<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/NCT02260531</url>
  </required_header>
  <id_info>
    <org_study_id>14-359</org_study_id>
    <nct_id>NCT02260531</nct_id>
  </id_info>
  <brief_title>Cabozantinib +/- Trastuzumab In Breast Cancer Patients w/ Brain Metastases</brief_title>
  <official_title>A Phase II Study of Cabozantinib Alone or in Combination With Trastuzumab in Breast Cancer Patients With Brain Metastases</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Dana-Farber Cancer Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Exelixis</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Genentech, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Dana-Farber Cancer Institute</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This research study is evaluating the effectiveness of the drug called cabozantinib (alone or&#xD;
      in combination with trastuzumab) as a possible treatment for advanced breast cancer in which&#xD;
      the cancer has spread to the brain.&#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 not approved cabozantinib for your&#xD;
      specific disease but it has been approved for other uses.&#xD;
&#xD;
      Few treatments exist for brain metastases from breast cancer. Radiation and surgery are&#xD;
      generally included as a possible standard of care treatments for this diagnosis.&#xD;
&#xD;
      In this research study, the investigator are looking at how well cabozantinib works in&#xD;
      treating breast cancer that has spread to the brain. Cabozantinib has been used in some phase&#xD;
      I studies and information from those other research studies suggests that cabozantinib may&#xD;
      help to shrink or stabilize the participant's breast cancer. In addition, information from&#xD;
      these studies has shown that cabozantinib may pass through the blood brain barrier (a&#xD;
      protective layer that prevents most large molecules and cells found in the blood from&#xD;
      entering the brain tissue) and may be an effective treatment for brain metastases.&#xD;
&#xD;
      If the participant has HER2-positive breast cancer, they will receive trastuzumab in addition&#xD;
      to cabozantinib. Trastuzumab is an FDA approved drug for the treatment of HER2-positive&#xD;
      metastatic breast cancer. However, the combination of cabozantinib and trastuzumab has not&#xD;
      yet been tested. Trastuzumab may help to shrink or stabilize breast cancer in combination&#xD;
      with cabozantinib. If the participant's breast cancer is HER2-negative, they will not receive&#xD;
      trastuzumab as part of this clinical trial.&#xD;
&#xD;
      The names of the study interventions involved in this study are:&#xD;
&#xD;
        -  Cabozantinib (XL184)&#xD;
&#xD;
        -  Trastuzumab (herceptin) (participants with HER2-positive disease only)&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 2014</start_date>
  <completion_date type="Actual">March 17, 2020</completion_date>
  <primary_completion_date type="Actual">January 4, 2019</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>CNS Objective Response Rate (ORR)</measure>
    <time_frame>Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion of 6 cycles could reduce frequency of assessments to every 3 cycles. Response was evaluated up to 25 months.</time_frame>
    <description>The central nervous system (CNS) ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria in the evaluation CNS lesions on treatment: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>CNS Volumetric Objective Response Rate (ORR)</measure>
    <time_frame>Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion of 6 cycles could reduce frequency of assessments to every 3 cycles. Response was evaluated up to 25 months .</time_frame>
    <description>CNS volumetric ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) defined as:&#xD;
CR&#xD;
Complete resolution of all measurable (≥ 1 cm diameter) and non-measurable brain metastases&#xD;
No new CNS lesions (new lesion defined as ≥ 6 mm diameter) PR&#xD;
≥ 50% reduction in the volumetric sum of all measurable (≥ 1 cm diameter) brain metastases compared to baseline&#xD;
No progression of non-measurable lesions&#xD;
No new lesions (new lesion defined as ≥ 6 mm)&#xD;
ORR also requires:&#xD;
Stable or decreasing steroid dose&#xD;
No new/progressive tumor-related neurologic signs or symptoms</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Non-CNS Objective Response Rate (ORR)</measure>
    <time_frame>Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion of 6 cycles could reduce frequency of assessments to every 3 cycles. Response was evaluated up to 25 months.</time_frame>
    <description>The non-central nervous system (CNS) ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria in the evaluation non-CNS lesions on treatment: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median Progression-Free Survival (PFS)</measure>
    <time_frame>Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. Follow-up time is up to 25 months.</time_frame>
    <description>Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) or death. Per RECIST 1.1 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>12-Week Clinical Benefit Rate</measure>
    <time_frame>Evaluate at 12 weeks.</time_frame>
    <description>Clinical benefit rate (CBR) was defined as the percentage of patients achieving complete response (CR), partial response (PR), or stable disease (SD) based on RECIST 1.1 criteria by 12 weeks. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PD is at least a 20% increase in sum LD of target lesions (smallest sum LD reference), new lesions, and/or unequivocal progression of existing non-target lesions. Stable disease (SD) is defined as any condition not meeting the above criteria.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>First Progression Site</measure>
    <time_frame>Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. Follow-up time is up to 25 months.</time_frame>
    <description>Site that a patient has his/her first tumor progression (CNS vs Non-CNS)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>Off-treatment patients followed every 6 months until death. Follow-up time is up to 25 months.</time_frame>
    <description>OS based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of Grade 4 Treatment-Related Toxicity</measure>
    <time_frame>Participants should be re-evaluated for response every 6 weeks. Patients with stable or responsive disease after completion of 6 cycles may have the frequency of scans reduced to once every 3 cycles, and in long-term follow-up every 6 months until death.</time_frame>
    <description>All grade 4 adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv4 as reported on case report forms were counted. Incidence is the number of patients experiencing at least one treatment-related grade 4 AE of any type during the time of observation.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">36</enrollment>
  <condition>Breast Cancer</condition>
  <condition>Brain Tumor - Metastatic</condition>
  <arm_group>
    <arm_group_label>Cohort 1 - Cabozantinib, Trastuzumab for HER2+</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>HER2-positive&#xD;
Cabozantinib- orally administered daily per treatment cycle, 60 mg per day&#xD;
Trastuzumab- IV administered once per cycle, 8 mg/kg IV loading dose followed by 6 mg/kg IV Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 2 - Cabozantinib for ER+ and/or PR+</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Hormone receptor-positive (ER+ and/or PR+)&#xD;
- Cabozantinib- orally administered daily per treatment cycle, 60 mg per day Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 3 - Cabozantinib for ER-, PR-, HER2-</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Triple negative (ER-, PR-, HER2-)&#xD;
- Cabozantinib- orally administered daily per treatment cycle, 60 mg per day Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cabozantinib</intervention_name>
    <arm_group_label>Cohort 1 - Cabozantinib, Trastuzumab for HER2+</arm_group_label>
    <arm_group_label>Cohort 2 - Cabozantinib for ER+ and/or PR+</arm_group_label>
    <arm_group_label>Cohort 3 - Cabozantinib for ER-, PR-, HER2-</arm_group_label>
    <other_name>Cometriq®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Trastuzumab</intervention_name>
    <arm_group_label>Cohort 1 - Cabozantinib, Trastuzumab for HER2+</arm_group_label>
    <other_name>Herceptin</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must have histologically or cytologically confirmed invasive breast cancer,&#xD;
             with stage IV disease.&#xD;
&#xD;
          -  New or progressive CNS lesions, as assessed by the patient's treating physician.&#xD;
&#xD;
          -  For patients who have received prior cranial radiation, no increase in corticosteroid&#xD;
             dose in the week prior to the baseline brain MRI&#xD;
&#xD;
          -  Discontinued prior therapy (with the exception of trastuzumab for patients with HER2+&#xD;
             breast cancer)&#xD;
&#xD;
          -  Recovery to baseline or ≤ Grade 1 CTCAE v.4.0 from toxicities related to any prior&#xD;
             treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive&#xD;
             therapy;&#xD;
&#xD;
          -  The subject has an ECOG performance status of 0 or 1&#xD;
&#xD;
          -  Patients must have normal organ and marrow function and laboratory values as follows&#xD;
             within 14 days before the first dose of cabozantinib&#xD;
&#xD;
          -  Sexually active subjects (men and women) must agree to use medically accepted barrier&#xD;
             methods of contraception (e.g., male or female condom) during the course of the study&#xD;
             and for 4 months after the last dose of study drug(s)&#xD;
&#xD;
          -  Subjects of childbearing potential must not be pregnant at screening.&#xD;
&#xD;
          -  Patients on bisphosphonates may continue receiving bisphosphonate therapy during&#xD;
             study. Patients wanting to initiate bisphosphonate therapy may do so.&#xD;
&#xD;
          -  The subject has had an assessment of all known disease sites eg, by computerized&#xD;
             tomography (CT) scan, magnetic resonance imaging (MRI), bone scan as appropriate,&#xD;
             within 28 days before the first dose of cabozantinib&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  The subject has received cabozantinib or another c-Met inhibitor (please note ARQ 197&#xD;
             is not considered a MET inhibitor for purposes of this study given data to suggest it&#xD;
             inhibits tubulin)&#xD;
&#xD;
          -  The subject has uncontrolled, significant intercurrent or recent illness&#xD;
&#xD;
          -  Leptomeningeal disease as the only site of CNS involvement&#xD;
&#xD;
          -  Known contraindication to MRI with gadolinium contrast, such as cardiac pacemaker,&#xD;
             shrapnel, or ocular foreign body&#xD;
&#xD;
          -  More than 2 seizures over the last 4 weeks prior to study entry&#xD;
&#xD;
          -  Grade 1 or higher CNS hemorrhage on baseline brain MRI, or history of grade 2 or&#xD;
             higher CNS hemorrhage within 12 months&#xD;
&#xD;
          -  Has experienced clinically-significant GI bleeding within 6 months before first dose&#xD;
             of cabozantinib; hemoptysis of ≥ 0.5 teaspoon (2.5ml) of red blood within 3 months&#xD;
             before the first dose of cabozantinib; any other signs indicative of pulmonary&#xD;
             hemorrhage within 3 months before the first dose of cabozantinib&#xD;
&#xD;
          -  The subject has tumor in contact with, invading or encasing any major blood vessels&#xD;
&#xD;
          -  The subject has evidence of tumor invading the GI tract (esophagus, stomach, small or&#xD;
             large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor&#xD;
             within 28 days before the first dose of cabozantinib&#xD;
&#xD;
          -  The subject requires concomitant treatment, in therapeutic doses, with anticoagulants.&#xD;
             Low dose aspirin (≤ 81 mg/day), low-dose warfarin ( ≤1 mg/day), and prophylactic LMWH&#xD;
             are permitted.&#xD;
&#xD;
          -  The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT) test&#xD;
             ≥1.3 × the laboratory ULN within 7 days before the first dose of cabozantinib.&#xD;
&#xD;
          -  Inability to swallow intact tablets&#xD;
&#xD;
          -  Pregnant or lactating females&#xD;
&#xD;
          -  Diagnosis of another malignancy within 2 years before the first dose of cabozantinib,&#xD;
             except for superficial skin cancers, or localized, low grade tumors deemed cured and&#xD;
             not treated with systemic therapy&#xD;
&#xD;
          -  Subjects with clinically relevant ongoing complications from prior radiation therapy&#xD;
             are not eligible&#xD;
&#xD;
          -  The subject is known to be positive for the human immunodeficiency virus (HIV)&#xD;
&#xD;
          -  Subjects with clinically relevant ongoing complications from prior surgery are not&#xD;
             eligible&#xD;
&#xD;
          -  QTcF &gt; 500 msec on average of screening EKGs performed within 28 days of first dose of&#xD;
             cabozantinib. Three EKGs must be performed at screening. If the average of these three&#xD;
             consecutive results for QTcF is &gt; 500 msec, the subject is ineligible.&#xD;
&#xD;
          -  Active infection requiring IV antibiotics at Day 1 of cycle 1&#xD;
&#xD;
          -  No prior lapatinib within 7 days prior to initiation of protocol treatment&#xD;
&#xD;
          -  Receive concurrent investigational agents while on study&#xD;
&#xD;
          -  Receive any concurrent chemotherapy, radiotherapy, or hormonal therapy while on study&#xD;
&#xD;
          -  Previously identified allergy or hypersensitivity to components of the cabozantinib&#xD;
             formulations&#xD;
&#xD;
          -  The subject requires chronic concomitant treatment with strong CYP3A4 inducers&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Sara Tolaney, MD, MPH</last_name>
    <role>Principal Investigator</role>
    <affiliation>Dana-Farber Cancer Institute</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Massachusetts General Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dana-Farber Cancer Institute</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2021</verification_date>
  <study_first_submitted>September 17, 2014</study_first_submitted>
  <study_first_submitted_qc>October 6, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 9, 2014</study_first_posted>
  <results_first_submitted>February 24, 2021</results_first_submitted>
  <results_first_submitted_qc>April 27, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">May 18, 2021</results_first_posted>
  <last_update_submitted>May 18, 2021</last_update_submitted>
  <last_update_submitted_qc>May 18, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">May 20, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Dana-Farber Cancer Institute</investigator_affiliation>
    <investigator_full_name>Sara Tolaney</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Metastatic breast cancer and brain metastases</keyword>
  <keyword>HER-2 Positive Breast Cancer</keyword>
  <keyword>ER-Positive PR-Positive HER-2 Negative Breast Cancer</keyword>
  <keyword>ER-Negative PR-Negative HER2-Negative Breast Cancer</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
    <mesh_term>Neoplasm Metastasis</mesh_term>
    <mesh_term>Brain Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Trastuzumab</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>July 17, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/31/NCT02260531/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>36 patients were enrolled between November 2014 and June 2018</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Cohort 1 - Cabozantinib, Trastuzumab for HER2+</title>
          <description>HER2-positive&#xD;
Cabozantinib- orally administered daily per treatment cycle&#xD;
Trastuzumab- IV administered once per cycle&#xD;
MRI- Baseline, Cycle 2 Day 1, and every 2 cycles&#xD;
Magnetic Resonance Angiography (MRA ), Baseline, Cycle 2 Day 1,&#xD;
Cabozantinib: One, 60 mg tablet daily of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops.&#xD;
Trastuzumab: For HER2-Positive participants only. Administered by IV on day 1 of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops.</description>
        </group>
        <group group_id="P2">
          <title>Cohort 2 - Cabozantinib for ER+ and/or PR+</title>
          <description>Hormone receptor-positive (ER+ and/or PR+)&#xD;
Cabozantinib- orally administered daily per treatment cycle&#xD;
MRI- Baseline, Cycle 2 Day 1, and every 2 cycles&#xD;
Magnetic Resonance Angiography (MRA ), Baseline, Cycle 2 Day 1,&#xD;
Cabozantinib: One, 60 mg tablet daily of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops.</description>
        </group>
        <group group_id="P3">
          <title>Cohort 3 - Cabozantinib for ER-, PR-, HER2-</title>
          <description>Triple negative (ER-, PR-, HER2-)&#xD;
Cabozantinib- orally administered daily per treatment cycle&#xD;
MRI- Baseline, Cycle 2 Day 1, and every 2 cycles&#xD;
Magnetic Resonance Angiography (MRA ), Baseline, Cycle 2 Day 1,&#xD;
Cabozantinib: One, 60 mg tablet daily of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="21"/>
                <participants group_id="P2" count="7"/>
                <participants group_id="P3" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="21"/>
                <participants group_id="P2" count="7"/>
                <participants group_id="P3" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Cohort 1 - Cabozantinib, Trastuzumab for HER2+</title>
          <description>HER2-positive&#xD;
Cabozantinib- orally administered daily per treatment cycle&#xD;
Trastuzumab- IV administered once per cycle&#xD;
MRI- Baseline, Cycle 2 Day 1, and every 2 cycles&#xD;
Magnetic Resonance Angiography (MRA ), Baseline, Cycle 2 Day 1,&#xD;
Cabozantinib: One, 60 mg tablet daily of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops.&#xD;
Trastuzumab: For HER2-Positive participants only. Administered by IV on day 1 of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops.</description>
        </group>
        <group group_id="B2">
          <title>Cohort 2 - Cabozantinib for ER+ and/or PR+</title>
          <description>Hormone receptor-positive (ER+ and/or PR+)&#xD;
Cabozantinib- orally administered daily per treatment cycle&#xD;
MRI- Baseline, Cycle 2 Day 1, and every 2 cycles&#xD;
Magnetic Resonance Angiography (MRA ), Baseline, Cycle 2 Day 1,&#xD;
Cabozantinib: One, 60 mg tablet daily of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops.</description>
        </group>
        <group group_id="B3">
          <title>Cohort 3 - Cabozantinib for ER-, PR-, HER2-</title>
          <description>Triple negative (ER-, PR-, HER2-)&#xD;
Cabozantinib- orally administered daily per treatment cycle&#xD;
MRI- Baseline, Cycle 2 Day 1, and every 2 cycles&#xD;
Magnetic Resonance Angiography (MRA ), Baseline, Cycle 2 Day 1,&#xD;
Cabozantinib: One, 60 mg tablet daily of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops.</description>
        </group>
        <group group_id="B4">
          <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="21"/>
            <count group_id="B2" value="7"/>
            <count group_id="B3" value="8"/>
            <count group_id="B4" value="36"/>
          </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="52" lower_limit="28" upper_limit="69"/>
                    <measurement group_id="B2" value="48" lower_limit="40" upper_limit="62"/>
                    <measurement group_id="B3" value="48" lower_limit="33" upper_limit="62"/>
                    <measurement group_id="B4" value="50" lower_limit="28" upper_limit="69"/>
                  </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="21"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="8"/>
                    <measurement group_id="B4" value="36"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_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>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="19"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="8"/>
                    <measurement group_id="B4" value="32"/>
                  </measurement_list>
                </category>
                <category>
                  <title>African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="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="0"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="21"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="8"/>
                    <measurement group_id="B4" value="36"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Prior anti-HER2 therapy-Trastuzumab</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="21"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="21"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Prior anti-HER2 therapy-Lapatinib</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>ECOG performance status</title>
          <description>ECOG performance status:&#xD;
0 - Normal activity. Fully active, able to carry on all pre-disease performance without restriction.&#xD;
1 - Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature (e.g., light housework, office work).</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>0</title>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="17"/>
                  </measurement_list>
                </category>
                <category>
                  <title>1</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="7"/>
                    <measurement group_id="B4" value="19"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Prior Stereotactic radiosurgery</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="7"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="12"/>
                  </measurement_list>
                </category>
                <category>
                  <title>No</title>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="7"/>
                    <measurement group_id="B4" value="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Prior Whole brain radiation</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="16"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="25"/>
                  </measurement_list>
                </category>
                <category>
                  <title>No</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>No Prior CNS radiation</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Surgical resection of CNS metastasis</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="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>No</title>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="6"/>
                    <measurement group_id="B4" value="32"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sites of metastatic disease</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Lung</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="14"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Liver</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Bone</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Breast (Ipsilateral or Contralateral) or chest wall</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Lymph nodes</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Number of sites of metastases at study entry</title>
          <units>Sites</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2" lower_limit="1" upper_limit="4"/>
                    <measurement group_id="B2" value="1" lower_limit="1" upper_limit="3"/>
                    <measurement group_id="B3" value="2" lower_limit="1" upper_limit="3"/>
                    <measurement group_id="B4" value="2" lower_limit="1" upper_limit="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>CNS Objective Response Rate (ORR)</title>
        <description>The central nervous system (CNS) ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria in the evaluation CNS lesions on treatment: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.</description>
        <time_frame>Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion of 6 cycles could reduce frequency of assessments to every 3 cycles. Response was evaluated up to 25 months.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1 - Cabozantinib, Trastuzumab for HER2+</title>
            <description>HER2-positive&#xD;
Cabozantinib- orally administered daily per treatment cycle&#xD;
Trastuzumab- IV administered once per cycle&#xD;
MRI- Baseline, Cycle 2 Day 1, and every 2 cycles&#xD;
Magnetic Resonance Angiography (MRA ), Baseline, Cycle 2 Day 1,&#xD;
Cabozantinib: One, 60 mg tablet daily of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops.&#xD;
Trastuzumab: For HER2-Positive participants only. Administered by IV on day 1 of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops.</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2 - Cabozantinib for ER+ and/or PR+</title>
            <description>Hormone receptor-positive (ER+ and/or PR+)&#xD;
Cabozantinib- orally administered daily per treatment cycle&#xD;
MRI- Baseline, Cycle 2 Day 1, and every 2 cycles&#xD;
Magnetic Resonance Angiography (MRA ), Baseline, Cycle 2 Day 1,&#xD;
Cabozantinib: One, 60 mg tablet daily of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops.</description>
          </group>
          <group group_id="O3">
            <title>Cohort 3 - Cabozantinib for ER-, PR-, HER2-</title>
            <description>Triple negative (ER-, PR-, HER2-)&#xD;
Cabozantinib- orally administered daily per treatment cycle&#xD;
MRI- Baseline, Cycle 2 Day 1, and every 2 cycles&#xD;
Magnetic Resonance Angiography (MRA ), Baseline, Cycle 2 Day 1,&#xD;
Cabozantinib: One, 60 mg tablet daily of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops.</description>
          </group>
        </group_list>
        <measure>
          <title>CNS Objective Response Rate (ORR)</title>
          <description>The central nervous system (CNS) ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria in the evaluation CNS lesions on treatment: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.</description>
          <units>percentage of participants</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="21"/>
                <count group_id="O2" value="7"/>
                <count group_id="O3" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5" lower_limit=".2" upper_limit="24"/>
                    <measurement group_id="O2" value="14" lower_limit=".4" upper_limit="58"/>
                    <measurement group_id="O3" value="0" lower_limit="0" upper_limit="37"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>CNS Volumetric Objective Response Rate (ORR)</title>
        <description>CNS volumetric ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) defined as:&#xD;
CR&#xD;
Complete resolution of all measurable (≥ 1 cm diameter) and non-measurable brain metastases&#xD;
No new CNS lesions (new lesion defined as ≥ 6 mm diameter) PR&#xD;
≥ 50% reduction in the volumetric sum of all measurable (≥ 1 cm diameter) brain metastases compared to baseline&#xD;
No progression of non-measurable lesions&#xD;
No new lesions (new lesion defined as ≥ 6 mm)&#xD;
ORR also requires:&#xD;
Stable or decreasing steroid dose&#xD;
No new/progressive tumor-related neurologic signs or symptoms</description>
        <time_frame>Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion of 6 cycles could reduce frequency of assessments to every 3 cycles. Response was evaluated up to 25 months .</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1 - Cabozantinib, Trastuzumab for HER2+</title>
            <description>HER2-positive&#xD;
Cabozantinib- orally administered daily per treatment cycle, 60 mg per day&#xD;
Trastuzumab- IV administered once per cycle, 8 mg/kg IV loading dose followed by 6 mg/kg IV Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2 - Cabozantinib for ER+ and/or PR+</title>
            <description>Hormone receptor-positive (ER+ and/or PR+)&#xD;
- Cabozantinib- orally administered daily per treatment cycle, 60 mg per day Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.</description>
          </group>
          <group group_id="O3">
            <title>Cohort 3 - Cabozantinib for ER-, PR-, HER2-</title>
            <description>Triple negative (ER-, PR-, HER2-)&#xD;
- Cabozantinib- orally administered daily per treatment cycle, 60 mg per day Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.</description>
          </group>
        </group_list>
        <measure>
          <title>CNS Volumetric Objective Response Rate (ORR)</title>
          <description>CNS volumetric ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) defined as:&#xD;
CR&#xD;
Complete resolution of all measurable (≥ 1 cm diameter) and non-measurable brain metastases&#xD;
No new CNS lesions (new lesion defined as ≥ 6 mm diameter) PR&#xD;
≥ 50% reduction in the volumetric sum of all measurable (≥ 1 cm diameter) brain metastases compared to baseline&#xD;
No progression of non-measurable lesions&#xD;
No new lesions (new lesion defined as ≥ 6 mm)&#xD;
ORR also requires:&#xD;
Stable or decreasing steroid dose&#xD;
No new/progressive tumor-related neurologic signs or symptoms</description>
          <units>percentage of participants</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="21"/>
                <count group_id="O2" value="7"/>
                <count group_id="O3" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5" lower_limit="0.2" upper_limit="24"/>
                    <measurement group_id="O2" value="0" lower_limit="0" upper_limit="41"/>
                    <measurement group_id="O3" value="0" lower_limit="0" upper_limit="37"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Non-CNS Objective Response Rate (ORR)</title>
        <description>The non-central nervous system (CNS) ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria in the evaluation non-CNS lesions on treatment: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.</description>
        <time_frame>Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion of 6 cycles could reduce frequency of assessments to every 3 cycles. Response was evaluated up to 25 months.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1 - Cabozantinib, Trastuzumab for HER2+</title>
            <description>HER2-positive&#xD;
Cabozantinib- orally administered daily per treatment cycle&#xD;
Trastuzumab- IV administered once per cycle&#xD;
MRI- Baseline, Cycle 2 Day 1, and every 2 cycles&#xD;
Magnetic Resonance Angiography (MRA ), Baseline, Cycle 2 Day 1,&#xD;
Cabozantinib: One, 60 mg tablet daily of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops.&#xD;
Trastuzumab: For HER2-Positive participants only. Administered by IV on day 1 of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops.</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2 - Cabozantinib for ER+ and/or PR+</title>
            <description>Hormone receptor-positive (ER+ and/or PR+)&#xD;
Cabozantinib- orally administered daily per treatment cycle&#xD;
MRI- Baseline, Cycle 2 Day 1, and every 2 cycles&#xD;
Magnetic Resonance Angiography (MRA ), Baseline, Cycle 2 Day 1,&#xD;
Cabozantinib: One, 60 mg tablet daily of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops.</description>
          </group>
          <group group_id="O3">
            <title>Cohort 3 - Cabozantinib for ER-, PR-, HER2-</title>
            <description>Triple negative (ER-, PR-, HER2-)&#xD;
Cabozantinib- orally administered daily per treatment cycle&#xD;
MRI- Baseline, Cycle 2 Day 1, and every 2 cycles&#xD;
Magnetic Resonance Angiography (MRA ), Baseline, Cycle 2 Day 1,&#xD;
Cabozantinib: One, 60 mg tablet daily of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops.</description>
          </group>
        </group_list>
        <measure>
          <title>Non-CNS Objective Response Rate (ORR)</title>
          <description>The non-central nervous system (CNS) ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria in the evaluation non-CNS lesions on treatment: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.</description>
          <units>percentage of participants</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="21"/>
                <count group_id="O2" value="7"/>
                <count group_id="O3" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0" lower_limit="0" upper_limit="16"/>
                    <measurement group_id="O2" value="0" lower_limit="0" upper_limit="41"/>
                    <measurement group_id="O3" value="0" lower_limit="0" upper_limit="37"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Median Progression-Free Survival (PFS)</title>
        <description>Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) or death. Per RECIST 1.1 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.</description>
        <time_frame>Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. Follow-up time is up to 25 months.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1 - Cabozantinib, Trastuzumab for HER2+</title>
            <description>HER2-positive&#xD;
Cabozantinib- orally administered daily per treatment cycle&#xD;
Trastuzumab- IV administered once per cycle&#xD;
MRI- Baseline, Cycle 2 Day 1, and every 2 cycles&#xD;
Magnetic Resonance Angiography (MRA ), Baseline, Cycle 2 Day 1,&#xD;
Cabozantinib: One, 60 mg tablet daily of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops.&#xD;
Trastuzumab: For HER2-Positive participants only. Administered by IV on day 1 of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops.</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2 - Cabozantinib for ER+ and/or PR+</title>
            <description>Hormone receptor-positive (ER+ and/or PR+)&#xD;
Cabozantinib- orally administered daily per treatment cycle&#xD;
MRI- Baseline, Cycle 2 Day 1, and every 2 cycles&#xD;
Magnetic Resonance Angiography (MRA ), Baseline, Cycle 2 Day 1,&#xD;
Cabozantinib: One, 60 mg tablet daily of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops.</description>
          </group>
          <group group_id="O3">
            <title>Cohort 3 - Cabozantinib for ER-, PR-, HER2-</title>
            <description>Triple negative (ER-, PR-, HER2-)&#xD;
Cabozantinib- orally administered daily per treatment cycle&#xD;
MRI- Baseline, Cycle 2 Day 1, and every 2 cycles&#xD;
Magnetic Resonance Angiography (MRA ), Baseline, Cycle 2 Day 1,&#xD;
Cabozantinib: One, 60 mg tablet daily of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops.</description>
          </group>
        </group_list>
        <measure>
          <title>Median Progression-Free Survival (PFS)</title>
          <description>Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) or death. Per RECIST 1.1 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.</description>
          <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="21"/>
                <count group_id="O2" value="7"/>
                <count group_id="O3" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.1" lower_limit="2.8" upper_limit="6.2"/>
                    <measurement group_id="O2" value="0.8" lower_limit="0.5" upper_limit="NA">Insufficient number of participants with events</measurement>
                    <measurement group_id="O3" value="2.4" lower_limit="2.0" upper_limit="NA">Insufficient number of participants with events</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>12-Week Clinical Benefit Rate</title>
        <description>Clinical benefit rate (CBR) was defined as the percentage of patients achieving complete response (CR), partial response (PR), or stable disease (SD) based on RECIST 1.1 criteria by 12 weeks. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PD is at least a 20% increase in sum LD of target lesions (smallest sum LD reference), new lesions, and/or unequivocal progression of existing non-target lesions. Stable disease (SD) is defined as any condition not meeting the above criteria.</description>
        <time_frame>Evaluate at 12 weeks.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1 - Cabozantinib, Trastuzumab for HER2+</title>
            <description>HER2-positive&#xD;
Cabozantinib- orally administered daily per treatment cycle&#xD;
Trastuzumab- IV administered once per cycle&#xD;
MRI- Baseline, Cycle 2 Day 1, and every 2 cycles&#xD;
Magnetic Resonance Angiography (MRA ), Baseline, Cycle 2 Day 1,&#xD;
Cabozantinib: One, 60 mg tablet daily of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops.&#xD;
Trastuzumab: For HER2-Positive participants only. Administered by IV on day 1 of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops.</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2 - Cabozantinib for ER+ and/or PR+</title>
            <description>Hormone receptor-positive (ER+ and/or PR+)&#xD;
Cabozantinib- orally administered daily per treatment cycle&#xD;
MRI- Baseline, Cycle 2 Day 1, and every 2 cycles&#xD;
Magnetic Resonance Angiography (MRA ), Baseline, Cycle 2 Day 1,&#xD;
Cabozantinib: One, 60 mg tablet daily of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops.</description>
          </group>
          <group group_id="O3">
            <title>Cohort 3 - Cabozantinib for ER-, PR-, HER2-</title>
            <description>Triple negative (ER-, PR-, HER2-)&#xD;
Cabozantinib- orally administered daily per treatment cycle&#xD;
MRI- Baseline, Cycle 2 Day 1, and every 2 cycles&#xD;
Magnetic Resonance Angiography (MRA ), Baseline, Cycle 2 Day 1,&#xD;
Cabozantinib: One, 60 mg tablet daily of each 21 day cycle. Number of Cycles: until progression or unacceptable toxicity develops.</description>
          </group>
        </group_list>
        <measure>
          <title>12-Week Clinical Benefit Rate</title>
          <description>Clinical benefit rate (CBR) was defined as the percentage of patients achieving complete response (CR), partial response (PR), or stable disease (SD) based on RECIST 1.1 criteria by 12 weeks. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PD is at least a 20% increase in sum LD of target lesions (smallest sum LD reference), new lesions, and/or unequivocal progression of existing non-target lesions. Stable disease (SD) is defined as any condition not meeting the above criteria.</description>
          <units>percentage of participants</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="21"/>
                <count group_id="O2" value="7"/>
                <count group_id="O3" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="43" lower_limit="24" upper_limit="63"/>
                    <measurement group_id="O2" value="14" lower_limit="0.4" upper_limit="58"/>
                    <measurement group_id="O3" value="13" lower_limit="1" upper_limit="47"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>First Progression Site</title>
        <description>Site that a patient has his/her first tumor progression (CNS vs Non-CNS)</description>
        <time_frame>Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. Follow-up time is up to 25 months.</time_frame>
        <population>Data was not collected</population>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1 - Cabozantinib, Trastuzumab for HER2+</title>
            <description>HER2-positive&#xD;
Cabozantinib- orally administered daily per treatment cycle, 60 mg per day&#xD;
Trastuzumab- IV administered once per cycle, 8 mg/kg IV loading dose followed by 6 mg/kg IV Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.&#xD;
Trastuzumab</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2 - Cabozantinib for ER+ and/or PR+</title>
            <description>Hormone receptor-positive (ER+ and/or PR+)&#xD;
- Cabozantinib- orally administered daily per treatment cycle, 60 mg per day Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.</description>
          </group>
          <group group_id="O3">
            <title>Cohort 3 - Cabozantinib for ER-, PR-, HER2-</title>
            <description>Triple negative (ER-, PR-, HER2-)&#xD;
- Cabozantinib- orally administered daily per treatment cycle, 60 mg per day Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.</description>
          </group>
        </group_list>
        <measure>
          <title>First Progression Site</title>
          <description>Site that a patient has his/her first tumor progression (CNS vs Non-CNS)</description>
          <population>Data was not collected</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
                <count group_id="O3" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival (OS)</title>
        <description>OS based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive.</description>
        <time_frame>Off-treatment patients followed every 6 months until death. Follow-up time is up to 25 months.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1 - Cabozantinib, Trastuzumab for HER2+</title>
            <description>HER2-positive&#xD;
Cabozantinib- orally administered daily per treatment cycle&#xD;
Trastuzumab- IV administered once per cycle&#xD;
MRI- Baseline, Cycle 2 Day 1, and every 2 cycles&#xD;
Magnetic Resonance Angiography (MRA ), Baseline, Cycle 2 Day 1,</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2 - Cabozantinib for ER+ and/or PR+</title>
            <description>Hormone receptor-positive (ER+ and/or PR+)&#xD;
Cabozantinib- orally administered daily per treatment cycle&#xD;
MRI- Baseline, Cycle 2 Day 1, and every 2 cycles&#xD;
Magnetic Resonance Angiography (MRA ), Baseline, Cycle 2 Day 1,</description>
          </group>
          <group group_id="O3">
            <title>Cohort 3 - Cabozantinib for ER-, PR-, HER2-</title>
            <description>Triple negative (ER-, PR-, HER2-)&#xD;
Cabozantinib- orally administered daily per treatment cycle&#xD;
MRI- Baseline, Cycle 2 Day 1, and every 2 cycles&#xD;
Magnetic Resonance Angiography (MRA ), Baseline, Cycle 2 Day 1,</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival (OS)</title>
          <description>OS based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive.</description>
          <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="21"/>
                <count group_id="O2" value="7"/>
                <count group_id="O3" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13.8" lower_limit="8.2" upper_limit="NA">Insufficient number of participants with events</measurement>
                    <measurement group_id="O2" value="NA" lower_limit="NA" upper_limit="NA">Insufficient number of participants with events</measurement>
                    <measurement group_id="O3" value="5.1" lower_limit="2.1" upper_limit="NA">Insufficient number of participants with events</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Incidence of Grade 4 Treatment-Related Toxicity</title>
        <description>All grade 4 adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv4 as reported on case report forms were counted. Incidence is the number of patients experiencing at least one treatment-related grade 4 AE of any type during the time of observation.</description>
        <time_frame>Participants should be re-evaluated for response every 6 weeks. Patients with stable or responsive disease after completion of 6 cycles may have the frequency of scans reduced to once every 3 cycles, and in long-term follow-up every 6 months until death.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Cohort 1 - Cabozantinib, Trastuzumab for HER2+</title>
            <description>HER2-positive&#xD;
Cabozantinib- orally administered daily per treatment cycle, 60 mg per day&#xD;
Trastuzumab- IV administered once per cycle, 8 mg/kg IV loading dose followed by 6 mg/kg IV Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.</description>
          </group>
          <group group_id="O2">
            <title>Cohort 2 - Cabozantinib for ER+ and/or PR+</title>
            <description>Hormone receptor-positive (ER+ and/or PR+)&#xD;
- Cabozantinib- orally administered daily per treatment cycle, 60 mg per day Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.</description>
          </group>
          <group group_id="O3">
            <title>Cohort 3 - Cabozantinib for ER-, PR-, HER2-</title>
            <description>Triple negative (ER-, PR-, HER2-)&#xD;
- Cabozantinib- orally administered daily per treatment cycle, 60 mg per day Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.</description>
          </group>
        </group_list>
        <measure>
          <title>Incidence of Grade 4 Treatment-Related Toxicity</title>
          <description>All grade 4 adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv4 as reported on case report forms were counted. Incidence is the number of patients experiencing at least one treatment-related grade 4 AE of any type during the time of observation.</description>
          <units>participants</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="21"/>
                <count group_id="O2" value="7"/>
                <count group_id="O3" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4" lower_limit="1.05" upper_limit="8.82"/>
                    <measurement group_id="O2" value="0" lower_limit="0" upper_limit="2.87"/>
                    <measurement group_id="O3" value="0" lower_limit="0" upper_limit="2.96"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death.</time_frame>
      <desc>All toxicities should be graded according to the Common Terminology Criteria for Adverse Events (Version 4.0)</desc>
      <group_list>
        <group group_id="E1">
          <title>Cohort 1 - Cabozantinib, Trastuzumab for HER2+</title>
          <description>HER2-positive&#xD;
Cabozantinib- orally administered daily per treatment cycle, 60 mg per day&#xD;
Trastuzumab- IV administered once per cycle, 8 mg/kg IV loading dose followed by 6 mg/kg IV Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.</description>
        </group>
        <group group_id="E2">
          <title>Cohort 2 - Cabozantinib for ER+ and/or PR+</title>
          <description>Hormone receptor-positive (ER+ and/or PR+)&#xD;
- Cabozantinib- orally administered daily per treatment cycle, 60 mg per day Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.</description>
        </group>
        <group group_id="E3">
          <title>Cohort 3 - Cabozantinib for ER-, PR-, HER2-</title>
          <description>Triple negative (ER-, PR-, HER2-)&#xD;
- Cabozantinib- orally administered daily per treatment cycle, 60 mg per day Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.</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="11" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="8" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="6" 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="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" 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="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Portal vein thrombosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Ejection fraction decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Lipase increased</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Serum amylase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Palmar-plantar erythrodysesthesia syndrome</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="21" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="7"/>
                <counts group_id="E3" 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="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Blood and lymphatic system disorders - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Palpitations</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Cardiac disorders - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Vertigo</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Ear pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Hearing impaired</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Ear and labyrinth disorders - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Hypothyroidism</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Endocrine disorders - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Blurred vision</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Dry eye</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Eye disorders - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Bloating</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" 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="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Colitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Duodenal hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Dysphagia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Flatulence</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Hemorrhoids</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Pancreatitis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Stomach pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Toothache</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Gastrointestinal disorders - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="2" 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="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Edema trunk</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="7" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Gait disturbance</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>General disorders and administration site conditions - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Papulopustular rash</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Upper respiratory infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Eye infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Skin infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" 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="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Vaginal infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Infections and infestations - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Bruising</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Injury, poisoning and procedural complications - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Ejection fraction decreased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Activated partial thromboplastin time prolonged</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Lipase increased</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Serum amylase increased</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Investigations - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" 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="4" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Hypoglycemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Hypomagnesemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Muscle weakness lower limb</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Muscle weakness right-sided</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Muscle weakness upper limb</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" 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="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Musculoskeletal and connective tissue disorder - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dysarthria</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Dysphasia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Paresthesia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Presyncope</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Seizure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Ataxia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Cognitive disturbance</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Facial nerve disorder</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Peripheral sensory neuropathy</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Sinus pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Tremor</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Nervous system disorders - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Restlessness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Confusion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Personality change</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Urinary urgency</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Urinary incontinence</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Dysmenorrhea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Irregular menstruation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Productive cough</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Tracheal fistula</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Tracheal mucositis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Voice alteration</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Nail discoloration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Palmar-plantar erythrodysesthesia syndrome</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" 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="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="2" 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="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
              <event>
                <sub_title>Vascular disorders - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="7"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="8"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>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>Sara Tolaney, MD, MPH</name_or_title>
      <organization>Dana-Farber Cancer Institute</organization>
      <phone>617-632-3800</phone>
      <email>Sara_Tolaney@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/NCT02260531
org study id: 14-359
nct id: NCT02260531
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
This research study is evaluating the effectiveness of the drug called cabozantinib (alone or
      in combination with trastuzumab) as a possible treatment for advanced breast cancer in which
      the cancer has spread to the brain.
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 not approved cabozantinib for your
      specific disease but it has been approved for other uses.

      Few treatments exist for brain metastases from breast cancer. Radiation and surgery are
      generally included as a possible standard of care treatments for this diagnosis.

      In this research study, the investigator are looking at how well cabozantinib works in
      treating breast cancer that has spread to the brain. Cabozantinib has been used in some phase
      I studies and information from those other research studies suggests that cabozantinib may
      help to shrink or stabilize the participant's breast cancer. In addition, information from
      these studies has shown that cabozantinib may pass through the blood brain barrier (a
      protective layer that prevents most large molecules and cells found in the blood from
      entering the brain tissue) and may be an effective treatment for brain metastases.

      If the participant has HER2-positive breast cancer, they will receive trastuzumab in addition
      to cabozantinib. Trastuzumab is an FDA approved drug for the treatment of HER2-positive
      metastatic breast cancer. However, the combination of cabozantinib and trastuzumab has not
      yet been tested. Trastuzumab may help to shrink or stabilize breast cancer in combination
      with cabozantinib. If the participant's breast cancer is HER2-negative, they will not receive
      trastuzumab as part of this clinical trial.

      The names of the study interventions involved in this study are:

        -  Cabozantinib (XL184)

        -  Trastuzumab (herceptin) (participants with HER2-positive disease only)
allocation: Non-Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: CNS Objective Response Rate (ORR)
time frame: Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion of 6 cycles could reduce frequency of assessments to every 3 cycles. Response was evaluated up to 25 months.
description: The central nervous system (CNS) ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria in the evaluation CNS lesions on treatment: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.
measure: CNS Volumetric Objective Response Rate (ORR)
time frame: Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion of 6 cycles could reduce frequency of assessments to every 3 cycles. Response was evaluated up to 25 months .
description: CNS volumetric ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) defined as:
CR
Complete resolution of all measurable (≥ 1 cm diameter) and non-measurable brain metastases
No new CNS lesions (new lesion defined as ≥ 6 mm diameter) PR
≥ 50% reduction in the volumetric sum of all measurable (≥ 1 cm diameter) brain metastases compared to baseline
No progression of non-measurable lesions
No new lesions (new lesion defined as ≥ 6 mm)
ORR also requires:
Stable or decreasing steroid dose
No new/progressive tumor-related neurologic signs or symptoms
measure: Non-CNS Objective Response Rate (ORR)
time frame: Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion of 6 cycles could reduce frequency of assessments to every 3 cycles. Response was evaluated up to 25 months.
description: The non-central nervous system (CNS) ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria in the evaluation non-CNS lesions on treatment: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.
measure: Median Progression-Free Survival (PFS)
time frame: Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. Follow-up time is up to 25 months.
description: Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) or death. Per RECIST 1.1 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.
measure: 12-Week Clinical Benefit Rate
time frame: Evaluate at 12 weeks.
description: Clinical benefit rate (CBR) was defined as the percentage of patients achieving complete response (CR), partial response (PR), or stable disease (SD) based on RECIST 1.1 criteria by 12 weeks. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PD is at least a 20% increase in sum LD of target lesions (smallest sum LD reference), new lesions, and/or unequivocal progression of existing non-target lesions. Stable disease (SD) is defined as any condition not meeting the above criteria.
measure: First Progression Site
time frame: Disease assessments occurred every 6 cycles. Patients with stable or responsive disease after completion could reduce frequency to every 3 cycles. In long-term follow-up, assessments occurred every 6 months until death. Follow-up time is up to 25 months.
description: Site that a patient has his/her first tumor progression (CNS vs Non-CNS)
measure: Overall Survival (OS)
time frame: Off-treatment patients followed every 6 months until death. Follow-up time is up to 25 months.
description: OS based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive.
measure: Incidence of Grade 4 Treatment-Related Toxicity
time frame: Participants should be re-evaluated for response every 6 weeks. Patients with stable or responsive disease after completion of 6 cycles may have the frequency of scans reduced to once every 3 cycles, and in long-term follow-up every 6 months until death.
description: All grade 4 adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv4 as reported on case report forms were counted. Incidence is the number of patients experiencing at least one treatment-related grade 4 AE of any type during the time of observation.
arm group label: Cohort 1 - Cabozantinib, Trastuzumab for HER2+
arm group type: Experimental
description: HER2-positive
Cabozantinib- orally administered daily per treatment cycle, 60 mg per day
Trastuzumab- IV administered once per cycle, 8 mg/kg IV loading dose followed by 6 mg/kg IV Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.
arm group label: Cohort 2 - Cabozantinib for ER+ and/or PR+
arm group type: Experimental
description: Hormone receptor-positive (ER+ and/or PR+)
- Cabozantinib- orally administered daily per treatment cycle, 60 mg per day Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.
arm group label: Cohort 3 - Cabozantinib for ER-, PR-, HER2-
arm group type: Experimental
description: Triple negative (ER-, PR-, HER2-)
- Cabozantinib- orally administered daily per treatment cycle, 60 mg per day Cycle duration equals 3 weeks. Patients are treated indefinitely based on unacceptable toxicity, disease progression, or withdrawal for other reasons.
intervention type: Drug
intervention name: Cabozantinib
arm group label: Cohort 1 - Cabozantinib, Trastuzumab for HER2+
arm group label: Cohort 2 - Cabozantinib for ER+ and/or PR+
arm group label: Cohort 3 - Cabozantinib for ER-, PR-, HER2-
other name: Cometriq®
intervention type: Drug
intervention name: Trastuzumab
arm group label: Cohort 1 - Cabozantinib, Trastuzumab for HER2+
other name: Herceptin
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Sara Tolaney, MD, MPH
role: Principal Investigator
affiliation: Dana-Farber Cancer Institute
facility: 
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Dana-Farber Cancer Institute
investigator full name: Sara Tolaney
investigator title: Principal Investigator
mesh term: Breast Neoplasms
mesh term: Neoplasm Metastasis
mesh term: Brain Neoplasms
mesh term: Trastuzumab
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 