<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/NCT02226276</url>
  </required_header>
  <id_info>
    <org_study_id>14099</org_study_id>
    <secondary_id>NCI-2014-01812</secondary_id>
    <secondary_id>14099</secondary_id>
    <nct_id>NCT02226276</nct_id>
  </id_info>
  <brief_title>Copper Cu 64-DOTA-Trastuzumab PET in Predicting Response to Treatment With Ado-Trastuzumab Emtansine in Patients With Metastatic HER2 Positive Breast Cancer</brief_title>
  <official_title>A Pilot Study of 64Cu-DOTA-Trastuzumab Positron Emission Tomography in Treatment of Advanced HER2 Positive Breast Cancer With the Antibody Drug Conjugate Ado-trastuzumab Emtansine</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>City of Hope Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>City of Hope Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This pilot clinical trial studies how well copper Cu 64-tetra-azacyclododecanetetra-acetic&#xD;
      acid (DOTA)-trastuzumab positron emission tomography (PET) works in predicting response to&#xD;
      treatment with ado-trastuzumab emtansine in patients with human epidermal growth factor&#xD;
      receptor 2 (HER2) positive breast cancer that has spread to other places in the body. Copper&#xD;
      Cu 64-DOTA-trastuzumab is a chemotherapy drug (trastuzumab) attached to a radioactive&#xD;
      substance. Diagnostic procedures using PET may allow scanners to take pictures of where the&#xD;
      drug travels in the body and may help doctors identify which patients may benefit from&#xD;
      treatment with ado-trastuzumab emtansine.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. Correlate uptake of 64Cu-DOTA-trastuzumab (copper Cu 64-DOTA-trastuzumab) PET by&#xD;
      individual tumors with subsequent tumor response to ado-trastuzumab emtansine as assessed by&#xD;
      serial 18F-fludeoxyglucose (FDG) (fludeoxyglucose F 18)/PET-computed tomography (CT).&#xD;
&#xD;
      II. Compare tumor uptake of 64Cu-DOTA-trastuzumab PET between patients who do and patients&#xD;
      who do not respond to ado-trastuzumab emtansine.&#xD;
&#xD;
      III. Obtain tumor tissue for subsequent assessment of the presence of putative molecular&#xD;
      mechanisms of resistance (MMRs) to ado-trastuzumab emtansine. When funding becomes available,&#xD;
      those samples will be used to explore the correlation between the presence of MMRs as&#xD;
      assessed by histopathology and tumor response to ado-trastuzumab emtansine both in univariate&#xD;
      analysis and in combination with tumor uptake of 64Cu-DOTA-trastuzumab as measured with&#xD;
      PET/CT.&#xD;
&#xD;
      OUTLINE:&#xD;
&#xD;
      Patients undergo whole body fludeoxyglucose F 18 PET/CT. Patients then receive trastuzumab&#xD;
      intravenously (IV) over 15 minutes immediately before receiving copper Cu 64-DOTA-trastuzumab&#xD;
      IV and then undergo PET scans at 24 and 48 hours. Patients then receive ado-trastuzumab&#xD;
      emtansine IV every 3 weeks until complete response or disease progression at the discretion&#xD;
      of the treating oncologist. Patients undergo restaging by whole body fludeoxyglucose F 18&#xD;
      PET/CT every 6 weeks for 1 year after initiation of treatment until disease progression.&#xD;
&#xD;
      After completion of study treatment, patients are followed up for 1 year.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date>January 7, 2015</start_date>
  <completion_date type="Anticipated">December 30, 2023</completion_date>
  <primary_completion_date type="Actual">December 7, 2021</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Relationship Between Average Tumor Uptake of Copper Cu 64-DOTA-trastuzumab as Measured by PET and Patient Best Response</measure>
    <time_frame>Baseline</time_frame>
    <description>Relationship between patient best response to T-DM1 and measured tumor uptake of 64Cu-DOTA-trastuzumab employed a t-test with a 0.05 two-sided significance level comparing average uptake in responsive vs non-responsive patients. Tumor uptake measured as SUV defined as SUV = AC(tsc) Wb /[Dinj exp(-λ(tsc - tinj)] , where AC(tsc) is the activity concentration in the volume of interest (VOI, e. g., a tumor), Wb is the patient's body weight, Dinj is the activity injected at time tinj, and λ is the decay constant for the injected radioisotope. AC(tsc) is determined from the spatial density of counts acquired from the VOI. Tumor uptake was measured in terms of maximum voxel standardized uptake value, SUVmax. Response assessment adhered to Positron Emission Tomography (PET) Response Criteria in Solid Tumors (PERCIST 1.0).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Relationship Between Tumor Minimum Uptake of Copper Cu 64-DOTA-trastuzumab as Measured by PET and Patient Best Response</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>Relationship between patient best response to T-DM1 and measured tumor uptake of 64Cu-DOTA-trastuzumab employed a t-test with a 0.05 two-sided significance level comparing minimum uptake in responsive vs non-responsive patients. Tumor uptake measured as SUV defined as SUV = AC(tsc) Wb /[Dinj exp(-λ(tsc - tinj)] , where AC(tsc) is the activity concentration in the volume of interest (VOI, e. g., a tumor), Wb is the patient's body weight, Dinj is the activity injected at time tinj, and λ is the decay constant for the injected radioisotope. AC(tsc) is determined from the spatial density of counts acquired from the VOI. Tumor uptake was measured in terms of minimum voxel standardized uptake value, SUVmin. Response assessment adhered to Positron Emission Tomography (PET) Response Criteria in Solid Tumors (PERCIST 1.0).</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">10</enrollment>
  <condition>Bone Metastases</condition>
  <condition>HER2-positive Breast Cancer</condition>
  <condition>Liver Metastases</condition>
  <condition>Lung Metastases</condition>
  <condition>Recurrent Breast Cancer</condition>
  <condition>Soft Tissue Metastases</condition>
  <condition>Stage IV Breast Cancer</condition>
  <arm_group>
    <arm_group_label>Diagnostic (copper Cu 64-DOTA-trastuzumab PET)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients undergo whole body fludeoxyglucose F 18 PET/CT. Patients then receive trastuzumab IV over 15 minutes immediately before receiving copper Cu 64-DOTA-trastuzumab IV and then undergo PET scans at 24 and 48 hours. Patients then receive ado-trastuzumab emtansine IV every 3 weeks until complete response or disease progression at the discretion of the treating oncologist. Patients undergo restaging by whole body fludeoxyglucose F 18 PET/CT every 6 weeks after initiation of treatment until disease progression.</description>
  </arm_group>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>fludeoxyglucose F 18</intervention_name>
    <description>Undergo fludeoxyglucose F 18 PET/CT</description>
    <arm_group_label>Diagnostic (copper Cu 64-DOTA-trastuzumab PET)</arm_group_label>
    <other_name>18FDG</other_name>
    <other_name>FDG</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>positron emission tomography</intervention_name>
    <description>Undergo fludeoxyglucose F 18 PET/CT</description>
    <arm_group_label>Diagnostic (copper Cu 64-DOTA-trastuzumab PET)</arm_group_label>
    <other_name>FDG-PET</other_name>
    <other_name>PET</other_name>
    <other_name>PET scan</other_name>
    <other_name>tomography, emission computed</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>computed tomography</intervention_name>
    <description>Undergo fludeoxyglucose F 18 PET/CT</description>
    <arm_group_label>Diagnostic (copper Cu 64-DOTA-trastuzumab PET)</arm_group_label>
    <other_name>tomography, computed</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>trastuzumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Diagnostic (copper Cu 64-DOTA-trastuzumab PET)</arm_group_label>
    <other_name>anti-c-erB-2</other_name>
    <other_name>Herceptin</other_name>
    <other_name>MOAB HER2</other_name>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>copper Cu 64-DOTA-trastuzumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Diagnostic (copper Cu 64-DOTA-trastuzumab PET)</arm_group_label>
    <other_name>64Cu-DOTA-trastuzumab</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>positron emission tomography</intervention_name>
    <description>Undergo copper Cu-DOTA-trastuzumab PET</description>
    <arm_group_label>Diagnostic (copper Cu 64-DOTA-trastuzumab PET)</arm_group_label>
    <other_name>FDG-PET</other_name>
    <other_name>PET</other_name>
    <other_name>PET scan</other_name>
    <other_name>tomography, emission computed</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>ado-trastuzumab emtansine</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Diagnostic (copper Cu 64-DOTA-trastuzumab PET)</arm_group_label>
    <other_name>Kadcyla</other_name>
    <other_name>T-DM1</other_name>
    <other_name>trastuzumab-DM1</other_name>
    <other_name>trastuzumab-MCC-DM1</other_name>
    <other_name>trastuzumab-MCC-DM1 antibody-drug conjugate</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>laboratory biomarker analysis</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Diagnostic (copper Cu 64-DOTA-trastuzumab PET)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Participants must be women who have histological confirmation of metastatic invasive&#xD;
             breast cancer that has metastasized outside the region of the primary tumor and&#xD;
             axilla; biopsy must be obtained prior to initiation of chemotherapy; it should be&#xD;
             performed within 28 days prior to enrollment (patients with a biopsy of recurrent&#xD;
             disease that is HER2-positive and have not received HER2-directed therapy since the&#xD;
             biopsy can exceed the 28-day window up to 6 months); patients must have metastatic&#xD;
             disease in lung, liver, soft-tissue or bone to qualify for the study (more than one&#xD;
             site is permissible)&#xD;
&#xD;
          -  At least 1 site of metastasis &gt;= 20 mm in mean diameter must be identified&#xD;
&#xD;
          -  The cancer must over express HER2 as determined by immunohistochemistry (IHC) and/or&#xD;
             fluorescence in situ hybridization (FISH)&#xD;
&#xD;
          -  Patients may not have received trastuzumab within 6 weeks of projected&#xD;
             64Cu-DOTA-trastuzumab/PET-CT&#xD;
&#xD;
          -  Participants must have normal cardiac ejection fraction&#xD;
&#xD;
          -  Ability to provide informed consent&#xD;
&#xD;
          -  Patients that may need dose reduction to commence cycle 1 treatment&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-2&#xD;
&#xD;
          -  Negative serum pregnancy test (female of childbearing potential only)&#xD;
&#xD;
          -  Patients must have adequate cardiac function; left ventricular ejection fraction&#xD;
             (LVEF) &gt;= 50% as determined by multi gated acquisition (MUGA) scan or echocardiogram&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Participants who have received trastuzumab within the prior 36 days&#xD;
&#xD;
          -  Participants who are not considered candidates for ado-trastuzumab-emtansine&#xD;
&#xD;
          -  No metastatic sites &gt;= 20 mm&#xD;
&#xD;
          -  Concurrent malignancy other than skin cancer - Inability to provide informed consent&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Joanne Mortimer</last_name>
    <role>Principal Investigator</role>
    <affiliation>City of Hope Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>City of Hope Medical Center</name>
      <address>
        <city>Duarte</city>
        <state>California</state>
        <zip>91010</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>August 25, 2014</study_first_submitted>
  <study_first_submitted_qc>August 25, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 27, 2014</study_first_posted>
  <results_first_submitted>February 2, 2022</results_first_submitted>
  <results_first_submitted_qc>June 29, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">July 20, 2022</results_first_posted>
  <last_update_submitted>February 21, 2023</last_update_submitted>
  <last_update_submitted_qc>February 21, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 23, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <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>Neoplasms, Second Primary</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Copper</mesh_term>
    <mesh_term>Trastuzumab</mesh_term>
    <mesh_term>Ado-Trastuzumab Emtansine</mesh_term>
    <mesh_term>Maytansine</mesh_term>
    <mesh_term>Fluorodeoxyglucose F18</mesh_term>
    <mesh_term>Immunoconjugates</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 18, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/76/NCT02226276/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Diagnostic (Copper Cu 64-DOTA-trastuzumab PET)</title>
          <description>Patients undergo whole body fludeoxyglucose F 18 PET/CT. Patients then receive trastuzumab IV (45 mg) over 15 minutes immediately before receiving copper Cu 64-DOTA-trastuzumab IV (&lt;15 mCi; protein dose 5 mg) and then undergo PET scans at 24 and 48 hours. Patients then receive ado-trastuzumab emtansine IV (3.6 mg/kg) every 3 weeks until complete response or disease progression at the discretion of the treating oncologist. Patients undergo restaging by whole body fludeoxyglucose F 18 PET/CT every 6 weeks after initiation of treatment until disease progression.&#xD;
fludeoxyglucose F 18: Undergo fludeoxyglucose F 18 PET/CT&#xD;
positron emission tomography: Undergo fludeoxyglucose F 18 PET/CT&#xD;
computed tomography: Undergo fludeoxyglucose F 18 PET/CT&#xD;
trastuzumab: Given IV&#xD;
copper Cu 64-DOTA-trastuzumab: Given IV&#xD;
positron emission tomography: Undergo copper Cu-DOTA-trastuzumab PET&#xD;
ado-trastuzumab emtansine: Given IV&#xD;
laboratory biomarker analysis: Correlative studies</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Diagnostic (Copper Cu 64-DOTA-trastuzumab PET)</title>
          <description>Patients undergo whole body fludeoxyglucose F 18 PET/CT. Patients then receive trastuzumab IV (45 mg) over 15 minutes immediately before receiving copper Cu 64-DOTA-trastuzumab IV (&lt;15 mCi; protein dose 5 mg) and then undergo PET scans at 24 and 48 hours. Patients then receive ado-trastuzumab emtansine IV (3.6 mg/kg) every 3 weeks until complete response or disease progression at the discretion of the treating oncologist. Patients undergo restaging by whole body fludeoxyglucose F 18 PET/CT every 6 weeks after initiation of treatment until disease progression.&#xD;
fludeoxyglucose F 18: Undergo fludeoxyglucose F 18 PET/CT&#xD;
positron emission tomography: Undergo fludeoxyglucose F 18 PET/CT&#xD;
computed tomography: Undergo fludeoxyglucose F 18 PET/CT&#xD;
trastuzumab: Given IV&#xD;
copper Cu 64-DOTA-trastuzumab: Given IV&#xD;
positron emission tomography: Undergo copper Cu-DOTA-trastuzumab PET&#xD;
ado-trastuzumab emtansine: Given IV&#xD;
laboratory biomarker analysis: Correlative studies</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="10"/>
          </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="54" lower_limit="46" upper_limit="83"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" 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>Caucasian</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Asian</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hispanic</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>African American</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Relationship Between Average Tumor Uptake of Copper Cu 64-DOTA-trastuzumab as Measured by PET and Patient Best Response</title>
        <description>Relationship between patient best response to T-DM1 and measured tumor uptake of 64Cu-DOTA-trastuzumab employed a t-test with a 0.05 two-sided significance level comparing average uptake in responsive vs non-responsive patients. Tumor uptake measured as SUV defined as SUV = AC(tsc) Wb /[Dinj exp(-λ(tsc - tinj)] , where AC(tsc) is the activity concentration in the volume of interest (VOI, e. g., a tumor), Wb is the patient's body weight, Dinj is the activity injected at time tinj, and λ is the decay constant for the injected radioisotope. AC(tsc) is determined from the spatial density of counts acquired from the VOI. Tumor uptake was measured in terms of maximum voxel standardized uptake value, SUVmax. Response assessment adhered to Positron Emission Tomography (PET) Response Criteria in Solid Tumors (PERCIST 1.0).</description>
        <time_frame>Baseline</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Diagnostic (Copper Cu 64-DOTA-trastuzumab PET)</title>
            <description>Patients undergo whole body fludeoxyglucose F 18 PET/CT. Patients then receive trastuzumab IV (45 mg) over 15 minutes immediately before receiving copper Cu 64-DOTA-trastuzumab IV (&lt;15 mCi; protein dose 5 mg) and then undergo PET scans at 24 and 48 hours. Patients then receive ado-trastuzumab emtansine IV (3.6 mg/kg) every 3 weeks until complete response or disease progression at the discretion of the treating oncologist. Patients undergo restaging by whole body fludeoxyglucose F 18 PET/CT every 6 weeks after initiation of treatment until disease progression.&#xD;
fludeoxyglucose F 18: Undergo fludeoxyglucose F 18 PET/CT&#xD;
positron emission tomography: Undergo fludeoxyglucose F 18 PET/CT&#xD;
computed tomography: Undergo fludeoxyglucose F 18 PET/CT&#xD;
trastuzumab: Given IV&#xD;
copper Cu 64-DOTA-trastuzumab: Given IV&#xD;
positron emission tomography: Undergo copper Cu-DOTA-trastuzumab PET&#xD;
ado-trastuzumab emtansine: Given IV&#xD;
laboratory biomarker analysis: Correlative studies</description>
          </group>
        </group_list>
        <measure>
          <title>Relationship Between Average Tumor Uptake of Copper Cu 64-DOTA-trastuzumab as Measured by PET and Patient Best Response</title>
          <description>Relationship between patient best response to T-DM1 and measured tumor uptake of 64Cu-DOTA-trastuzumab employed a t-test with a 0.05 two-sided significance level comparing average uptake in responsive vs non-responsive patients. Tumor uptake measured as SUV defined as SUV = AC(tsc) Wb /[Dinj exp(-λ(tsc - tinj)] , where AC(tsc) is the activity concentration in the volume of interest (VOI, e. g., a tumor), Wb is the patient's body weight, Dinj is the activity injected at time tinj, and λ is the decay constant for the injected radioisotope. AC(tsc) is determined from the spatial density of counts acquired from the VOI. Tumor uptake was measured in terms of maximum voxel standardized uptake value, SUVmax. Response assessment adhered to Positron Emission Tomography (PET) Response Criteria in Solid Tumors (PERCIST 1.0).</description>
          <units>SUVmax (g/mL)</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.1" lower_limit="0.5" upper_limit="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>&lt;0.05</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Relationship Between Tumor Minimum Uptake of Copper Cu 64-DOTA-trastuzumab as Measured by PET and Patient Best Response</title>
        <description>Relationship between patient best response to T-DM1 and measured tumor uptake of 64Cu-DOTA-trastuzumab employed a t-test with a 0.05 two-sided significance level comparing minimum uptake in responsive vs non-responsive patients. Tumor uptake measured as SUV defined as SUV = AC(tsc) Wb /[Dinj exp(-λ(tsc - tinj)] , where AC(tsc) is the activity concentration in the volume of interest (VOI, e. g., a tumor), Wb is the patient's body weight, Dinj is the activity injected at time tinj, and λ is the decay constant for the injected radioisotope. AC(tsc) is determined from the spatial density of counts acquired from the VOI. Tumor uptake was measured in terms of minimum voxel standardized uptake value, SUVmin. Response assessment adhered to Positron Emission Tomography (PET) Response Criteria in Solid Tumors (PERCIST 1.0).</description>
        <time_frame>Up to 1 year</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Diagnostic (Copper Cu 64-DOTA-trastuzumab PET)</title>
            <description>Patients undergo whole body fludeoxyglucose F 18 PET/CT. Patients then receive trastuzumab IV (45 mg) over 15 minutes immediately before receiving copper Cu 64-DOTA-trastuzumab IV (&lt;15 mCi; protein dose 5 mg) and then undergo PET scans at 24 and 48 hours. Patients then receive ado-trastuzumab emtansine IV (3.6 mg/kg) every 3 weeks until complete response or disease progression at the discretion of the treating oncologist. Patients undergo restaging by whole body fludeoxyglucose F 18 PET/CT every 6 weeks after initiation of treatment until disease progression.&#xD;
fludeoxyglucose F 18: Undergo fludeoxyglucose F 18 PET/CT&#xD;
positron emission tomography: Undergo fludeoxyglucose F 18 PET/CT&#xD;
computed tomography: Undergo fludeoxyglucose F 18 PET/CT&#xD;
trastuzumab: Given IV&#xD;
copper Cu 64-DOTA-trastuzumab: Given IV&#xD;
positron emission tomography: Undergo copper Cu-DOTA-trastuzumab PET&#xD;
ado-trastuzumab emtansine: Given IV&#xD;
laboratory biomarker analysis: Correlative studies</description>
          </group>
        </group_list>
        <measure>
          <title>Relationship Between Tumor Minimum Uptake of Copper Cu 64-DOTA-trastuzumab as Measured by PET and Patient Best Response</title>
          <description>Relationship between patient best response to T-DM1 and measured tumor uptake of 64Cu-DOTA-trastuzumab employed a t-test with a 0.05 two-sided significance level comparing minimum uptake in responsive vs non-responsive patients. Tumor uptake measured as SUV defined as SUV = AC(tsc) Wb /[Dinj exp(-λ(tsc - tinj)] , where AC(tsc) is the activity concentration in the volume of interest (VOI, e. g., a tumor), Wb is the patient's body weight, Dinj is the activity injected at time tinj, and λ is the decay constant for the injected radioisotope. AC(tsc) is determined from the spatial density of counts acquired from the VOI. Tumor uptake was measured in terms of minimum voxel standardized uptake value, SUVmin. Response assessment adhered to Positron Emission Tomography (PET) Response Criteria in Solid Tumors (PERCIST 1.0).</description>
          <units>SUVmin (g/mL)</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.1" lower_limit="3" upper_limit="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>&lt;0.01</p_value>
            <method>t-test, 2 sided</method>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse events occurred over a period of 3 years and 8 months.</time_frame>
      <desc>&quot;Other Adverse Events&quot; include all events that were not severe adverse events regardless of grade or relation to treatment.</desc>
      <group_list>
        <group group_id="E1">
          <title>Diagnostic (Copper Cu 64-DOTA-trastuzumab PET)</title>
          <description>Patients undergo whole body fludeoxyglucose F 18 PET/CT. Patients then receive trastuzumab IV (45 mg) over 15 minutes immediately before receiving copper Cu 64-DOTA-trastuzumab IV (&lt;15 mCi; protein dose 5 mg) and then undergo PET scans at 24 and 48 hours. Patients then receive ado-trastuzumab emtansine IV (3.6 mg/kg) every 3 weeks until complete response or disease progression at the discretion of the treating oncologist. Patients undergo restaging by whole body fludeoxyglucose F 18 PET/CT every 6 weeks after initiation of treatment until disease progression.&#xD;
fludeoxyglucose F 18: Undergo fludeoxyglucose F 18 PET/CT&#xD;
positron emission tomography: Undergo fludeoxyglucose F 18 PET/CT&#xD;
computed tomography: Undergo fludeoxyglucose F 18 PET/CT&#xD;
trastuzumab: Given IV&#xD;
copper Cu 64-DOTA-trastuzumab: Given IV&#xD;
positron emission tomography: Undergo copper Cu-DOTA-trastuzumab PET&#xD;
ado-trastuzumab emtansine: Given IV&#xD;
laboratory biomarker analysis: Correlative studies</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Non-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="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Abdominal infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Skin infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Bone pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Confusion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hallucinations</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Bronchopulmonary hemorrhage</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypoxia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Respiratory failure</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" events="64" subjects_affected="9" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>bleeding from gums</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>bleeding from hard palate</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>bleeding from the hard palate</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent epistaxis - R nostril</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent nosebleed</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>lump in the R axilla</sub_title>
                <counts group_id="E1" events="4" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>petechie</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>thrombocytopenia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Aortic valve disease</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Sinus tachycardia</sub_title>
                <counts group_id="E1" events="34" subjects_affected="5" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Ventricular tachycardia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent PVCs to auscultation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent tachycardia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Vertigo</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Cushingoid</sub_title>
                <counts group_id="E1" events="11" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypothyroidism</sub_title>
                <counts group_id="E1" events="42" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>low cortisol level</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>low cortisol level (under investigation with endocrinology)</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Blurred vision</sub_title>
                <counts group_id="E1" events="6" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Decreased Peripheral Vision</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Decreased Peripheral dcreased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Decreased Peripherla Vision</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Decreased Peropheral Vision</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Decreased peripherla vision</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Dry eye</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Eyelid function disorder</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Photophobia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Visual Symptoms</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Visual Symptoms</sub_title>
                <counts group_id="E1" events="7" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Visual symptoms - only when she is tired</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>decreased peripheral vision</sub_title>
                <counts group_id="E1" events="10" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>decreased peripheral vision after sugery</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>decreased peripheral vision after surgery</sub_title>
                <counts group_id="E1" events="5" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>decreased peripheral vision after the 2/8 surgery</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>decreased peripheral vision after the surger</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>decreased peripheral vision after the surgery</sub_title>
                <counts group_id="E1" events="8" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>dicreased peripheral vision</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>hyperropia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent blurry eye</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent blurry eye (when reading for a long time)</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent blurry eye when reads for long time</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>photosensitivity</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>shaking of eyes during C4 infusion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>shaking of eyes during trastuzumab emtansine infusion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>shaking of eyes during trastuzumab emtansive</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>stye</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>tired eyes - when reads for a long time</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>tired eyes when reads for a long time</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>visual symptoms</sub_title>
                <counts group_id="E1" events="16" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>visual symptoms (only when tired)</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>visual symptoms - only when tired</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>visual symptoms only when tired</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>whipple in the left eye</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal distension</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="11" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Bloating</sub_title>
                <counts group_id="E1" events="5" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="32" subjects_affected="7" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="23" subjects_affected="4" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" events="19" subjects_affected="3" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Dysphagia</sub_title>
                <counts group_id="E1" events="8" subjects_affected="4" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Gastritis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Gastroesophageal reflux disease</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Heartburn</sub_title>
                <counts group_id="E1" events="8" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="75" subjects_affected="7" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Rectal hemorrhage</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Tongue feels raw, Hurting</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Tongue feels raw, hurting</sub_title>
                <counts group_id="E1" events="7" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Tounge feels raw, Hurting</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="17" subjects_affected="7" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>decreased appetite</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>epigastric discomfort</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>flactuating appetite after Keppra increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>glossitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>heartburn</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>increased appetite</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>increased thirst</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>indigestion</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent constipation</sub_title>
                <counts group_id="E1" events="11" subjects_affected="3" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent diarrhea</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent nausea</sub_title>
                <counts group_id="E1" events="15" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent nausea - after Keppra increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent nausea after Keppra increased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent rectal bleeding</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent vomiting</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent vomitting</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>low appetite</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>occasional blood in stool</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>occasional blood in stool while having hard stool</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>occasional constipation</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>plaque small white side of tongue</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>rectal bleeding</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>red, raw tongue</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>small white plaque L side of tongue</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>tenderness in mid-left abdomen w touch</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>tenderness in mid-left abdomen w/ touch</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>tongue feels raw, hurting</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>unable to eruct</sub_title>
                <counts group_id="E1" events="9" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Edema limbs</sub_title>
                <counts group_id="E1" events="6" subjects_affected="3" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="117" subjects_affected="10" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" events="5" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Flu like symptoms</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Localized edema</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Malaise</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Neck edema</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>abscess</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>low-grade temperature</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Rhinitis infective</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Sinusitis</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Upper respiratory infection</sub_title>
                <counts group_id="E1" events="6" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" events="8" subjects_affected="5" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>low grade temperature</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>oral thrush</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>shingles</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>suspected bacteremia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>yeast infection</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Bruising</sub_title>
                <counts group_id="E1" events="9" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Dermatitis radiation</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Fracture</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="24" subjects_affected="5" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" events="67" subjects_affected="7" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" events="71" subjects_affected="8" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Creatinine increased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Electrocardiogram QT corrected interval</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hemoglobin increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="19" subjects_affected="5" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="13" subjects_affected="3" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="95" subjects_affected="8" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Weight gain</sub_title>
                <counts group_id="E1" events="7" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" events="34" subjects_affected="4" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" events="18" subjects_affected="7" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypercalcemia</sub_title>
                <counts group_id="E1" events="38" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" events="19" subjects_affected="4" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hyperkalemia</sub_title>
                <counts group_id="E1" events="5" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypermagnesemia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypertriglyceridemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" events="19" subjects_affected="6" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypocalcemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypoglycemia</sub_title>
                <counts group_id="E1" events="6" subjects_affected="3" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" events="23" subjects_affected="6" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" events="35" subjects_affected="8" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Obesity</sub_title>
                <counts group_id="E1" events="20" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>occasional night sweats</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Arthritis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Avascular necrosis</sub_title>
                <counts group_id="E1" events="28" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="8" subjects_affected="4" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Bone pain</sub_title>
                <counts group_id="E1" events="6" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Chest wall pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Dupuytren's contracture</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Flank pain</sub_title>
                <counts group_id="E1" events="5" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" events="11" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Joint range of motion decreased cervical</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>L ankle swelling and pain</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>L big toe bends in toward other toes</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>L big toe bends in towards other toes</sub_title>
                <counts group_id="E1" events="5" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>L big toe bends toward other toes</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>L big toe bends towards other toes</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>L hand is curled inward</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>L shoulder and L middle finger joint pain</sub_title>
                <counts group_id="E1" events="4" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>L shoulder pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>L sided limp</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Muscle weakness left-sided</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" events="10" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Neck pain</sub_title>
                <counts group_id="E1" events="8" subjects_affected="3" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Osteopenia</sub_title>
                <counts group_id="E1" events="9" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Osteoporosis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" events="13" subjects_affected="5" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>R elbow pain</sub_title>
                <counts group_id="E1" events="13" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>R shoulder and arm pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>R shoulder pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>R shoulder, arm pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>R shoulder/arm pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>arthritis R shoulder</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>avascular necrosis L humerus</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>bilateral elbow pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>bilateral shoulder and neck pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>bunionette</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>car accident injuries</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>car accident on 6/19/2018</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>cramping</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>decreased mobility and pain in L arm</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>decreased mobility and pain in left arm/difficulty making fi</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>decreased mobility, pain left arm</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>decreased mobility, pain L arm</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>decreased mobility, pain L arm, difficulty making fist w L h</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>decreased mobility, pain L arm/difficulty making fist L hand</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>decreased mobility, pain in L arm</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>decreased mobility, pain left arm, difficulty making fist w</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>decreased mobility, pain left arm, difficulty making fist wi</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>decreased mobility/pain L arm, difficulty making fist L hand</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>decreased mobility/pain left arm, difficulty making fist wit</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>decreased mobility/pain left arm/difficulty making fist with</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>difficulty making fist with L arm</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>difficulty making fist with L hand</sub_title>
                <counts group_id="E1" events="4" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>dupuytrens contracture status post surgery</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent L should pain - movement dependent</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent L shoulder pain - movement dependent</sub_title>
                <counts group_id="E1" events="6" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent L shoulder pain movement dependent</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent bilateral rib pain</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent lower back pain</sub_title>
                <counts group_id="E1" events="6" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>left shoulder pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>mid-back pain</sub_title>
                <counts group_id="E1" events="5" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>muscle cramps - both legs and back</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>neck stiffness</sub_title>
                <counts group_id="E1" events="4" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>osteopenia</sub_title>
                <counts group_id="E1" events="23" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>overall myalgia and body stiffness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>pain and decreased mobility both arms</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>pain and decreased mobility in both arms</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>pain and swelling - back of L knee</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>pain in neck and shoulders</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>pain in the thighs (front of thighs and glutes)</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>pain in the thighs - front of thighs and glutes</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>right elbow pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>rotator cuff injury</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>rotator cuff injury R arm</sub_title>
                <counts group_id="E1" events="14" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>shoulder pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>stiffness in knee and back</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>swollen area of R side of R foot</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>swollen area on R side of R foot</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Tumor pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Ataxia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="14" subjects_affected="5" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" events="12" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Dysphasia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="55" subjects_affected="4" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>L arm - pain of full abduction</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>L arm - pain on full abduction</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>L hand curled inward</sub_title>
                <counts group_id="E1" events="13" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>L side hemoplegia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>L side weak (as per getting up from squat, dragging)</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>L sided hemiparesis</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>L sided hemiplegia</sub_title>
                <counts group_id="E1" events="14" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>L sided hemoplegia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>L upper eyelid ptosis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Lethargy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Memory impairment</sub_title>
                <counts group_id="E1" events="7" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Paresthesia</sub_title>
                <counts group_id="E1" events="22" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Peripheral motor neuropathy</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Peripheral sensory neuropathy</sub_title>
                <counts group_id="E1" events="62" subjects_affected="8" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Recurrent laryngeal nerve palsy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Somnolence</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent dizziness w/ position change - preexisting as p</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent dizziness w/ position change)</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent headache</sub_title>
                <counts group_id="E1" events="8" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent headache (2 weeks after TX)</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent headache (only scar pain when bends, lean over)</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent headache (only scar pain, when bends, lean over</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent sensitivity - feet - bottoms</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent sensitivity - feet bottoms</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent sensitivity feet botoms</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>l sided hemiplegia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>left sided hemiplegia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>migraine</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>pain at the base of the neck</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>sensitivity - feet bottoms</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>sensory neuropathy L arm</sub_title>
                <counts group_id="E1" events="17" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>sensory neuropathy left arm</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>sensory neurophathy left arm</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>vocal cord paralysis</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Agitation</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" events="31" subjects_affected="3" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Confusion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" events="7" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" events="25" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>anxiety re new brain lesions</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>emotional distress</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Hematuria</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Proteinuria</sub_title>
                <counts group_id="E1" events="5" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>UTI symptoms (dysuria, abdominal pain, changes in UA)</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>UTI symptoms - dysuria, abdominal pain, changes in UA)</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Urinary frequency</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Urinary retention</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Urinary tract pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>dysuria</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>hot urine</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>polyuria</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Irregular menstruation</sub_title>
                <counts group_id="E1" events="6" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Vaginal hemorrhage</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>candidiasis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Allergic rhinitis</sub_title>
                <counts group_id="E1" events="5" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="29" subjects_affected="4" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" events="15" subjects_affected="5" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" events="44" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hoarseness</sub_title>
                <counts group_id="E1" events="9" subjects_affected="3" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypoxia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Laryngospasm</sub_title>
                <counts group_id="E1" events="12" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Productive cough</sub_title>
                <counts group_id="E1" events="7" subjects_affected="3" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Pulmonary hypertension</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Sore throat</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>URI</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Voice alteration</sub_title>
                <counts group_id="E1" events="7" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>allergic rhinitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>allergic symptoms</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>allergies - patient reported</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>asthmatic bronchtis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>chest congestion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>cold symptoms</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>crackles in LLL (both insp and expiration)</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>decreased O2 saturation</sub_title>
                <counts group_id="E1" events="8" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>decreased oxygen saturation</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>dry cough</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>dry cough (chronic as per patient), noted in the CRU</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>inspiratory crackles - left posterior lung base</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent chest discomofort</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent drippy nose following TX</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent drippy nose following treatment</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent dyspnea (only when activity and speech at the s</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>intermittent dyspnea only when activity and speech at the sa</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>occasional cough</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>occasional cough (provoked by food smell as per patient)</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>occasional cough provoked by food smells as per patient</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>occasional sputum build up in the throat</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>occasional sputum build up in the troat</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>possible small airway dysfunction</sub_title>
                <counts group_id="E1" events="6" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>possible small airways dysfunction</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>productive cough w/ white or clear phlegm</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>productive cough with white or clear phlegm</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>rales and wheezes in LLL</sub_title>
                <counts group_id="E1" events="7" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>rhinorrhea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>rhnorrhea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>scattered wheezes R upper lobe</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>scattered wheezes in R upper lob</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>scattered wheezes in R upper lobe</sub_title>
                <counts group_id="E1" events="5" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>scattered wheezes in the R upper lobe</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>small airway dysfunction</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>sounds while sleeping</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>sputum build up in the throat</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>wheezing after excercise</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>wheezing after exercise</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>wheezing/cracking breath w/ expiration</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>worsening of L mid and lower lobe interst and ground glass o</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>worsening of L mid and lower lobe lung interst and ground gl</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" events="12" subjects_affected="4" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Erythema multiforme</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Nail ridging</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Peeling of skin on feet</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Petechiae</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Photosensitivity</sub_title>
                <counts group_id="E1" events="34" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Rash acneiform</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Skin ulceration</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Urticaria</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>capillary hemangioma</sub_title>
                <counts group_id="E1" events="5" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>erythema in response to RX therapy</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>occasional pain in the incision area</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>occasional soreness to the incision area</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>occasional soreness to the incison area</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>petechiae</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>scabs and bruises on the back of L arm</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>skin lesions from cupping</sub_title>
                <counts group_id="E1" events="4" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>skin lessions from cupping</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>skin peeling at feet</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>skin spot removed from the nose</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>small raised bump on the R inner thigh</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>sores on fingers</sub_title>
                <counts group_id="E1" events="8" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>weak nails</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Social circumstances</title>
            <event_list>
              <event>
                <sub_title>menopausal like symptoms</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hot flashes</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="119" subjects_affected="9" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" events="11" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Lymphedema</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Paul Frankel, Ph.D.</name_or_title>
      <organization>City of Hope</organization>
      <phone>626-218-5265</phone>
      <email>pfrankel@coh.org</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02226276
org study id: 14099
secondary id: NCI-2014-01812
secondary id: 14099
nct id: NCT02226276
lead sponsor: 
collaborator: 
has dmc: Yes
This pilot clinical trial studies how well copper Cu 64-tetra-azacyclododecanetetra-acetic
      acid (DOTA)-trastuzumab positron emission tomography (PET) works in predicting response to
      treatment with ado-trastuzumab emtansine in patients with human epidermal growth factor
      receptor 2 (HER2) positive breast cancer that has spread to other places in the body. Copper
      Cu 64-DOTA-trastuzumab is a chemotherapy drug (trastuzumab) attached to a radioactive
      substance. Diagnostic procedures using PET may allow scanners to take pictures of where the
      drug travels in the body and may help doctors identify which patients may benefit from
      treatment with ado-trastuzumab emtansine.
PRIMARY OBJECTIVES:

      I. Correlate uptake of 64Cu-DOTA-trastuzumab (copper Cu 64-DOTA-trastuzumab) PET by
      individual tumors with subsequent tumor response to ado-trastuzumab emtansine as assessed by
      serial 18F-fludeoxyglucose (FDG) (fludeoxyglucose F 18)/PET-computed tomography (CT).

      II. Compare tumor uptake of 64Cu-DOTA-trastuzumab PET between patients who do and patients
      who do not respond to ado-trastuzumab emtansine.

      III. Obtain tumor tissue for subsequent assessment of the presence of putative molecular
      mechanisms of resistance (MMRs) to ado-trastuzumab emtansine. When funding becomes available,
      those samples will be used to explore the correlation between the presence of MMRs as
      assessed by histopathology and tumor response to ado-trastuzumab emtansine both in univariate
      analysis and in combination with tumor uptake of 64Cu-DOTA-trastuzumab as measured with
      PET/CT.

      OUTLINE:

      Patients undergo whole body fludeoxyglucose F 18 PET/CT. Patients then receive trastuzumab
      intravenously (IV) over 15 minutes immediately before receiving copper Cu 64-DOTA-trastuzumab
      IV and then undergo PET scans at 24 and 48 hours. Patients then receive ado-trastuzumab
      emtansine IV every 3 weeks until complete response or disease progression at the discretion
      of the treating oncologist. Patients undergo restaging by whole body fludeoxyglucose F 18
      PET/CT every 6 weeks for 1 year after initiation of treatment until disease progression.

      After completion of study treatment, patients are followed up for 1 year.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Diagnostic
masking: None (Open Label)
measure: Relationship Between Average Tumor Uptake of Copper Cu 64-DOTA-trastuzumab as Measured by PET and Patient Best Response
time frame: Baseline
description: Relationship between patient best response to T-DM1 and measured tumor uptake of 64Cu-DOTA-trastuzumab employed a t-test with a 0.05 two-sided significance level comparing average uptake in responsive vs non-responsive patients. Tumor uptake measured as SUV defined as SUV = AC(tsc) Wb /[Dinj exp(-λ(tsc - tinj)] , where AC(tsc) is the activity concentration in the volume of interest (VOI, e. g., a tumor), Wb is the patient's body weight, Dinj is the activity injected at time tinj, and λ is the decay constant for the injected radioisotope. AC(tsc) is determined from the spatial density of counts acquired from the VOI. Tumor uptake was measured in terms of maximum voxel standardized uptake value, SUVmax. Response assessment adhered to Positron Emission Tomography (PET) Response Criteria in Solid Tumors (PERCIST 1.0).
measure: Relationship Between Tumor Minimum Uptake of Copper Cu 64-DOTA-trastuzumab as Measured by PET and Patient Best Response
time frame: Up to 1 year
description: Relationship between patient best response to T-DM1 and measured tumor uptake of 64Cu-DOTA-trastuzumab employed a t-test with a 0.05 two-sided significance level comparing minimum uptake in responsive vs non-responsive patients. Tumor uptake measured as SUV defined as SUV = AC(tsc) Wb /[Dinj exp(-λ(tsc - tinj)] , where AC(tsc) is the activity concentration in the volume of interest (VOI, e. g., a tumor), Wb is the patient's body weight, Dinj is the activity injected at time tinj, and λ is the decay constant for the injected radioisotope. AC(tsc) is determined from the spatial density of counts acquired from the VOI. Tumor uptake was measured in terms of minimum voxel standardized uptake value, SUVmin. Response assessment adhered to Positron Emission Tomography (PET) Response Criteria in Solid Tumors (PERCIST 1.0).
arm group label: Diagnostic (copper Cu 64-DOTA-trastuzumab PET)
arm group type: Experimental
description: Patients undergo whole body fludeoxyglucose F 18 PET/CT. Patients then receive trastuzumab IV over 15 minutes immediately before receiving copper Cu 64-DOTA-trastuzumab IV and then undergo PET scans at 24 and 48 hours. Patients then receive ado-trastuzumab emtansine IV every 3 weeks until complete response or disease progression at the discretion of the treating oncologist. Patients undergo restaging by whole body fludeoxyglucose F 18 PET/CT every 6 weeks after initiation of treatment until disease progression.
intervention type: Radiation
intervention name: fludeoxyglucose F 18
description: Undergo fludeoxyglucose F 18 PET/CT
arm group label: Diagnostic (copper Cu 64-DOTA-trastuzumab PET)
other name: 18FDG
other name: FDG
intervention type: Procedure
intervention name: positron emission tomography
description: Undergo fludeoxyglucose F 18 PET/CT
arm group label: Diagnostic (copper Cu 64-DOTA-trastuzumab PET)
other name: FDG-PET
other name: PET
other name: PET scan
other name: tomography, emission computed
intervention type: Procedure
intervention name: computed tomography
description: Undergo fludeoxyglucose F 18 PET/CT
arm group label: Diagnostic (copper Cu 64-DOTA-trastuzumab PET)
other name: tomography, computed
intervention type: Biological
intervention name: trastuzumab
description: Given IV
arm group label: Diagnostic (copper Cu 64-DOTA-trastuzumab PET)
other name: anti-c-erB-2
other name: Herceptin
other name: MOAB HER2
intervention type: Radiation
intervention name: copper Cu 64-DOTA-trastuzumab
description: Given IV
arm group label: Diagnostic (copper Cu 64-DOTA-trastuzumab PET)
other name: 64Cu-DOTA-trastuzumab
intervention type: Procedure
intervention name: positron emission tomography
description: Undergo copper Cu-DOTA-trastuzumab PET
arm group label: Diagnostic (copper Cu 64-DOTA-trastuzumab PET)
other name: FDG-PET
other name: PET
other name: PET scan
other name: tomography, emission computed
intervention type: Biological
intervention name: ado-trastuzumab emtansine
description: Given IV
arm group label: Diagnostic (copper Cu 64-DOTA-trastuzumab PET)
other name: Kadcyla
other name: T-DM1
other name: trastuzumab-DM1
other name: trastuzumab-MCC-DM1
other name: trastuzumab-MCC-DM1 antibody-drug conjugate
intervention type: Other
intervention name: laboratory biomarker analysis
description: Correlative studies
arm group label: Diagnostic (copper Cu 64-DOTA-trastuzumab PET)
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Joanne Mortimer
role: Principal Investigator
affiliation: City of Hope Medical Center
facility: 
country: United States
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Neoplasm Metastasis
mesh term: Neoplasms, Second Primary
mesh term: Copper
mesh term: Trastuzumab
mesh term: Ado-Trastuzumab Emtansine
mesh term: Maytansine
mesh term: Fluorodeoxyglucose F18
mesh term: Immunoconjugates
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 