<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/NCT02236000</url>
  </required_header>
  <id_info>
    <org_study_id>NSABP FB-10</org_study_id>
    <nct_id>NCT02236000</nct_id>
  </id_info>
  <brief_title>A Dose-Escalation Study Evaluating the Combination of Trastuzumab Emtansine (T-DM1) With Neratinib in Women With Metastatic HER2-Positive Breast Cancer</brief_title>
  <official_title>A Phase Ib/II Dose-Escalation Study Evaluating the Combination of Trastuzumab Emtansine (T-DM1) With Neratinib in Women With Metastatic HER2-Positive Breast Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>NSABP Foundation Inc</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Puma Biotechnology, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>NSABP Foundation Inc</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study is being done for the following reasons:&#xD;
&#xD;
        -  The study has two parts. The purpose of the first part (Phase I) of the study is to find&#xD;
           out the highest dose of neratinib that can be given safely with T-DM1.&#xD;
&#xD;
        -  The purpose of the second part of the study (Phase II) is to find out whether the dose&#xD;
           of neratinib with T-DM1 determined in Phase I will keep breast cancer from getting worse&#xD;
           for a period of time.&#xD;
&#xD;
        -  In order to learn more about study therapy levels in blood and discover genetic and&#xD;
           protein changes associated with cancer, the study includes special research tests using&#xD;
           samples from blood and from breast tumor. Blood samples will be collected before study&#xD;
           treatment, once during treatment, and after study treatment stops.&#xD;
&#xD;
        -  In the optional part of this study, three biopsies will be performed to obtain fresh&#xD;
           tumor samples from an area where your cancer has spread.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The FB-10 study is designed as an open label, single arm, Phase Ib/II study with a&#xD;
      dose-escalation phase and an expanded cohort (phase II) to evaluate the combination of&#xD;
      trastuzumab emtansine (T-DM1) with neratinib in women with metastatic, HER2-positive breast&#xD;
      cancer. The primary aim of the phase Ib portion of this study is to determine the safety and&#xD;
      tolerability of the two-drug combination. The primary aim of the phase II portion is to&#xD;
      demonstrate efficacy.&#xD;
&#xD;
      Patients will receive concurrent therapy with T-DM1 (3.6 mg/kg IV) on Day 1 of a 3-week (21&#xD;
      day) cycle and neratinib as a continuous daily oral dose. The neratinib dose-escalation will&#xD;
      include 4 dose levels (120 mg, 160 mg, 200 mg, and 240 mg). At the recommended phase II dose&#xD;
      (RP2D) of the T-DM1 and neratinib combination, up to 39 additional patients will be treated.&#xD;
&#xD;
      The sample size of the phase I portion of the study was 27 patients. The sample size of the&#xD;
      Phase II portion will be 22 evaluable patients (and 4 replacement patients). The total study&#xD;
      enrollment, phase Ib and II, will be a maximum of 50 patients.&#xD;
&#xD;
      Submission of diagnostic tumor samples and blood samples for FB-10 correlative science&#xD;
      studies will be a study requirement for all patients. Blood samples for pharmacokinetics&#xD;
      (PKs) and for future study will be collected prior to administration of study therapy on&#xD;
      Cycle 1/Day 1, Cycle 1/Day 8, and Cycle 2/Day1.&#xD;
&#xD;
      A tumor biopsy will be procured from an accessible site of metastasis before study therapy is&#xD;
      initiated (after the patient has signed the consent and has been screened for eligibility).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>August 2014</start_date>
  <completion_date type="Actual">August 2021</completion_date>
  <primary_completion_date type="Actual">December 2020</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Evaluable Patients With Dose Limiting Toxicity Events in Phase 1</measure>
    <time_frame>Day 1, 8, and 15 of cycle 1.</time_frame>
    <description>If 1 of 3 patients in this cohort experiences a dose limiting toxicity (DLT), 3 more patients will be added at the same dose level. If 0 of 3 initial patients or 1 of 6 patients in an expanded cohort experiences a DLT, the dose for the next cohort will be escalated to dose level 2; otherwise, the combination will be considered too toxic.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Overall Response Rate (ORR) by Measurement of Target Lesions in Phase II</measure>
    <time_frame>Every 42 days after the start of protocol therapy through disease progression, approximately 2 years</time_frame>
    <description>Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), &gt;=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression-free Survival (PFS) Time From Start of Study Therapy to Disease Progression or Death From Any Cause</measure>
    <time_frame>Every 42 days after the start of protocol therapy through disease progression, approximately 2 years</time_frame>
    <description>Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse Events Experienced by Participants as a Measure of Toxicity</measure>
    <time_frame>Day 1, 8, 15 of cycle one, day 1 of each subsequent cycle, at the end of protocol therapy and 30 days following the end of protocol therapy. Duration of therapy varied across patients from a few days to a couple of years.</time_frame>
    <description>Summary of frequency and severity of serious adverse events,</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Benefit Rate (Phase II)</measure>
    <time_frame>Every 63 days after the start of study therapy until disease progression or until 30 days following the end of protocol therapy if due to another cause. Duration of therapy varied across patients from a few days to a couple of years.</time_frame>
    <description>Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0) for target lesions assessed by MRI or CT; Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), &gt;=30% decrease in the sum of new lesions; Stable Disease (SD) otherwise; Clinical Benefit (CB) = CR+PR+SD (confirmation of response not required).</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">49</enrollment>
  <condition>Breast Cancer</condition>
  <arm_group>
    <arm_group_label>Neratinib and T-DM1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Neratinib</intervention_name>
    <description>Dose-Escalation Phase (Part 1) - Neratinib Dose-escalation will proceed on the basis of DLT during Cycle 1 starting at 120 mg/day.&#xD;
Dose level 1: 120 mg/day; Dose level 2: 160 mg/day; Dose level 3: 200 mg/day; Dose level 4: 240 mg/day&#xD;
Dose-evaluation Phase (Part 2) - Patients will receive the highest dose of neratinib with T-DM1 found in Phase I as study therapy</description>
    <arm_group_label>Neratinib and T-DM1</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>T-DM1</intervention_name>
    <description>Dose-Escalation Phase (Part 1) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.&#xD;
Dose-evaluation Phase (Part 2) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.</description>
    <arm_group_label>Neratinib and T-DM1</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  The ECOG performance status must be less than or equal to 2.&#xD;
&#xD;
          -  Patients must have the ability to swallow oral medication.&#xD;
&#xD;
          -  Patients must have histologic or cytologic confirmation of the diagnosis of invasive&#xD;
             adenocarcinoma of the breast.&#xD;
&#xD;
          -  Patients must have had anti-HER2 based therapy with pertuzumab and trastuzumab for&#xD;
             neoadjuvant therapy, adjuvant therapy or with first line therapy for metastatic&#xD;
             disease (which may include trastuzumab and pertuzumab either sequentially or in&#xD;
             combination).&#xD;
&#xD;
          -  There must be documentation that the patient has evidence of measurable metastatic&#xD;
             breast cancer that is accessible to biopsy at study entry.&#xD;
&#xD;
          -  Patients must have estrogen receptor (ER) analysis performed prior to study entry. If&#xD;
             ER analysis is negative, then progesterone receptor (PgR) analysis must also be&#xD;
             performed. (Patients are eligible with either hormone receptor-positive or hormone&#xD;
             receptor-negative tumors.)&#xD;
&#xD;
          -  Breast cancer must be determined by local testing to be human epidermal growth factor&#xD;
             receptor 2 (HER2)-positive prior to study entry using American Society of Clinical&#xD;
             Oncology (ASCO) - College of American Pathologists (CAP) HER2 test guidelines.&#xD;
&#xD;
          -  At the time of study entry, blood counts performed within 4 weeks prior to study entry&#xD;
             must meet the following criteria:&#xD;
&#xD;
               -  absolute neutrophil count (ANC) must be greater than or equal to 1000/mm3;&#xD;
&#xD;
               -  platelet count must be greater than or equal to 100,000/mm3; and&#xD;
&#xD;
               -  hemoglobin must be greater than or equal to 9 g/dL. (Note: Patient must have&#xD;
                  discontinued growth factors greater than or equal to two weeks prior to entry&#xD;
                  labs.)&#xD;
&#xD;
          -  The following criteria for evidence of adequate hepatic function performed within 4&#xD;
             weeks prior to study entry must be met:&#xD;
&#xD;
               -  Total bilirubin must be less than or equal to 1.5 x upper limit of normal (ULN),&#xD;
                  and&#xD;
&#xD;
               -  aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be less&#xD;
                  than or equal to 1.5 x ULN for the lab or less than or equal to 5 x ULN if liver&#xD;
                  metastasis.&#xD;
&#xD;
          -  Serum creatinine performed within 4 weeks prior to study entry must be less than or&#xD;
             equal to 1.5 x ULN for the lab.&#xD;
&#xD;
          -  The left ventricular ejection fraction (LVEF) assessment by 2-D echocardiogram or&#xD;
             multi-gated acquisition (MUGA) scan performed within 90 days prior to study entry must&#xD;
             be greater than or equal to 50% regardless of the facility's lower limit of normal&#xD;
             (LLN).&#xD;
&#xD;
          -  Patients with reproductive potential must agree to use an effective non-hormonal&#xD;
             method of contraception during therapy, and for at least 7 months after the last dose&#xD;
             of study therapy.&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
          -  Previous therapy with T-DM1 or any HER2 tyrosine kinase inhibitor (TKI) including&#xD;
             neratinib for any malignancy.&#xD;
&#xD;
          -  Symptomatic brain metastases or brain metastases requiring chronic steroids to control&#xD;
             symptoms.&#xD;
&#xD;
          -  Active hepatitis B or hepatitis C with abnormal liver function tests; HIV positive&#xD;
             patients receiving antivirals.&#xD;
&#xD;
          -  Lung disease resulting in dyspnea at rest.&#xD;
&#xD;
          -  Active infection or chronic infection requiring chronic suppressive antibiotics.&#xD;
&#xD;
          -  Malabsorption syndrome, ulcerative colitis, inflammatory bowel disease, resection of&#xD;
             the stomach or small bowel, or other disease or condition significantly affecting&#xD;
             gastrointestinal function.&#xD;
&#xD;
          -  Persistent greater than or equal to grade 2 diarrhea regardless of etiology.&#xD;
&#xD;
          -  Conditions that would prohibit intermittent administration of corticosteroids for&#xD;
             T-DM1 premedication.&#xD;
&#xD;
          -  Chronic daily treatment with corticosteroids with a dose of greater than or equal to&#xD;
             10 mg/day methylprednisolone equivalent (excluding inhaled steroids).&#xD;
&#xD;
          -  Uncontrolled hypertension defined as a systolic BP greater than 150 mmHg or diastolic&#xD;
             BP greater than 90 mmHg, with or without anti-hypertensive medications. (Patients with&#xD;
             hypertension that is well controlled on medication are eligible.)&#xD;
&#xD;
          -  Cardiac disease (history of and/or active disease) that would preclude the use of any&#xD;
             of the drugs included in the treatment regimen. This includes but is not confined to:&#xD;
&#xD;
               -  Active cardiac disease: symptomatic angina pectoris within the past 90 days that&#xD;
                  required the initiation of or increase in anti-anginal medication or other&#xD;
                  intervention; ventricular arrhythmias except for benign premature ventricular&#xD;
                  contractions; supraventricular and nodal arrhythmias requiring a pacemaker or not&#xD;
                  controlled with medication; conduction abnormality requiring a pacemaker;&#xD;
                  valvular disease with documented compromise in cardiac function; and symptomatic&#xD;
                  pericarditis&#xD;
&#xD;
               -  History of cardiac disease: myocardial infarction documented by elevated cardiac&#xD;
                  enzymes or persistent regional wall abnormalities on assessment of left&#xD;
                  ventricular (LV) function; history of documented congestive heart failure (CHF);&#xD;
                  and documented cardiomyopathy&#xD;
&#xD;
          -  Other nonmalignant systemic disease that would preclude the patient from receiving&#xD;
             study treatment or would prevent required follow up.&#xD;
&#xD;
          -  Pregnancy or lactation at the time of study entry. (Note: Pregnancy testing should be&#xD;
             performed within 14 days prior to study entry according to institutional standards for&#xD;
             women of childbearing potential.)&#xD;
&#xD;
          -  The investigator should assess the patient to determine if she has any psychiatric or&#xD;
             addictive disorder or other condition that, in the opinion of the investigator, would&#xD;
             preclude her from meeting the study requirements.&#xD;
&#xD;
          -  Use of any investigational agent within 4 weeks prior to study entry.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Norman Wolmark, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>NSABP Foundation Inc</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Cleveland Clinic Weston</name>
      <address>
        <city>Weston</city>
        <state>Florida</state>
        <zip>33331</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cancer Care Specialists of Central Illinois</name>
      <address>
        <city>Decatur</city>
        <state>Illinois</state>
        <zip>62526</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Crossroads Cancer Center</name>
      <address>
        <city>Effingham</city>
        <state>Illinois</state>
        <zip>62401</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cancer Care Specialists of Central Illinois-Swansea</name>
      <address>
        <city>Swansea</city>
        <state>Illinois</state>
        <zip>62226</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cleveland Clinic</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44195</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stephenson Cancer Center at the University of Oklahoma Health Services Center</name>
      <address>
        <city>Oklahoma City</city>
        <state>Oklahoma</state>
        <zip>73104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UPMC- Hillman Cancer Center-Monroeville</name>
      <address>
        <city>Monroeville</city>
        <state>Pennsylvania</state>
        <zip>15146</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Alleheny General Hospital</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15212</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hillman Cancer Center</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15213</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Magee Womens Hospital of UPMC</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15213</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Pittsburgh</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15213</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UPMC- St. Margaret</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UPMC Hillman Cancer Center North Hills at Passavant</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15237</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Women &amp; Infants Hospital of Rhode Island</name>
      <address>
        <city>Providence</city>
        <state>Rhode Island</state>
        <zip>02905</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>West Virginia University</name>
      <address>
        <city>Morgantown</city>
        <state>West Virginia</state>
        <zip>26501</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>September 2, 2014</study_first_submitted>
  <study_first_submitted_qc>September 5, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 10, 2014</study_first_posted>
  <results_first_submitted>June 27, 2022</results_first_submitted>
  <results_first_submitted_qc>January 10, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">January 26, 2023</results_first_posted>
  <last_update_submitted>January 10, 2023</last_update_submitted>
  <last_update_submitted_qc>January 10, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">January 26, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>NSABP</keyword>
  <keyword>Trastuzumab Emtansine</keyword>
  <keyword>T DM1</keyword>
  <keyword>Neratinib</keyword>
  <keyword>Metastatic Breast Cancer</keyword>
  <keyword>HER2 positive</keyword>
  <keyword>Dose Escalation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
  </condition_browse>
  <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>January 3, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/00/NCT02236000/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Phase 1 consisted of 4 parts involving increasing doses of Neratinib in each part. Together, 27 patients were enrolled. In Phase II, 22 patients were enrolled. Therefore 49 patients were enrolled in both phases of the trial.</recruitment_details>
      <pre_assignment_details>Endpoint information is not available for 1 patient.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Phase 1-Neratinib 120mg; T-DM1 3.6mg/kg</title>
          <description>Dose Level 1- Neratinib 120mg T-DM1 3.6.mg/kg</description>
        </group>
        <group group_id="P2">
          <title>Phase 1-Neratinib 160 mg; T-DM1 3.6mg/kg</title>
          <description>Dose Level 2- Neratinib 160 mg T-DM1 3.6mg/kg</description>
        </group>
        <group group_id="P3">
          <title>Phase 1-Neratinib 200mg; T-DM1 3.6mg/kg</title>
          <description>Dose Level 3- Neratinib 200mg T-DM1 3.6mg/kg</description>
        </group>
        <group group_id="P4">
          <title>Phase 1 Neratinib 240; T-DM1 3.6mg/kg</title>
          <description>Dose Level 4- Neratinib 240mg T-DM1 3.6 mg/kg</description>
        </group>
        <group group_id="P5">
          <title>Neratinib and T-DM1 Part 2 (Phase II)</title>
          <description>Dose-evaluation Phase (Part 2)-Patients will receive the highest dose of neratinib with T-DM1 found in Phase I as study therapy. Dose-evaluation Phase (Part 2)-Trastuzumab ematansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 ever 21 days.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="10"/>
                <participants group_id="P3" count="8"/>
                <participants group_id="P4" count="3"/>
                <participants group_id="P5" count="22"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
                <participants group_id="P2" count="10"/>
                <participants group_id="P3" count="8"/>
                <participants group_id="P4" count="3"/>
                <participants group_id="P5" count="22"/>
              </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_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Phase 1-Neratinib 120mg; T-DM1 3.6mg/kg</title>
          <description>Dose Level 1-Neratinib 120mg T-DM1 3.6mg/kg</description>
        </group>
        <group group_id="B2">
          <title>Phase 1-Neratinib160mg; T-DM1 3.6mg/kg</title>
          <description>Dose Level 2-Neratinib 160mg T-DM1 3.6mg/kg</description>
        </group>
        <group group_id="B3">
          <title>Phase 1-Neratinib 200mg; T-DM1 3.6mg/kg</title>
          <description>Dose Level 3-Neratinib 200mg T-DM1 3.6 mg/kg</description>
        </group>
        <group group_id="B4">
          <title>Phase 1 Neratinib 240mg; T-DM1 3.6mg/kg</title>
          <description>Dose Level 4-Neratinib 240mg T-DM1 3.6mg/kg</description>
        </group>
        <group group_id="B5">
          <title>Neratinib and T-DM1 Part 2 (Phase II)</title>
          <description>Dose-evaluation Phase (Part 2) - Patients will receive the highest dose of neratinib with T-DM1 found in Phase I as study therapy.&#xD;
Dose-evaluation Phase (Part 2) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.</description>
        </group>
        <group group_id="B6">
          <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="6"/>
            <count group_id="B2" value="10"/>
            <count group_id="B3" value="8"/>
            <count group_id="B4" value="3"/>
            <count group_id="B5" value="22"/>
            <count group_id="B6" value="49"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="47.8" spread="15.30"/>
                    <measurement group_id="B2" value="51.1" spread="13.24"/>
                    <measurement group_id="B3" value="51.0" spread="9.40"/>
                    <measurement group_id="B4" value="42.0" spread="7.00"/>
                    <measurement group_id="B5" value="55.5" spread="10.35"/>
                    <measurement group_id="B6" value="52.08" spread="11.25"/>
                  </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="6"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="8"/>
                    <measurement group_id="B4" value="3"/>
                    <measurement group_id="B5" value="22"/>
                    <measurement group_id="B6" value="49"/>
                  </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="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="0"/>
                  </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="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="2"/>
                    <measurement group_id="B6" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="8"/>
                    <measurement group_id="B4" value="3"/>
                    <measurement group_id="B5" value="20"/>
                    <measurement group_id="B6" value="46"/>
                  </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="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="0"/>
                  </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="1"/>
                    <measurement group_id="B6" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="1"/>
                    <measurement group_id="B6" 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 group_id="B6" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="6"/>
                    <measurement group_id="B4" value="3"/>
                    <measurement group_id="B5" value="20"/>
                    <measurement group_id="B6" value="41"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="3"/>
                  </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="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                    <measurement group_id="B6" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Evaluable Patients With Dose Limiting Toxicity Events in Phase 1</title>
        <description>If 1 of 3 patients in this cohort experiences a dose limiting toxicity (DLT), 3 more patients will be added at the same dose level. If 0 of 3 initial patients or 1 of 6 patients in an expanded cohort experiences a DLT, the dose for the next cohort will be escalated to dose level 2; otherwise, the combination will be considered too toxic.</description>
        <time_frame>Day 1, 8, and 15 of cycle 1.</time_frame>
        <population>ITT patients who are evaluable for toxicity during the 1st cycle (patients who completed Cycle 1 or had a DLT) of the Phase 1 portion of the study.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase 1 Neratinib 120mg; T-DM1 3.6mg/kg</title>
            <description>Dose Level 1-Neratinib 120mg T-DM1 3.6mg/kg</description>
          </group>
          <group group_id="O2">
            <title>Phase 1 Neratinib 160mg; T-DM1 3.6mg/kg</title>
            <description>Dose Level 2-Neratinib 160mg T-DM1 3.6mg/kg</description>
          </group>
          <group group_id="O3">
            <title>Phase 1 Neratinib 200mg; T-DM1 3.6mg/kg</title>
            <description>Dose Level 3-Neratinib 200mg T-DM1 3.6mg/kg</description>
          </group>
          <group group_id="O4">
            <title>Phase 1 Neratinib 240mg; T-DM1 3.6mg/kg</title>
            <description>Dose Level 4-Neratinib 240mg T-DM1 3.6mg/kg</description>
          </group>
          <group group_id="O5">
            <title>Neratinib and T-DM1</title>
            <description>Neratinib: Dose-Escalation Phase (Part 1) - Neratinib Dose-escalation will proceed on the basis of DLT during Cycle 1 starting at 120 mg/day.&#xD;
Dose level 1: 120 mg/day; Dose level 2: 160 mg/day; Dose level 3: 200 mg/day; Dose level 4: 240 mg/day&#xD;
Dose-evaluation Phase (Part 2) - Patients will receive the highest dose of neratinib with T-DM1 found in Phase I as study therapy&#xD;
T-DM1: Dose-Escalation Phase (Part 1) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.&#xD;
Dose-evaluation Phase (Part 2) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Evaluable Patients With Dose Limiting Toxicity Events in Phase 1</title>
          <description>If 1 of 3 patients in this cohort experiences a dose limiting toxicity (DLT), 3 more patients will be added at the same dose level. If 0 of 3 initial patients or 1 of 6 patients in an expanded cohort experiences a DLT, the dose for the next cohort will be escalated to dose level 2; otherwise, the combination will be considered too toxic.</description>
          <population>ITT patients who are evaluable for toxicity during the 1st cycle (patients who completed Cycle 1 or had a DLT) of the Phase 1 portion of the study.</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="6"/>
                <count group_id="O2" value="9"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="3"/>
                <count group_id="O5" value="26"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="4"/>
                    <measurement group_id="O4" value="2"/>
                    <measurement group_id="O5" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Overall Response Rate (ORR) by Measurement of Target Lesions in Phase II</title>
        <description>Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), &gt;=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.</description>
        <time_frame>Every 42 days after the start of protocol therapy through disease progression, approximately 2 years</time_frame>
        <population>ITT poplulation</population>
        <group_list>
          <group group_id="O1">
            <title>Neratinib and T-DM1</title>
            <description>Dose-evaluation Phase (Part 2) - Patients will receive the highest dose of neratinib with T-DM1 found in Phase I as study therapy&#xD;
Dose-evaluation Phase (Part 2) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Response Rate (ORR) by Measurement of Target Lesions in Phase II</title>
          <description>Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), &gt;=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.</description>
          <population>ITT poplulation</population>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>90% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="22"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="31.8" lower_limit="15.99" upper_limit="51.55"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression-free Survival (PFS) Time From Start of Study Therapy to Disease Progression or Death From Any Cause</title>
        <description>Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.</description>
        <time_frame>Every 42 days after the start of protocol therapy through disease progression, approximately 2 years</time_frame>
        <population>ITT population</population>
        <group_list>
          <group group_id="O1">
            <title>Phase 1 Neratinib 120mg; T-DM1 3.6mg/kg</title>
            <description>Dose Level 1-Neratinib 120mg T-DM1 3.6mg/kg</description>
          </group>
          <group group_id="O2">
            <title>Phase 1 Neratinib 160mg; T-DM1 3.6mg/kg</title>
            <description>Dose Level 2-Neratinib 160mg T-DM1 3.6mg/kg</description>
          </group>
          <group group_id="O3">
            <title>Phase 1 Neratinib 200mg; T-DM1 3.6mg/kg</title>
            <description>Dose Level 3-Neratinib 200mg T-DM1 3.6mg/kg</description>
          </group>
          <group group_id="O4">
            <title>Phase 1 Neratinib 240mg; T-DM1 3.6mg/kg</title>
            <description>Dose Level 4-Neratinib 240mg T-DM1 3.6mg/kg</description>
          </group>
          <group group_id="O5">
            <title>Neratinib and T-DM1 Part 1 (Phase I)</title>
            <description>Neratinib: Dose-Escalation Phase (Part 1) - Neratinib Dose-escalation will proceed on the basis of DLT during Cycle 1 starting at 120 mg/day.&#xD;
Dose level 1: 120 mg/day; Dose level 2: 160 mg/day; Dose level 3: 200 mg/day; Dose level 4: 240 mg/day&#xD;
T-DM1: Dose-Escalation Phase (Part 1) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.</description>
          </group>
          <group group_id="O6">
            <title>Neratinib and T-DM1 Part 2 (Phase II)</title>
            <description>Dose-evaluation Phase (Part 2) - Patients will receive the highest dose of neratinib with T-DM1 found in Phase I as study therapy.&#xD;
Dose-evaluation Phase (Part 2) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.</description>
          </group>
        </group_list>
        <measure>
          <title>Progression-free Survival (PFS) Time From Start of Study Therapy to Disease Progression or Death From Any Cause</title>
          <description>Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.</description>
          <population>ITT population</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="6"/>
                <count group_id="O2" value="10"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="3"/>
                <count group_id="O5" value="27"/>
                <count group_id="O6" value="22"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="40" lower_limit="22.00" upper_limit="72.29"/>
                    <measurement group_id="O2" value="15.4" lower_limit="2.00" upper_limit="NA">Small sample size results in infinite upper 95% confidence bound.</measurement>
                    <measurement group_id="O3" value="8.86" lower_limit="3.00" upper_limit="80.00"/>
                    <measurement group_id="O4" value="9.00" lower_limit="0.00" upper_limit="NA">Small sample size results in infinite upper 95% confidence bound.</measurement>
                    <measurement group_id="O5" value="22" lower_limit="3.29" upper_limit="NA">Small sample size results in infinite upper 95% confidence bound.</measurement>
                    <measurement group_id="O6" value="27" lower_limit="8" upper_limit="61"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Adverse Events Experienced by Participants as a Measure of Toxicity</title>
        <description>Summary of frequency and severity of serious adverse events,</description>
        <time_frame>Day 1, 8, 15 of cycle one, day 1 of each subsequent cycle, at the end of protocol therapy and 30 days following the end of protocol therapy. Duration of therapy varied across patients from a few days to a couple of years.</time_frame>
        <population>ITT population</population>
        <group_list>
          <group group_id="O1">
            <title>Phase 1 Neratinib 120mg; T-DM1 3.6mg/kg</title>
            <description>Dose Level 1-Neratinib 120mg T-DM1 3.6mg/kg</description>
          </group>
          <group group_id="O2">
            <title>Phase 1 Neratinib 160mg; T-DM1 3.6mg/kg</title>
            <description>Dose Level 2-Neratinib 160mg T-DM1 3.6mg/kg</description>
          </group>
          <group group_id="O3">
            <title>Phase 1 Neratinib 200mg; T-DM1 3.6mg/kg</title>
            <description>Dose Level 3-Neratinib 200mg T-DM1 3.6mg/kg</description>
          </group>
          <group group_id="O4">
            <title>Phase 1 Neratinib 240mg; T-DM1 3.6mg/kg</title>
            <description>Dose Level 4-Neratinib 240mg T-DM1 3.6mg/kg</description>
          </group>
          <group group_id="O5">
            <title>Neratinib and T-DM-1 Part 2 (Phase 2)</title>
            <description>Dose-evaluation Phase (Part 2) - Patients will receive the highest dose of neratinib with T-DM1 found in Phase I as study therapy.&#xD;
Dose-evaluation Phase (Part 2) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.</description>
          </group>
        </group_list>
        <measure>
          <title>Adverse Events Experienced by Participants as a Measure of Toxicity</title>
          <description>Summary of frequency and severity of serious adverse events,</description>
          <population>ITT population</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="6"/>
                <count group_id="O2" value="10"/>
                <count group_id="O3" value="8"/>
                <count group_id="O4" value="3"/>
                <count group_id="O5" value="22"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="3"/>
                    <measurement group_id="O3" value="3"/>
                    <measurement group_id="O4" value="0"/>
                    <measurement group_id="O5" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Clinical Benefit Rate (Phase II)</title>
        <description>Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0) for target lesions assessed by MRI or CT; Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), &gt;=30% decrease in the sum of new lesions; Stable Disease (SD) otherwise; Clinical Benefit (CB) = CR+PR+SD (confirmation of response not required).</description>
        <time_frame>Every 63 days after the start of study therapy until disease progression or until 30 days following the end of protocol therapy if due to another cause. Duration of therapy varied across patients from a few days to a couple of years.</time_frame>
        <population>ITT population</population>
        <group_list>
          <group group_id="O1">
            <title>Neratinib and T-DM1</title>
            <description>Dose-evaluation Phase (Part 2) - Patients will receive the highest dose of neratinib with T-DM1 found in Phase I as study therapy.&#xD;
Dose-evaluation Phase (Part 2) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.</description>
          </group>
        </group_list>
        <measure>
          <title>Clinical Benefit Rate (Phase II)</title>
          <description>Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0) for target lesions assessed by MRI or CT; Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), &gt;=30% decrease in the sum of new lesions; Stable Disease (SD) otherwise; Clinical Benefit (CB) = CR+PR+SD (confirmation of response not required).</description>
          <population>ITT population</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="22"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From cycle 1 day 1 until 30 days after the end of protocol therapy (or start of new therapy if it occurred before). The duration of therapy varied across patients from a few days to a couple of years as it was to be given until disease progression or intolerable toxicity.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Phase 1 Neratinib 120mg; T-DM1 3.6mg/kg</title>
          <description>Neratinib 120mg T-DM1 3.6mg/kg</description>
        </group>
        <group group_id="E2">
          <title>Phase 1 Neratinib 160mg; T-DM1 3.6mg/kg</title>
          <description>Neratinib 160mg T-DM1 3.6mg/kg</description>
        </group>
        <group group_id="E3">
          <title>Phase 1 Neratinib 200mg; T-DM1 3.6mg/kg</title>
          <description>Neratinib 200mg T-DM1 3.6mg/kg</description>
        </group>
        <group group_id="E4">
          <title>Phase 1 Neratinib 240mg; T-DM1 3.6mg/kg</title>
          <description>Neratinib 240mg T-DM1 3.6mg/kg</description>
        </group>
        <group group_id="E5">
          <title>Neratinib and T-DM1 Part 1 (Phase 1)</title>
          <description>Neratinib: Dose-Escalation Phase (Part 1) - Neratinib Dose-escalation will proceed on the basis of DLT during Cycle 1 starting at 120 mg/day.&#xD;
Dose level 1: 120 mg/day; Dose level 2: 160 mg/day; Dose level 3: 200 mg/day; Dose level 4: 240 mg/day&#xD;
T-DM1: Dose-Escalation Phase (Part 1) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.</description>
        </group>
        <group group_id="E6">
          <title>Neratinib and T-DM1Part 1 (Phase 2)</title>
          <description>Dose-evaluation Phase (Part 2) - Patients will receive the highest dose of neratinib with T-DM1 found in Phase I as study therapy.&#xD;
Dose-evaluation Phase (Part 2) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.</description>
        </group>
      </group_list>
      <serious_events>
        <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="0" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="8"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="7" subjects_at_risk="27"/>
                <counts group_id="E6" subjects_affected="10" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E6" events="4" subjects_affected="4" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Gastric ulcer</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Arthritis infective</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E6" events="1" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Cystitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E6" events="1" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Osteomyelitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E6" events="1" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Soft tissue infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E6" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Ankle fracture</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E6" events="1" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Infusion related reaction</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E6" events="1" subjects_affected="1" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood creatinine increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E6" events="1" subjects_affected="1" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="3" subjects_affected="3" subjects_at_risk="27"/>
                <counts group_id="E6" events="3" subjects_affected="3" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Hypokalaemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E6" events="2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Hypocalcaemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E6" events="1" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Hypomagnesaemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E6" events="1" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Hyponatraemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E6" events="1" subjects_affected="1" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Muscular weakness</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E6" events="1" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Neck pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E6" events="1" subjects_affected="1" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Paraesthesia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E6" events="1" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Depressed level of consciousness</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </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" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E6" events="1" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Renal failure</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Haematoma</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E6" events="1" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="1" subjects_affected="1" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <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="6" subjects_at_risk="6"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="8" subjects_at_risk="8"/>
                <counts group_id="E4" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E5" subjects_affected="27" subjects_at_risk="27"/>
                <counts group_id="E6" subjects_affected="22" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E3" events="4" subjects_affected="4" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="8" subjects_affected="8" subjects_at_risk="27"/>
                <counts group_id="E6" events="5" subjects_affected="5" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Leukopenia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Sinus tachycardia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" events="6" subjects_affected="6" subjects_at_risk="6"/>
                <counts group_id="E2" events="9" subjects_affected="9" subjects_at_risk="10"/>
                <counts group_id="E3" events="7" subjects_affected="7" subjects_at_risk="8"/>
                <counts group_id="E4" events="3" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E5" events="25" subjects_affected="25" subjects_at_risk="27"/>
                <counts group_id="E6" events="19" subjects_affected="19" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="6" subjects_affected="6" subjects_at_risk="6"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="10"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="8"/>
                <counts group_id="E4" events="3" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E5" events="18" subjects_affected="18" subjects_at_risk="27"/>
                <counts group_id="E6" events="9" subjects_affected="9" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="6"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="10"/>
                <counts group_id="E3" events="4" subjects_affected="4" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="12" subjects_affected="12" subjects_at_risk="27"/>
                <counts group_id="E6" events="8" subjects_affected="8" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="6"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="10"/>
                <counts group_id="E3" events="4" subjects_affected="4" subjects_at_risk="8"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" events="13" subjects_affected="13" subjects_at_risk="27"/>
                <counts group_id="E6" events="7" subjects_affected="7" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" events="5" subjects_affected="5" subjects_at_risk="27"/>
                <counts group_id="E6" events="4" subjects_affected="4" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Abdominal distension</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" events="3" subjects_affected="3" subjects_at_risk="27"/>
                <counts group_id="E6" events="2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Stomatitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E6" events="2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="3" subjects_affected="3" subjects_at_risk="27"/>
                <counts group_id="E6" subjects_affected="4" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Gastroesophageal reflux disease</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Abdominal pain upper</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="6"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="10"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="8"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E5" events="14" subjects_affected="14" subjects_at_risk="27"/>
                <counts group_id="E6" events="12" subjects_affected="12" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E6" events="3" subjects_affected="3" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Oedema peripheral</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E6" events="2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Influenza like illness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E6" events="2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="3" subjects_affected="3" subjects_at_risk="27"/>
                <counts group_id="E6" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Lip infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Paronychia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" events="6" subjects_affected="6" subjects_at_risk="6"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="10"/>
                <counts group_id="E3" events="6" subjects_affected="6" subjects_at_risk="8"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" events="19" subjects_affected="19" subjects_at_risk="27"/>
                <counts group_id="E6" events="9" subjects_affected="9" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="6"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="10"/>
                <counts group_id="E3" events="4" subjects_affected="4" subjects_at_risk="8"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" events="14" subjects_affected="14" subjects_at_risk="27"/>
                <counts group_id="E6" events="6" subjects_affected="6" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="6"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="10"/>
                <counts group_id="E3" events="4" subjects_affected="4" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="13" subjects_affected="13" subjects_at_risk="27"/>
                <counts group_id="E6" events="5" subjects_affected="5" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Weight decreased</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="6"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="10"/>
                <counts group_id="E3" events="6" subjects_affected="6" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="14" subjects_affected="14" subjects_at_risk="27"/>
                <counts group_id="E6" events="5" subjects_affected="5" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Blood creatinine increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="4" subjects_affected="4" subjects_at_risk="27"/>
                <counts group_id="E6" events="3" subjects_affected="3" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E6" events="2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="6"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="10"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="8"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" events="10" subjects_affected="10" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Blood alkaline phosphatase increased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="10"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="8"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" events="10" subjects_affected="10" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="4" subjects_affected="4" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>White blood cell count decreased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="4" subjects_affected="4" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hypokalaemia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="6"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E3" events="5" subjects_affected="5" subjects_at_risk="8"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" events="11" subjects_affected="11" subjects_at_risk="27"/>
                <counts group_id="E6" events="15" subjects_affected="15" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="10"/>
                <counts group_id="E3" events="4" subjects_affected="4" subjects_at_risk="8"/>
                <counts group_id="E4" events="3" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E5" events="13" subjects_affected="13" subjects_at_risk="27"/>
                <counts group_id="E6" events="5" subjects_affected="5" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Hypoalbuminaemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="5" subjects_affected="5" subjects_at_risk="27"/>
                <counts group_id="E6" events="4" subjects_affected="4" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Hyponatraemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="8"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" events="6" subjects_affected="6" subjects_at_risk="27"/>
                <counts group_id="E6" events="4" subjects_affected="4" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E3" events="5" subjects_affected="5" subjects_at_risk="8"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" events="9" subjects_affected="9" subjects_at_risk="27"/>
                <counts group_id="E6" events="2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Hypomagnesaemia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E6" events="2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="6" subjects_affected="6" subjects_at_risk="10"/>
                <counts group_id="E3" events="4" subjects_affected="4" subjects_at_risk="8"/>
                <counts group_id="E4" events="3" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E5" events="13" subjects_affected="13" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Hypocalcaemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Hypernatraemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="8"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" events="6" subjects_affected="6" subjects_at_risk="27"/>
                <counts group_id="E6" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E6" events="4" subjects_affected="4" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" events="4" subjects_affected="4" subjects_at_risk="27"/>
                <counts group_id="E6" events="2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E6" events="2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" events="4" subjects_affected="4" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="3" subjects_affected="3" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Muscular weakness</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Neck pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Peripheral sensory neuropathy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E6" events="4" subjects_affected="4" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" events="4" subjects_affected="4" subjects_at_risk="27"/>
                <counts group_id="E6" events="3" subjects_affected="3" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="8"/>
                <counts group_id="E4" events="2" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E5" events="7" subjects_affected="7" subjects_at_risk="27"/>
                <counts group_id="E6" events="2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E6" events="2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Confusional state</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Epitaxis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="3" subjects_affected="3" subjects_at_risk="27"/>
                <counts group_id="E6" events="2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="3" subjects_affected="3" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Oropharyngeal pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="3" subjects_affected="3" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Rhinitis allergic</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Upper-airway cough syndrome</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E6" events="3" subjects_affected="3" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Dermatitis acneiform</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Embolism</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="0" subjects_affected="0" subjects_at_risk="27"/>
                <counts group_id="E6" events="3" subjects_affected="3" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="6"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="6" subjects_affected="6" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="6"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="8"/>
                <counts group_id="E4" events="0" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E5" events="2" subjects_affected="2" subjects_at_risk="27"/>
                <counts group_id="E6" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Judy Langer, Director of Regulatory Affairs</name_or_title>
      <organization>NSABP Foundation, Inc.</organization>
      <phone>412-339-5300</phone>
      <email>judy.langer@nsabp.org</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/NCT02236000
org study id: NSABP FB-10
nct id: NCT02236000
lead sponsor: 
collaborator: 
has dmc: No
This study is being done for the following reasons:

        -  The study has two parts. The purpose of the first part (Phase I) of the study is to find
           out the highest dose of neratinib that can be given safely with T-DM1.

        -  The purpose of the second part of the study (Phase II) is to find out whether the dose
           of neratinib with T-DM1 determined in Phase I will keep breast cancer from getting worse
           for a period of time.

        -  In order to learn more about study therapy levels in blood and discover genetic and
           protein changes associated with cancer, the study includes special research tests using
           samples from blood and from breast tumor. Blood samples will be collected before study
           treatment, once during treatment, and after study treatment stops.

        -  In the optional part of this study, three biopsies will be performed to obtain fresh
           tumor samples from an area where your cancer has spread.
The FB-10 study is designed as an open label, single arm, Phase Ib/II study with a
      dose-escalation phase and an expanded cohort (phase II) to evaluate the combination of
      trastuzumab emtansine (T-DM1) with neratinib in women with metastatic, HER2-positive breast
      cancer. The primary aim of the phase Ib portion of this study is to determine the safety and
      tolerability of the two-drug combination. The primary aim of the phase II portion is to
      demonstrate efficacy.

      Patients will receive concurrent therapy with T-DM1 (3.6 mg/kg IV) on Day 1 of a 3-week (21
      day) cycle and neratinib as a continuous daily oral dose. The neratinib dose-escalation will
      include 4 dose levels (120 mg, 160 mg, 200 mg, and 240 mg). At the recommended phase II dose
      (RP2D) of the T-DM1 and neratinib combination, up to 39 additional patients will be treated.

      The sample size of the phase I portion of the study was 27 patients. The sample size of the
      Phase II portion will be 22 evaluable patients (and 4 replacement patients). The total study
      enrollment, phase Ib and II, will be a maximum of 50 patients.

      Submission of diagnostic tumor samples and blood samples for FB-10 correlative science
      studies will be a study requirement for all patients. Blood samples for pharmacokinetics
      (PKs) and for future study will be collected prior to administration of study therapy on
      Cycle 1/Day 1, Cycle 1/Day 8, and Cycle 2/Day1.

      A tumor biopsy will be procured from an accessible site of metastasis before study therapy is
      initiated (after the patient has signed the consent and has been screened for eligibility).
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of Evaluable Patients With Dose Limiting Toxicity Events in Phase 1
time frame: Day 1, 8, and 15 of cycle 1.
description: If 1 of 3 patients in this cohort experiences a dose limiting toxicity (DLT), 3 more patients will be added at the same dose level. If 0 of 3 initial patients or 1 of 6 patients in an expanded cohort experiences a DLT, the dose for the next cohort will be escalated to dose level 2; otherwise, the combination will be considered too toxic.
measure: Overall Response Rate (ORR) by Measurement of Target Lesions in Phase II
time frame: Every 42 days after the start of protocol therapy through disease progression, approximately 2 years
description: Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
measure: Progression-free Survival (PFS) Time From Start of Study Therapy to Disease Progression or Death From Any Cause
time frame: Every 42 days after the start of protocol therapy through disease progression, approximately 2 years
description: Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
measure: Adverse Events Experienced by Participants as a Measure of Toxicity
time frame: Day 1, 8, 15 of cycle one, day 1 of each subsequent cycle, at the end of protocol therapy and 30 days following the end of protocol therapy. Duration of therapy varied across patients from a few days to a couple of years.
description: Summary of frequency and severity of serious adverse events,
measure: Clinical Benefit Rate (Phase II)
time frame: Every 63 days after the start of study therapy until disease progression or until 30 days following the end of protocol therapy if due to another cause. Duration of therapy varied across patients from a few days to a couple of years.
description: Per Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.0) for target lesions assessed by MRI or CT; Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of new lesions; Stable Disease (SD) otherwise; Clinical Benefit (CB) = CR+PR+SD (confirmation of response not required).
arm group label: Neratinib and T-DM1
arm group type: Experimental
intervention type: Drug
intervention name: Neratinib
description: Dose-Escalation Phase (Part 1) - Neratinib Dose-escalation will proceed on the basis of DLT during Cycle 1 starting at 120 mg/day.
Dose level 1: 120 mg/day; Dose level 2: 160 mg/day; Dose level 3: 200 mg/day; Dose level 4: 240 mg/day
Dose-evaluation Phase (Part 2) - Patients will receive the highest dose of neratinib with T-DM1 found in Phase I as study therapy
arm group label: Neratinib and T-DM1
intervention type: Drug
intervention name: T-DM1
description: Dose-Escalation Phase (Part 1) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.
Dose-evaluation Phase (Part 2) - Trastuzumab emtansine (T-DM1) will be given at 3.6 mg/kg IV Day 1 every 21 days.
arm group label: Neratinib and T-DM1
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Norman Wolmark, MD
role: Principal Investigator
affiliation: NSABP Foundation Inc
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
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facility: 
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facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Breast Neoplasms
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 