<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/NCT03289039</url>
  </required_header>
  <id_info>
    <org_study_id>17-318</org_study_id>
    <nct_id>NCT03289039</nct_id>
  </id_info>
  <brief_title>Neratinib +/- Fulvestrant in HER2+, ER+ Metastatic Breast Cancer</brief_title>
  <official_title>A Phase 2 Study of Neratinib With or Without Fulvestrant in HER2-Positive, ER-Positive Metastatic Breast Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Dana-Farber Cancer Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Puma Biotechnology, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Dana-Farber Cancer Institute</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This research study is studying a drug called Neratinib with and without Fulvestrant as&#xD;
      possible treatments for HER2-positive breast cancer .&#xD;
&#xD;
      The interventions involved in this study are:&#xD;
&#xD;
        -  Neratinib and Fulvestrant&#xD;
&#xD;
        -  Neratinib alone&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This research study is a Phase II clinical trial. Phase II clinical trials test the safety&#xD;
      and effectiveness of an investigational intervention to learn whether the intervention works&#xD;
      in treating a specific disease. &quot;Investigational&quot; means that the intervention is being&#xD;
      studied.&#xD;
&#xD;
      The FDA (the U.S. Food and Drug Administration) has approved Neratinib as a treatment for&#xD;
      breast cancer. Fulvestrant has been FDA approved for treatment of metastatic hormone receptor&#xD;
      positive breast cancer.&#xD;
&#xD;
      The purpose of this research study is to determine how well neratinib, by itself or together&#xD;
      with Fulvestrant, works in treating breast cancer that has spread to other parts of the body.&#xD;
      Neratinib is a recently discovered oral drug that may stop breast cancer cells from growing&#xD;
      abnormally by inhibiting (or blocking) members of a family of proteins that include Human&#xD;
      Epidermal Growth Factor Receptor 2 (HER2).&#xD;
&#xD;
      Neratinib has been used in other research studies and information from those other research&#xD;
      studies suggests that neratinib may help to shrink or stabilize HER2-positive breast cancer&#xD;
      in this research study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Slow accrual&#xD;
  </why_stopped>
  <start_date type="Actual">October 25, 2017</start_date>
  <completion_date type="Actual">July 20, 2021</completion_date>
  <primary_completion_date type="Actual">July 20, 2021</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Progression Free Survival</measure>
    <time_frame>Participants were followed for PFS up to 20.3 months from registration.</time_frame>
    <description>Progression-Free Survival (PFS) is defined as the time from randomization (or registration) to the earlier of progression or death due to any cause. Participants alive without disease progression are censored at date of last disease evaluation.&#xD;
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. Disease assessment were conducted at baseline and every two cycles after the first cycle.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>Participants were followed for up to 38.4 months (3 years and 2 months) from registration to removal from protocol therapy or death.</time_frame>
    <description>Overall Survival (OS) is defined as the time from randomization (or registration) to death due to any cause, or censored at date last known alive. Participants will be evaluated every 6 months for survival until death. Participants removed from protocol therapy for unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse event.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Response Rate</measure>
    <time_frame>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; Overall Response Rate(ORR) = (CR + PR)/sample size.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration Of Responses</measure>
    <time_frame>2 years</time_frame>
    <description>The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started, or death due to any cause. Participants without events reported are censored at the last disease evaluation).</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">21</enrollment>
  <condition>Breast Cancer</condition>
  <arm_group>
    <arm_group_label>Neratinib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Neratinib will be administered orally once daily&#xD;
Neratinib is dosed at 240mg (six 40mg tablets)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Neratinib + Fulvestrant</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Neratinib will be administered orally once daily&#xD;
Neratinib is dosed at 240mg (six 40mg tablets)&#xD;
Fulvestrant will be administered intramuscular as an injection (shot) on day 1 and 15 of cycle 1, day 1 of cycle 2, and then on day 1 of each subsequent cycle.&#xD;
Fulvestrant is dosed as 250 mg/5mL (x2) for a total of 500 mg via intramuscular injection (two injections).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Neratinib</intervention_name>
    <description>Neratinib is a recently discovered oral drug that may stop breast cancer cells from growing abnormally by inhibiting (or blocking) members of a family of proteins that include Human Epidermal Growth Factor Receptor 2 (HER2)</description>
    <arm_group_label>Neratinib</arm_group_label>
    <arm_group_label>Neratinib + Fulvestrant</arm_group_label>
    <other_name>Nerlynx</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fulvestrant</intervention_name>
    <description>Fulvestrant, works in treating breast cancer that has spread to other parts of the body</description>
    <arm_group_label>Neratinib + Fulvestrant</arm_group_label>
    <other_name>Faslodex</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Participants must have histologically or cytologically confirmed inoperable locally&#xD;
             advanced or metastatic ER+ breast cancer. To fulfill the requirement for ER+ disease,&#xD;
             a breast cancer must express, by immunohistochemistry (IHC), ER in ≥10% of cells, on&#xD;
             the most recent biopsy. If ER quantification is not available, a determination of ER+&#xD;
             by IHC will suffice. Central confirmation of ER status is not required.&#xD;
&#xD;
          -  Participants must have documented HER2+ disease by overexpression and/or gene&#xD;
             amplification on the most recent biopsy, per current ASCO-CAP (American Society of&#xD;
             Clinical Oncology - College of American Pathologists) guidelines. Central confirmation&#xD;
             of HER2 status is not required.&#xD;
&#xD;
          -  Participants must have received prior therapy with the following agents in any&#xD;
             combination, and in setting (i.e., neoadjuvant, adjuvant, metastatic, etc.). These&#xD;
             therapies do not need to be the most recent line of therapy.&#xD;
&#xD;
               -  Trastuzumab&#xD;
&#xD;
               -  Pertuzumab&#xD;
&#xD;
               -  Ado-trastuzumab emtansine (T-DM1)&#xD;
&#xD;
          -  Participants must agree to undergo a research biopsy of a reasonably accessible&#xD;
             metastatic lesion (chest wall, skin, subcutaneous tissue, lymph nodes, skin, breast,&#xD;
             bones, lung, and liver metastases). If a reasonably accessible metastatic lesion is&#xD;
             not available, the patient may go on study provided that archived tissue is available.&#xD;
             However, if a reasonably accessible site is available for biopsy, the patient must&#xD;
             agree to biopsy. Any patients not undergoing biopsy must be approved for study&#xD;
             enrollment by the Overall Principal Investigator at DFCI. Biopsies may be done with&#xD;
             local anesthesia or intravenous conscious sedation, according to institutional&#xD;
             guidelines. If a biopsy requires general anesthesia, then it is only allowed if&#xD;
             acquisition of tissue is clinically indicated, and excess tissue may be collected for&#xD;
             research purposes. Patients without sites available for biopsy must have available&#xD;
             tissue [archived formalin-fixed paraffin embedded blocks (FFPB), blocks from which&#xD;
             slides can be created, or fresh frozen tissue from original diagnosis or metastatic&#xD;
             setting] for correlative studies. Tissue needs to be located and available at the time&#xD;
             of registration See Section 9.3 for more details.&#xD;
&#xD;
          -  Women ≥ 18 years of age. Men are not eligible.&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (see Appendix A).&#xD;
&#xD;
          -  Participants must have normal organ and marrow function as described below:&#xD;
&#xD;
               -  Absolute neutrophil count ≥1,000/uL&#xD;
&#xD;
               -  Platelets ≥75,000/uL&#xD;
&#xD;
               -  Hemoglobin ≥8g/dL&#xD;
&#xD;
               -  Total bilirubin ≤ 1.5 X institutional upper limit of normal (ULN); in case of&#xD;
                  known Gilbert's syndrome, &lt;2 x ULN is allowed&#xD;
&#xD;
               -  AST(SGOT)/ALT(SGPT) ≤3X institutional ULN without liver metastases, or ≤5X&#xD;
                  institutional ULN with liver metastases&#xD;
&#xD;
               -  Creatinine clearance ≥ 50 mL/min&#xD;
&#xD;
               -  Left ventricular ejection fraction ≥50%, as determined by RVG (MUGA) or&#xD;
                  echocardiogram (ECHO) within 60 days prior to initiation of protocol therapy&#xD;
&#xD;
          -  Participants may have received any number of prior therapies as long as they have&#xD;
             adequate performance status and meet all other eligibility criteria.&#xD;
&#xD;
          -  Women of childbearing potential (including premenopausal women and women less than 12&#xD;
             months after menopause) must have a negative β-human chorionic gonadotropin (hCG)&#xD;
             urine pregnancy test within 4 weeks of registration.&#xD;
&#xD;
          -  The effects of neratinib and fulvestrant on the developing human fetus are unknown.&#xD;
             For this reason and because SERD agents are known to be teratogenic, women of&#xD;
             child-bearing potential must agree to be abstinent, or to use a highly effective&#xD;
             double barrier method of contraception (e.g, a combination of male condom with an&#xD;
             intravaginal device such as the cervical cap, diaphragm, or vaginal sponge with&#xD;
             spermicide) or a non-hormonal method, while enrolled in the study, until at least 28&#xD;
             days after the last dose of neratinib or 1 year after the last dose of fulvestrant.&#xD;
             Should a woman become pregnant or suspect she is pregnant while she is participating&#xD;
             in this study, she should inform her treating physician immediately. If a woman is of&#xD;
             childbearing potential, she must agree to use adequate contraception prior to the&#xD;
             study, for the duration of study participation, and for one year after completion of&#xD;
             the study drug.&#xD;
&#xD;
          -  Ability to understand and willingness to sign a written informed consent document.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Participants who have a history of allergic reactions attributed to compounds of&#xD;
             similar chemical or biologic composition to neratinib or fulvestrant.&#xD;
&#xD;
          -  Participants who have known hypersensitivity to any component of loperamide or&#xD;
             colestipol.&#xD;
&#xD;
          -  Participants who have received previous therapy with neratinib.&#xD;
&#xD;
          -  Participants who have received anti-cancer therapy (including chemotherapy, biological&#xD;
             therapy, investigational agents, hormonal therapy, or other anti-cancer therapy) or&#xD;
             radiotherapy within ≤14 days prior to the planned initiation of investigational&#xD;
             products, or those who have not recovered to grade ≤1from adverse events due to their&#xD;
             most recent therapy (excepting alopecia).&#xD;
&#xD;
          -  Participants who have had any major surgery ≤28 days prior to the planned initiation&#xD;
             of study therapy, or those who have not recovered from adverse events due to&#xD;
             agents/surgery administered more than 4 weeks earlier.&#xD;
&#xD;
          -  Participants who are receiving any other investigational agents.&#xD;
&#xD;
          -  Participants with known brain metastases that are untreated, symptomatic, or require&#xD;
             therapy to control symptoms. Participants with a history of treated central nervous&#xD;
             system (CNS) metastases are eligible. Treated brain metastases are defined as those&#xD;
             without ongoing requirement for corticosteroids, as ascertained by clinical&#xD;
             examination and/or brain imaging (magnetic resonance imaging or CT scan) completed&#xD;
             during screening. Any corticosteroid use for brain metastases must have been&#xD;
             discontinued without the subsequent appearance of symptoms for ≥ 7 days prior to&#xD;
             registration. Treatment for brain metastases may include whole brain radiotherapy,&#xD;
             radiosurgery, surgery or a combination as deemed appropriate by the treating&#xD;
             physician. Radiation therapy must be completed at least 14 days prior to registration.&#xD;
&#xD;
          -  Participant has active, uncontrolled cardiac disease, including cardiomyopathy,&#xD;
             congestive heart failure (New York Heart Association functional classification of ≥2),&#xD;
             unstable angina, myocardial infarction within 12 months of enrollment, or ventricular&#xD;
             arrhythmia.&#xD;
&#xD;
          -  Participant has a QTc interval &gt;470 ms or known history of QTc prolongation or Torsade&#xD;
             de Pointes.&#xD;
&#xD;
          -  Participant has an active infection or unexplained fever &gt;38.5°C (101.3°F).&#xD;
&#xD;
          -  Participant has had another malignancy within the past 5 years with the exception of&#xD;
             a) adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid&#xD;
             cancer; b) carcinoma in situ of the breast, cervix or vulva; or c) cancer considered&#xD;
             cured by surgical resection or unlikely to impact survival during the duration of the&#xD;
             study, such as localized transitional cell carcinoma of the bladder, or benign tumors&#xD;
             of the adrenal or pancreas.&#xD;
&#xD;
          -  Participant has significant chronic gastrointestinal disorder with diarrhea as a major&#xD;
             symptom (e.g., Crohn's disease, malabsorption, or Grade ≥2 (NCI CTCAE v.4.0) diarrhea&#xD;
             of any etiology at screening).&#xD;
&#xD;
          -  Participant has known active infection with hepatitis B or hepatitis C virus.&#xD;
             Hepatitis B and C serology testing is not required, unless active infection is&#xD;
             suspected.&#xD;
&#xD;
          -  Participant is unable or unwilling to swallow tablets.&#xD;
&#xD;
          -  Participant has evidence of significant medical illness, abnormal laboratory finding,&#xD;
             or psychiatric illness/social situations that would, in the Investigator's judgment,&#xD;
             limit compliance with study requirements.&#xD;
&#xD;
          -  Pregnant women are excluded from this study because fulvestrant is a SERD agent with&#xD;
             the potential for teratogenic or abortifacient effects. Because there is an unknown&#xD;
             but potential risk for adverse events in nursing infants secondary to treatment of the&#xD;
             mother with neratinib and/or fulvestrant, breastfeeding should be discontinued if the&#xD;
             mother is treated with neratinib and/or fulvestrant.&#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>Jose Leone, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Dana-Farber Cancer Institute</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Indiana University</name>
      <address>
        <city>Indianapolis</city>
        <state>Indiana</state>
        <zip>46202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Eastern Maine Medical Center</name>
      <address>
        <city>Brewer</city>
        <state>Maine</state>
        <zip>04412</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dana Farber Cancer Institute</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dana-Farber/New Hampshire Oncology-Hematology</name>
      <address>
        <city>Londonderry</city>
        <state>New Hampshire</state>
        <zip>03053</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Ohio State University</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43210</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UT Southwestern</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75390</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>September 18, 2017</study_first_submitted>
  <study_first_submitted_qc>September 18, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 20, 2017</study_first_posted>
  <results_first_submitted>November 15, 2022</results_first_submitted>
  <results_first_submitted_qc>March 17, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">March 21, 2023</results_first_posted>
  <last_update_submitted>March 17, 2023</last_update_submitted>
  <last_update_submitted_qc>March 17, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 21, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Dana-Farber Cancer Institute</investigator_affiliation>
    <investigator_full_name>Jose Pablo Leone</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Breast Cancer</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Fulvestrant</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>February 14, 2022</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/39/NCT03289039/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Neratinib</title>
          <description>Neratinib will be administered orally once daily&#xD;
Neratinib is dosed at 240mg (six 40mg tablets)&#xD;
Neratinib: Neratinib is a recently discovered oral drug that may stop breast cancer cells from growing abnormally by inhibiting (or blocking) members of a family of proteins that include Human Epidermal Growth Factor Receptor 2 (HER2)</description>
        </group>
        <group group_id="P2">
          <title>Neratinib + Fulvestrant</title>
          <description>Neratinib will be administered orally once daily&#xD;
Neratinib is dosed at 240mg (six 40mg tablets)&#xD;
Fulvestrant will be administered intramuscular as an injection (shot) on day 1 and 15 of cycle 1, day 1 of cycle 2, and then on day 1 of each subsequent cycle.&#xD;
Fulvestrant is dosed as 250 mg/5mL (x2) for a total of 500 mg via intramuscular injection (two injections).&#xD;
Neratinib: Neratinib is a recently discovered oral drug that may stop breast cancer cells from growing abnormally by inhibiting (or blocking) members of a family of proteins that include Human Epidermal Growth Factor Receptor 2 (HER2)&#xD;
Fulvestrant: Fulvestrant, works in treating breast cancer that has spread to other parts of the body</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="11"/>
                <participants group_id="P2" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
                <participants group_id="P2" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Became ineligible prior to treatment start</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>progressed before treatment start</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>The analysis population is only including treated patients.</population>
      <group_list>
        <group group_id="B1">
          <title>Neratinib</title>
          <description>Neratinib will be administered orally once daily&#xD;
Neratinib is dosed at 240mg (six 40mg tablets)&#xD;
Neratinib: Neratinib is a recently discovered oral drug that may stop breast cancer cells from growing abnormally by inhibiting (or blocking) members of a family of proteins that include Human Epidermal Growth Factor Receptor 2 (HER2)</description>
        </group>
        <group group_id="B2">
          <title>Neratinib + Fulvestrant</title>
          <description>Neratinib will be administered orally once daily&#xD;
Neratinib is dosed at 240mg (six 40mg tablets)&#xD;
Fulvestrant will be administered intramuscular as an injection (shot) on day 1 and 15 of cycle 1, day 1 of cycle 2, and then on day 1 of each subsequent cycle.&#xD;
Fulvestrant is dosed as 250 mg/5mL (x2) for a total of 500 mg via intramuscular injection (two injections).&#xD;
Neratinib: Neratinib is a recently discovered oral drug that may stop breast cancer cells from growing abnormally by inhibiting (or blocking) members of a family of proteins that include Human Epidermal Growth Factor Receptor 2 (HER2)&#xD;
Fulvestrant: Fulvestrant, works in treating breast cancer that has spread to other parts of the body</description>
        </group>
        <group group_id="B3">
          <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="10"/>
            <count group_id="B2" value="8"/>
            <count group_id="B3" value="18"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="55" lower_limit="28" upper_limit="73"/>
                    <measurement group_id="B2" value="55.5" lower_limit="36" upper_limit="66"/>
                    <measurement group_id="B3" value="55" lower_limit="28" upper_limit="73"/>
                  </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="10"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="18"/>
                  </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_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="18"/>
                  </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_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Race</title>
              <category_list>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Other</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="14"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Prior use of Fulvestrant</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Yes</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>No</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Prior lines of therapy</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Less than or equal to 3 lines</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Greater than 3 lines</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Progression Free Survival</title>
        <description>Progression-Free Survival (PFS) is defined as the time from randomization (or registration) to the earlier of progression or death due to any cause. Participants alive without disease progression are censored at date of last disease evaluation.&#xD;
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. Disease assessment were conducted at baseline and every two cycles after the first cycle.</description>
        <time_frame>Participants were followed for PFS up to 20.3 months from registration.</time_frame>
        <population>Only treated participants</population>
        <group_list>
          <group group_id="O1">
            <title>Neratinib</title>
            <description>Neratinib will be administered orally once daily&#xD;
Neratinib is dosed at 240mg (six 40mg tablets)&#xD;
Neratinib: Neratinib is a recently discovered oral drug that may stop breast cancer cells from growing abnormally by inhibiting (or blocking) members of a family of proteins that include Human Epidermal Growth Factor Receptor 2 (HER2)</description>
          </group>
          <group group_id="O2">
            <title>Neratinib + Fulvestrant</title>
            <description>Neratinib will be administered orally once daily&#xD;
Neratinib is dosed at 240mg (six 40mg tablets)&#xD;
Fulvestrant will be administered intramuscular as an injection (shot) on day 1 and 15 of cycle 1, day 1 of cycle 2, and then on day 1 of each subsequent cycle.&#xD;
Fulvestrant is dosed as 250 mg/5mL (x2) for a total of 500 mg via intramuscular injection (two injections).&#xD;
Neratinib: Neratinib is a recently discovered oral drug that may stop breast cancer cells from growing abnormally by inhibiting (or blocking) members of a family of proteins that include Human Epidermal Growth Factor Receptor 2 (HER2)&#xD;
Fulvestrant: Fulvestrant, works in treating breast cancer that has spread to other parts of the body</description>
          </group>
        </group_list>
        <measure>
          <title>Progression Free Survival</title>
          <description>Progression-Free Survival (PFS) is defined as the time from randomization (or registration) to the earlier of progression or death due to any cause. Participants alive without disease progression are censored at date of last disease evaluation.&#xD;
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. Disease assessment were conducted at baseline and every two cycles after the first cycle.</description>
          <population>Only treated participants</population>
          <units>months</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="10"/>
                <count group_id="O2" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Less than 4 prior lines of therapy; no prior use of fulvestrant</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="1"/>
                    <count group_id="O2" value="1"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="19.58" lower_limit="NA" upper_limit="NA">The sample size for this group is too small to have a valid interval.</measurement>
                    <measurement group_id="O2" value="1.74" lower_limit="NA" upper_limit="NA">The sample size for this group is too small to have a valid interval.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>More than 3 prior lines of therapy; no prior use of fulvestrant</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="7"/>
                    <count group_id="O2" value="7"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.81" lower_limit="1.81" upper_limit="NA">The sample size for this group is too small to have a valid interval.</measurement>
                    <measurement group_id="O2" value="3.84" lower_limit="1.61" upper_limit="NA">The sample size for this group is too small to have a valid interval.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>More than 3 prior lines of therapy; prior use of fulvestrant</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="2"/>
                    <count group_id="O2" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.42" lower_limit="5.55" upper_limit="NA">The sample size for this group is too small to have a valid interval.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.98</p_value>
            <method>Log Rank</method>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>1.06</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.27</ci_lower_limit>
            <ci_upper_limit>4.12</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival</title>
        <description>Overall Survival (OS) is defined as the time from randomization (or registration) to death due to any cause, or censored at date last known alive. Participants will be evaluated every 6 months for survival until death. Participants removed from protocol therapy for unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse event.</description>
        <time_frame>Participants were followed for up to 38.4 months (3 years and 2 months) from registration to removal from protocol therapy or death.</time_frame>
        <population>Only included the treated participants.</population>
        <group_list>
          <group group_id="O1">
            <title>Neratinib</title>
            <description>Neratinib will be administered orally once daily&#xD;
Neratinib is dosed at 240mg (six 40mg tablets)&#xD;
Neratinib: Neratinib is a recently discovered oral drug that may stop breast cancer cells from growing abnormally by inhibiting (or blocking) members of a family of proteins that include Human Epidermal Growth Factor Receptor 2 (HER2)</description>
          </group>
          <group group_id="O2">
            <title>Neratinib + Fulvestrant</title>
            <description>Neratinib will be administered orally once daily&#xD;
Neratinib is dosed at 240mg (six 40mg tablets)&#xD;
Fulvestrant will be administered intramuscular as an injection (shot) on day 1 and 15 of cycle 1, day 1 of cycle 2, and then on day 1 of each subsequent cycle.&#xD;
Fulvestrant is dosed as 250 mg/5mL (x2) for a total of 500 mg via intramuscular injection (two injections).&#xD;
Neratinib: Neratinib is a recently discovered oral drug that may stop breast cancer cells from growing abnormally by inhibiting (or blocking) members of a family of proteins that include Human Epidermal Growth Factor Receptor 2 (HER2)&#xD;
Fulvestrant: Fulvestrant, works in treating breast cancer that has spread to other parts of the body</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival</title>
          <description>Overall Survival (OS) is defined as the time from randomization (or registration) to death due to any cause, or censored at date last known alive. Participants will be evaluated every 6 months for survival until death. Participants removed from protocol therapy for unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse event.</description>
          <population>Only included the treated participants.</population>
          <units>months</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="10"/>
                <count group_id="O2" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Less than 4 prior lines of therapy; no prior fulvestrant use</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="1"/>
                    <count group_id="O2" value="1"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" lower_limit="NA" upper_limit="NA">Did not reach median survival.</measurement>
                    <measurement group_id="O2" value="12.22" lower_limit="NA" upper_limit="NA">Sample size too small to get a valid confidence interval.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>More than 3 prior lines of therapy; no prior fulvestrant use</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="7"/>
                    <count group_id="O2" value="7"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="20.17" lower_limit="12.91" upper_limit="NA">Sample size too small to get a valid confidence interval.</measurement>
                    <measurement group_id="O2" value="19.91" lower_limit="13.63" upper_limit="NA">Sample size too small to get a valid confidence interval.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>More than 3 prior lines of therapy; prior fulvestrant use</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="2"/>
                    <count group_id="O2" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="27.79" lower_limit="NA" upper_limit="NA">Sample size too small to get a valid confidence interval.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.89</p_value>
            <method>Log Rank</method>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>0.82</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.24</ci_lower_limit>
            <ci_upper_limit>2.81</ci_upper_limit>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Response Rate</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; Overall Response Rate(ORR) = (CR + PR)/sample size.</description>
        <time_frame>2 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Neratinib</title>
            <description>Neratinib will be administered orally once daily&#xD;
Neratinib is dosed at 240mg (six 40mg tablets)&#xD;
Neratinib: Neratinib is a recently discovered oral drug that may stop breast cancer cells from growing abnormally by inhibiting (or blocking) members of a family of proteins that include Human Epidermal Growth Factor Receptor 2 (HER2)</description>
          </group>
          <group group_id="O2">
            <title>Neratinib + Fulvestrant</title>
            <description>Neratinib will be administered orally once daily&#xD;
Neratinib is dosed at 240mg (six 40mg tablets)&#xD;
Fulvestrant will be administered intramuscular as an injection (shot) on day 1 and 15 of cycle 1, day 1 of cycle 2, and then on day 1 of each subsequent cycle.&#xD;
Fulvestrant is dosed as 250 mg/5mL (x2) for a total of 500 mg via intramuscular injection (two injections).&#xD;
Neratinib: Neratinib is a recently discovered oral drug that may stop breast cancer cells from growing abnormally by inhibiting (or blocking) members of a family of proteins that include Human Epidermal Growth Factor Receptor 2 (HER2)&#xD;
Fulvestrant: Fulvestrant, works in treating breast cancer that has spread to other parts of the body</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Response Rate</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; Overall Response Rate(ORR) = (CR + PR)/sample size.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Duration Of Responses</title>
        <description>The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started, or death due to any cause. Participants without events reported are censored at the last disease evaluation).</description>
        <time_frame>2 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Neratinib</title>
            <description>Neratinib will be administered orally once daily&#xD;
Neratinib is dosed at 240mg (six 40mg tablets)&#xD;
Neratinib: Neratinib is a recently discovered oral drug that may stop breast cancer cells from growing abnormally by inhibiting (or blocking) members of a family of proteins that include Human Epidermal Growth Factor Receptor 2 (HER2)</description>
          </group>
          <group group_id="O2">
            <title>Neratinib + Fulvestrant</title>
            <description>Neratinib will be administered orally once daily&#xD;
Neratinib is dosed at 240mg (six 40mg tablets)&#xD;
Fulvestrant will be administered intramuscular as an injection (shot) on day 1 and 15 of cycle 1, day 1 of cycle 2, and then on day 1 of each subsequent cycle.&#xD;
Fulvestrant is dosed as 250 mg/5mL (x2) for a total of 500 mg via intramuscular injection (two injections).&#xD;
Neratinib: Neratinib is a recently discovered oral drug that may stop breast cancer cells from growing abnormally by inhibiting (or blocking) members of a family of proteins that include Human Epidermal Growth Factor Receptor 2 (HER2)&#xD;
Fulvestrant: Fulvestrant, works in treating breast cancer that has spread to other parts of the body</description>
          </group>
        </group_list>
        <measure>
          <title>Duration Of Responses</title>
          <description>The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started, or death due to any cause. Participants without events reported are censored at the last disease evaluation).</description>
          <units>months</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" lower_limit="NA" upper_limit="NA">No patient had a response.</measurement>
                    <measurement group_id="O2" value="6.7" lower_limit="NA" upper_limit="NA">There was only one patient who had a response. The duration of response is 6.7 months.</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>38.4 months (3 years and 2 months)</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Neratinib</title>
          <description>Neratinib will be administered orally once daily&#xD;
Neratinib is dosed at 240mg (six 40mg tablets)&#xD;
Neratinib: Neratinib is a recently discovered oral drug that may stop breast cancer cells from growing abnormally by inhibiting (or blocking) members of a family of proteins that include Human Epidermal Growth Factor Receptor 2 (HER2)</description>
        </group>
        <group group_id="E2">
          <title>Neratinib + Fulvestrant</title>
          <description>Neratinib will be administered orally once daily&#xD;
Neratinib is dosed at 240mg (six 40mg tablets)&#xD;
Fulvestrant will be administered intramuscular as an injection (shot) on day 1 and 15 of cycle 1, day 1 of cycle 2, and then on day 1 of each subsequent cycle.&#xD;
Fulvestrant is dosed as 250 mg/5mL (x2) for a total of 500 mg via intramuscular injection (two injections).&#xD;
Neratinib: Neratinib is a recently discovered oral drug that may stop breast cancer cells from growing abnormally by inhibiting (or blocking) members of a family of proteins that include Human Epidermal Growth Factor Receptor 2 (HER2)&#xD;
Fulvestrant: Fulvestrant, works in treating breast cancer that has spread to other parts of the body</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Malaise</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Skin infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>CPK increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Confusion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Acute kidney injury</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Bladder perforation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Hypoxia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Respiratory, thoracic and mediastinal disorders</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Hearing impaired</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Adrenal insufficiency</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Gastroesophageal reflux disease</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Oral pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Flatulence</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Toothache</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Edema limbs</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>General disorders and administration site conditions - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Malaise</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Portal hypertension</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Sinusitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Skin infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Upper respiratory infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Bronchial infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Papulopustular rash</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Paronychia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Fracture</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Investigations - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Hypermagnesemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </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" subjects_affected="3" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Bone pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Neck pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Osteonecrosis of jaw</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Memory impairment</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Peripheral motor neuropathy</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Peripheral sensory neuropathy</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Lethargy</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Confusion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Acute kidney injury</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspareunia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Allergic rhinitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Pneumonitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Sore throat</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Hoarseness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </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" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Skin/subcutaneous tissue disorders; Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Rash acneiform</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hot flashes</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Hematoma</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Jose Pablo Leone, MD</name_or_title>
      <organization>Dana-Farber Cancer Institute</organization>
      <phone>617-632-3800</phone>
      <email>josep_leone@dfci.harvard.edu</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03289039
org study id: 17-318
nct id: NCT03289039
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This research study is studying a drug called Neratinib with and without Fulvestrant as
      possible treatments for HER2-positive breast cancer .

      The interventions involved in this study are:

        -  Neratinib and Fulvestrant

        -  Neratinib alone
This research study is a Phase II clinical trial. Phase II clinical trials test the safety
      and effectiveness of an investigational intervention to learn whether the intervention works
      in treating a specific disease. "Investigational" means that the intervention is being
      studied.

      The FDA (the U.S. Food and Drug Administration) has approved Neratinib as a treatment for
      breast cancer. Fulvestrant has been FDA approved for treatment of metastatic hormone receptor
      positive breast cancer.

      The purpose of this research study is to determine how well neratinib, by itself or together
      with Fulvestrant, works in treating breast cancer that has spread to other parts of the body.
      Neratinib is a recently discovered oral drug that may stop breast cancer cells from growing
      abnormally by inhibiting (or blocking) members of a family of proteins that include Human
      Epidermal Growth Factor Receptor 2 (HER2).

      Neratinib has been used in other research studies and information from those other research
      studies suggests that neratinib may help to shrink or stabilize HER2-positive breast cancer
      in this research study.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Progression Free Survival
time frame: Participants were followed for PFS up to 20.3 months from registration.
description: Progression-Free Survival (PFS) is defined as the time from randomization (or registration) to the earlier of progression or death due to any cause. Participants alive without disease progression are censored at date of last disease evaluation.
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. Disease assessment were conducted at baseline and every two cycles after the first cycle.
measure: Overall Survival
time frame: Participants were followed for up to 38.4 months (3 years and 2 months) from registration to removal from protocol therapy or death.
description: Overall Survival (OS) is defined as the time from randomization (or registration) to death due to any cause, or censored at date last known alive. Participants will be evaluated every 6 months for survival until death. Participants removed from protocol therapy for unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse event.
measure: Overall Response Rate
time frame: 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; Overall Response Rate(ORR) = (CR + PR)/sample size.
measure: Duration Of Responses
time frame: 2 years
description: The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started, or death due to any cause. Participants without events reported are censored at the last disease evaluation).
arm group label: Neratinib
arm group type: Experimental
description: Neratinib will be administered orally once daily
Neratinib is dosed at 240mg (six 40mg tablets)
arm group label: Neratinib + Fulvestrant
arm group type: Experimental
description: Neratinib will be administered orally once daily
Neratinib is dosed at 240mg (six 40mg tablets)
Fulvestrant will be administered intramuscular as an injection (shot) on day 1 and 15 of cycle 1, day 1 of cycle 2, and then on day 1 of each subsequent cycle.
Fulvestrant is dosed as 250 mg/5mL (x2) for a total of 500 mg via intramuscular injection (two injections).
intervention type: Drug
intervention name: Neratinib
description: Neratinib is a recently discovered oral drug that may stop breast cancer cells from growing abnormally by inhibiting (or blocking) members of a family of proteins that include Human Epidermal Growth Factor Receptor 2 (HER2)
arm group label: Neratinib
arm group label: Neratinib + Fulvestrant
other name: Nerlynx
intervention type: Drug
intervention name: Fulvestrant
description: Fulvestrant, works in treating breast cancer that has spread to other parts of the body
arm group label: Neratinib + Fulvestrant
other name: Faslodex
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Jose Leone, MD
role: Principal Investigator
affiliation: Dana-Farber Cancer Institute
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Dana-Farber Cancer Institute
investigator full name: Jose Pablo Leone
investigator title: Principal Investigator
mesh term: Breast Neoplasms
mesh term: Fulvestrant
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 