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Generalized weakness</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Pain</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Rhinitis infective</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Upper respiratory infection</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Urinary tract infection</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="2"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Alaline aminotransferase increased</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="2"/>
                    <measurement group_id="O4" value="4"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Alkaline phosphatase increased</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="3"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Alkaline phosphatase decreased</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Aspartate aminotransferase increased</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="3"/>
                    <measurement group_id="O4" value="7"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>CD4 lymphocytes decreased</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Creatinine increased</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Ejection fraction decreased</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="1"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>INR increased</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Lymphocyte count decreased</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="2"/>
                    <measurement group_id="O4" value="2"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Neutrophil count decreased</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="2"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Platelet count decreased</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="1"/>
                    <measurement group_id="O6" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Weight loss</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="4"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>White blood cell decreased</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="4"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Anorexia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="7"/>
                    <measurement group_id="O4" value="9"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Dehydration</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="6"/>
                    <measurement group_id="O5" value="1"/>
                    <measurement group_id="O6" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hypercalcemia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="2"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hyperglycemia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="2"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hyperkalemia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hypoalbuminemia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hypocalcemia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="2"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hypokalemia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hyponatremia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hypophosphatemia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Arthralgia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="2"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Back pain</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Bone pain</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Flank pain</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Generalized muscle weakness</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="2"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Joint range of motion decreased</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Leg cramp</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Muscle weakness left sided</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Muscle weakness lower limb</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Myalgia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Pain at injection site</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Pain in extremity</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Dizziness</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="2"/>
                    <measurement group_id="O4" value="4"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Dysgeusia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="3"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Headache</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="2"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Peripheral sensory neuropathy</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Syncope</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Depression</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Insomnia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Acute kidney injury</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Urinary tract obstruction</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Urine discoloration</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Urine odor</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Cough</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Dyspnea</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Epistaxis</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hoarseness</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Postnasal drip</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Rhinorrhea</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Alopecia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Dry hair</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Dry skin</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="2"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Nail changes</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Pruritus</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Rash acneiform</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="2"/>
                    <measurement group_id="O4" value="4"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Rash maculopapular</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Skin hyperpigmentation</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Sterile abscess at subcutaneous injection site</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hot flashes</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hypotension</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="1"/>
                    <measurement group_id="O5" value="0"/>
                    <measurement group_id="O6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Part II Fulvestrant-naive ER+ Cohort Only: Response Rate (RR)</title>
        <description>RR is defined as number of participants with complete response or partial response as best response.&#xD;
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.&#xD;
Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.</description>
        <time_frame>Through completion of treatment (median treatment time of 140.5 days, full range 48-770 days)</time_frame>
        <population>Only participants enrolled in the Part II fulvestrant-naive ER+ cohort is evaluable for this outcome measure. One participant was not evaluable in this cohort as the participant stopped treatment in cycle 1.</population>
        <group_list>
          <group group_id="O1">
            <title>Part I: Neratinib Only</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O2">
            <title>Part II: Neratinib Only (ER-)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O3">
            <title>Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O4">
            <title>Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O5">
            <title>Crossover: Neratinib + Trastuzumab</title>
            <description>-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks.</description>
          </group>
          <group group_id="O6">
            <title>Crossover: Neratinib + Fulvestrant + Trastuzumab</title>
            <description>-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Part II Fulvestrant-naive ER+ Cohort Only: Response Rate (RR)</title>
          <description>RR is defined as number of participants with complete response or partial response as best response.&#xD;
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.&#xD;
Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.</description>
          <population>Only participants enrolled in the Part II fulvestrant-naive ER+ cohort is evaluable for this outcome measure. One participant was not evaluable in this cohort as the participant stopped treatment in cycle 1.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="10"/>
                <count group_id="O4" value="0"/>
                <count group_id="O5" value="0"/>
                <count group_id="O6" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O3" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Part II Fulvestrant-treated ER+ Cohort Only: Response Rate (RR)</title>
        <description>RR is defined as number of participants with complete response or partial response as best response.&#xD;
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.&#xD;
Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.</description>
        <time_frame>Through completion of treatment (median treatment time of 168 days, full range 28-671 days)</time_frame>
        <population>Only participants enrolled in the fulvestrant-treated ER+ cohort are evaluable for this outcome measure. Three participants were not evaluable in this cohort as the participants stopped treatment in cycle 1.</population>
        <group_list>
          <group group_id="O1">
            <title>Part I: Neratinib Only</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O2">
            <title>Part II: Neratinib Only (ER-)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O3">
            <title>Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O4">
            <title>Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx)</title>
            <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
          </group>
          <group group_id="O5">
            <title>Crossover: Neratinib + Trastuzumab</title>
            <description>-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks.</description>
          </group>
          <group group_id="O6">
            <title>Crossover: Neratinib + Fulvestrant + Trastuzumab</title>
            <description>-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Part II Fulvestrant-treated ER+ Cohort Only: Response Rate (RR)</title>
          <description>RR is defined as number of participants with complete response or partial response as best response.&#xD;
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.&#xD;
Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.</description>
          <population>Only participants enrolled in the fulvestrant-treated ER+ cohort are evaluable for this outcome measure. Three participants were not evaluable in this cohort as the participants stopped treatment in cycle 1.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
                <count group_id="O4" value="21"/>
                <count group_id="O5" value="0"/>
                <count group_id="O6" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O4" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse events were tracked from start of treatment up to 28 days following the last day of study treatment. Median follow-up was 40 days, full range 52-798 days.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Part I: Neratinib Only</title>
          <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
        </group>
        <group group_id="E2">
          <title>Part II: Neratinib Only (ER-)</title>
          <description>-Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
        </group>
        <group group_id="E3">
          <title>Part II: Neratinib + Fulvestrant (ER+, Fulvestrant-naive)</title>
          <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
        </group>
        <group group_id="E4">
          <title>Part II: Neratinib + Fulvestrant (ER+. Prior Fulvestrant-tx)</title>
          <description>-Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.</description>
        </group>
        <group group_id="E5">
          <title>Crossover: Neratinib + Trastuzumab</title>
          <description>-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks.</description>
        </group>
        <group group_id="E6">
          <title>Crossover: Neratinib + Fulvestrant + Trastuzumab</title>
          <description>-If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="9" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="4" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="9" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial flutter</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Duodenal hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Bell's palsy</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Creatinine increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>INR increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Death due to disease progression</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Disease progression</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Expressive aphasia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Pneumonitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="11" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="24" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="4" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="6" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Thrombotic thrombocytopenia purpura</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Heart failure with preserved ejection fraction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>LVEF decrease</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Sinus tachycardia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Ventricular tachycardia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Ear pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Tinnitus</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Vertigo</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Blurred vision</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Conjunctivitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Double vision</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Dry eye</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Floaters</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Itchy eye</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Peripheral vision change</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Styes</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal cramping</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Abdominal fullness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="5" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Ascites</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Bloating</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="9" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="2" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="9" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="22" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="4" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Duodenal ulcer</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="6" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Dysphagia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Flatulence</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Gastroesophageal reflux disease</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Gastrointestinal illness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Hematochezia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="12" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="2" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Stomach pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Stomatitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="6" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="3" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Changes in dentition</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Edema face</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Edema limbs</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Failure-to-thrive</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="12" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="5" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Flu like symptoms</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Generalized weakness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Localized edema</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Allergic reaction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Bilateral breast infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Biliary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Bladder infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Bronchial infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Cold</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Gum infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Mucosal infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Rhinitis infective</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Shingles</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Sinusitis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Skin infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Stomach bug</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Strep throat</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Upper respiratory infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="4" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="2" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Wound infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Finger pad cut off</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Spinal fracture</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="5" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="6" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="8" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>CD4 lymphocytes decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Cardiac troponin increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Creatinine increased</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Ejection fraction decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="4" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="2" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="4" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="10" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="2" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="5" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Hypercalcemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Hyperkalemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Hyperphosphatemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Hypocalcemia</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="5" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="2" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Hypoproteinemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Type 2 Diabetes</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="4" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Bone pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Finger pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Flank pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Gait disturbance</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Joint range of motion decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Leg cramp</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Muscle weakness left-sided</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Muscle weakness lower limb</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Myositis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Neck pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Pain at injection site</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Shoulder tendonitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>New brain metastases</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="5" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="2" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Dysarthria</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="2" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Expressive aphasia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Extrapyramidal disorder</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Facial muscle weakness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="2" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Memory impairment</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Peripheral motor neuropathy</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Peripheral sensory neuropathy</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Presyncope</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Seizure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Sinus pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Altered mental status</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Confusion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Acute kidney injury</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Bilateral ureteral stent placement</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Cystitis noninfective</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Urge incontinence</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Urinary frequency</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Urinary retention</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Urinary tract obstruction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Urinary tract pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Urine discoloration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Urine odor</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Breast pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Pelvic pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Vaginal dryness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Chest tightness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="4" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="6" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Hoarseness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="3" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Hypoxia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Nose irritation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Pneumothorax</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Postnasal drip</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Pulmonary edema</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Rhinorrhea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Sneezing</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Sore throat</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Bug bite</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Dry hair</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Erythema</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Hyperhidrosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Nail changes</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>New skin lesion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Rash acneiform</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="4" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Rash maculopapular</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Skin hyperpigmentation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Sterile abscess at subcutaneous injection site</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Bilateral percutaneous nephrostomy tubes placement</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Chest wall port placement</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Nephrostomy tubes exchange</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hot flashes</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="16"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="24"/>
                <counts group_id="E5" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Cynthia Ma, M.D., Ph.D.</name_or_title>
      <organization>Washington University School of Medicine</organization>
      <phone>314-362-9383</phone>
      <email>cynthiaxma@wustl.edu</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01670877
org study id: 201209135
nct id: NCT01670877
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This phase II study will test cancer to see if it has a HER2 mutation and, if so, see how
      HER2 mutated cancer responds to treatment with neratinib.
Overexpression of HER2 due to gene amplification is an established therapeutic target in
      breast cancer for which multiple HER2 targeted drugs are now available. However, the majority
      of breast cancers are without HER2 overexpression/non-amplified and not currently eligible to
      receive HER2 targeted drugs. Advances in tumor genome sequencing technology led to the
      identification of recurrent HER2 mutations (HER2mut) in approximately 2% of HER2
      non-amplified primary breast cancers, and 3-5% of metastatic tumors. Importantly, tumor cells
      harboring HER2mut are sensitive to the anti-tumor effects of HER2-targeted agents in
      preclinical models, especially neratinib, a potent irreversible pan-HER inhibitor. However,
      neratinib monotherapy has demonstrated only modest single agent activity in HER2mut,,
      non-amplified metastatic breast cancer (MBC). Based on the hypothesis that the combination of
      neratinib and fulvestrant will be more effective than neratinib alone in ER+/HER2mut,
      non-amplified MBC the investigators conducted a single arm phase II study of neratinib plus
      fulvestrant with 2 cohorts, fulvestrant (FUL)-treated and FUL-naïve, for patients with
      ER+/HER2mut, non-amplified MBC to assess the anti-tumor effects of this combination. An
      exploratory ER-negative (ER-) HER2mut cohort was also included for the efficacy of neratinib
      monotherapy.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Part I Only: Clinical Benefit Rate (CR+PR+SD≥6months) of Patients Who Received Neratinib Alone
time frame: Through completion of treatment (median treatment time of 90 days, full range 54-716 days)
description: Imaging for clinical benefit rate occurred at baseline (for an initial comparison scan) and every 2 cycles (28 day length) thereafter.
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.
Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have had stable disease for at least 6 months.
measure: Part II ER-cohort Only: Clinical Benefit Rate (CR+PR+SD≥6months) of Neratinib in Patients With Metastatic HER2-, ER- Breast Cancer That Carry HER2 Mutation
time frame: Through completion of treatment (median treatment time of 62 days, full range 56-413 days)
description: Imaging for clinical benefit rate occurred at baseline (for an initial comparison scan) and every 2 cycles (28 day length) thereafter.
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.
Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have had stable disease for at least 6 months.
measure: Part II Fulvestrant-naive ER+ Cohort Only: Clinical Benefit (CR+PR+SD≥6 Months) of Neratinib + Fulvestrant in Patients With Metastatic HER2- ER+ Fulvestrant-naive Breast Cancer That Carry HER2 Mutation
time frame: Through completion of treatment (median treatment time of 140.5 days, full range 48-770 days)
description: Imaging for clinical benefit rate occurred at baseline (for an initial comparison scan) and every 2 cycles (28 day length) thereafter.
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.
Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have had stable disease for at least 6 months.
measure: Part II Fulvestrant-treated ER+ Cohort Only: Clinical Benefit Rate (CR+PR+SD≥6months) of Neratinib + Fulvestrant in Patients With Metastatic HER2- ER+ Fulvestrant-treated Breast Cancer That Carry HER2 Mutation
time frame: Through completion of treatment (median treatment time of 168 days, full range 28-671 days)
description: Imaging for clinical benefit rate occurred at baseline (for an initial comparison scan) and every 2 cycles (28 day length) thereafter.
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.
Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have had stable disease for at least 6 months.
measure: Progression-free Survival (PFS) of Patients Treated With Neratinib Alone in Patients With Metastatic HER2- But HER2 Mutated Breast Cancer by ER Status and by HER2 Mutations (Activating Versus Unknown Significance)
time frame: Through completion of follow-up; follow-up was through 30 days following completion of treatment (median follow-up of 92 days, full range 86 days-443 days)
description: Participants were followed for progressive disease from start of treatment until completion of follow-up.
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.
measure: Number of Participants With HER2 Mutation Subtype and Histology Subtype
time frame: At the time of enrollment
measure: Number of Participants With HER2 Mutation Subtype and Tumor Grade
time frame: A time of enrollment
description: -Cancer cells are graded when they are removed from the breast. The grade is based on how much the cancer cells look like normal cells.
A low grade number (grade 1) usually means the cancer is slower-growing and less likely to spread.
An intermediate grade number (grade 2) means the cancer is growing faster than a grade 1 cancer but slower than a grade 3 cancer.
A high grade number (grade 3) means a faster-growing cancer that's more likely to spread.
measure: Correlate the Presence of HER2 Mutation Subtype With Tumor Staging at Initial Diagnosis
time frame: At time of enrollment
description: Staging occurred at initial diagnosis after physical exam, mammogram, and other diagnostic imaging tests. The staging also takes into account pathology reports from the breast biopsy or surgery.
Stage I has a better outcome than Stage IV.
measure: Correlate the Presence of HER2 Mutation Subtype With Progression-free Survival
time frame: Through completion of follow-up; follow-up was through 30 days following completion of treatment (median follow-up of 142 days, full range 54-800 days)
description: Progression-free survival is defined as the number of weeks from start of treatment until disease progression or death.
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.
measure: Part II ER-cohort Only: Progression-free Survival (PFS)
time frame: Through completion of treatment (median treatment time of 62 days, full range 56-413 days)
description: Progression-free survival is defined as the number of weeks from start of treatment until disease progression or death.
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.
measure: Part II Fulvestrant-naive ER+ Cohort Only: Progression-free Survival (PFS)
time frame: Through completion of treatment (median treatment time of 140.5 days, full range 48-770 days)
description: Progression-free survival is defined as the number of weeks from start of treatment until disease progression or death.
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.
measure: Part II Fulvestrant-treated ER+ Cohort Only: Progression-free Survival (PFS)
time frame: Through completion of treatment (median treatment time of 168 days, full range 28-671 days)
description: Progression-free survival is defined as the number of weeks from start of treatment until disease progression or death.
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.
measure: Safety and Tolerability of Neratinib in Combination With Fulvestrant in Patients With HER2- ER+ HER2 Mutated Breast Cancer as Measured by Number of Participants With Related Adverse Events
time frame: Through completion of follow-up; follow-up was through 28 days following completion of treatment (median follow-up of 140 days, full range 52-798 days)
description: -CTCAE v 4.0 will be used to record adverse events. Related includes those possibly, probably, or definitely related to the treatment regimen.
measure: Part II Fulvestrant-naive ER+ Cohort Only: Response Rate (RR)
time frame: Through completion of treatment (median treatment time of 140.5 days, full range 48-770 days)
description: RR is defined as number of participants with complete response or partial response as best response.
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.
Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
measure: Part II Fulvestrant-treated ER+ Cohort Only: Response Rate (RR)
time frame: Through completion of treatment (median treatment time of 168 days, full range 28-671 days)
description: RR is defined as number of participants with complete response or partial response as best response.
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Disappearance of all non-target lesions and normalization of tumor marker level.
Partial response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
arm group label: Part I: Neratinib Only
arm group type: Experimental
description: -Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
arm group label: Part II: Neratinib Only (ER-)
arm group type: Experimental
description: -Patients will receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
arm group label: Part II: Neratinib + Fulvestrant (ER+, fulvestrant-naive)
arm group type: Experimental
description: -Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
arm group label: Part II: Neratinib + Fulvestrant (ER+. prior fulvestrant-tx)
arm group type: Experimental
description: -Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
arm group label: Crossover: Neratinib + Trastuzumab
arm group type: Experimental
description: -If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will continue to receive neratinib PO daily on Days 1-28. Each cycle is 4 weeks.
arm group label: Crossover: Neratinib + Fulvestrant + Trastuzumab
arm group type: Experimental
description: -If a participant experiences disease progression during Part I or Part II following neratinib, trastuzumab (or FDA approved biosimilar) may be added to the treatment regimen. Trastuzumab may be administered intravenously with a loading dose of 6 mg/kg then 4 mg/kg every 2 weeks. A cycle will be defined as 28 days. Patients will receive neratinib PO daily on Days 1-28 and fulvestrant on Day 1 of each cycle (and C1D15). Each cycle is 4 weeks.
intervention type: Drug
intervention name: Neratinib
arm group label: Crossover: Neratinib + Fulvestrant + Trastuzumab
arm group label: Crossover: Neratinib + Trastuzumab
arm group label: Part I: Neratinib Only
arm group label: Part II: Neratinib + Fulvestrant (ER+, fulvestrant-naive)
arm group label: Part II: Neratinib + Fulvestrant (ER+. prior fulvestrant-tx)
arm group label: Part II: Neratinib Only (ER-)
other name: PF-05208767
intervention type: Drug
intervention name: Fulvestrant
arm group label: Crossover: Neratinib + Fulvestrant + Trastuzumab
arm group label: Part II: Neratinib + Fulvestrant (ER+, fulvestrant-naive)
arm group label: Part II: Neratinib + Fulvestrant (ER+. prior fulvestrant-tx)
other name: Faslodex
intervention type: Drug
intervention name: Trastuzumab
arm group label: Crossover: Neratinib + Fulvestrant + Trastuzumab
arm group label: Crossover: Neratinib + Trastuzumab
other name: Herceptin
intervention type: Procedure
intervention name: Tumor biopsy
description: -Optional at baseline and disease progression
arm group label: Crossover: Neratinib + Fulvestrant + Trastuzumab
arm group label: Crossover: Neratinib + Trastuzumab
arm group label: Part I: Neratinib Only
arm group label: Part II: Neratinib + Fulvestrant (ER+, fulvestrant-naive)
arm group label: Part II: Neratinib + Fulvestrant (ER+. prior fulvestrant-tx)
arm group label: Part II: Neratinib Only (ER-)
intervention type: Procedure
intervention name: Research blood sample
description: -Baseline, cycle 1 day 15, cycle 2 day 1, cycle 3 day 1, day 1 of each odd cycle, end of treatment (progression)
arm group label: Crossover: Neratinib + Fulvestrant + Trastuzumab
arm group label: Crossover: Neratinib + Trastuzumab
arm group label: Part I: Neratinib Only
arm group label: Part II: Neratinib + Fulvestrant (ER+, fulvestrant-naive)
arm group label: Part II: Neratinib + Fulvestrant (ER+. prior fulvestrant-tx)
arm group label: Part II: Neratinib Only (ER-)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Cynthia Ma, M.D., Ph.D
role: Principal Investigator
affiliation: Washington University School of Medicine
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country: Canada
country: United States
url: http://www.siteman.wustl.edu
description: Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Trastuzumab
mesh term: Fulvestrant
sharing ipd: No
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