<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/NCT03007979</url>
  </required_header>
  <id_info>
    <org_study_id>201612098</org_study_id>
    <nct_id>NCT03007979</nct_id>
  </id_info>
  <brief_title>Alternative Dosing Schedule of Palbociclib in Metastatic Hormone Receptor Positive Breast Cancer</brief_title>
  <official_title>A Phase II Clinical Trial Assessing the Safety of an Alternative Dosing Schedule of Palbociclib in Metastatic Hormone Receptor Positive Breast Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Washington University School of Medicine</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Pfizer</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Washington University School of Medicine</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The investigators propose to conduct a study to test an alternative dosing schedule of&#xD;
      palbociclib. With the current three-week on and one week off schedule, a significant number&#xD;
      of patients develop grade 3 or higher degree of neutropenia and require dose reduction and&#xD;
      sometimes discontinuation. This potentially compromises the efficacy of the drug. In&#xD;
      addition, as the half-life of palbociclib is 27 hours, 1 week break with the standard 3 weeks&#xD;
      on and 1 week off dosing schedule could potentially lead to recovery of Rb phosphorylation&#xD;
      during the off week. Hence, the investigators propose a 5 days on and 2 days off schedule&#xD;
      each week without any weeks off drug. Although the cumulative doses each 28-day cycle is&#xD;
      roughly the same with this schedule compared to conventional dosing, the bone marrow is not&#xD;
      exposed to the drug continuously for 21 days and rather gets frequent breaks from therapy.&#xD;
      The investigators hypothesize that the 5 days on and 2 days off schedule is more tolerable&#xD;
      with less frequent high grade neutropenia and dose interruption/reduction. In addition, this&#xD;
      schedule also provides for a more continuous drug delivery to the patient since there is not&#xD;
      a week's break in therapy, which could ultimately prove to be more efficacious.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 15, 2017</start_date>
  <completion_date type="Actual">March 31, 2023</completion_date>
  <primary_completion_date type="Actual">March 13, 2020</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Rate of Grade 3 or Higher Neutropenia</measure>
    <time_frame>Through the first 29 days of treatment</time_frame>
    <description>The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.&#xD;
Grade 3 neutropenia: &lt;1000-500/mm^3; &lt;1.0-0.5 x 10e9/L&#xD;
Grade 4 neutropenia: &lt;500/mm^3; &lt;0.5 x 10e9/L</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Rate of Grade 3 or Higher Neutropenia</measure>
    <time_frame>Through 30 day follow-up (estimated to be 25 months)</time_frame>
    <description>The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.&#xD;
Grade 3 neutropenia: &lt;1000-500/mm^3; &lt;1.0-0.5 x 10e9/L&#xD;
Grade 4 neutropenia: &lt;500/mm^3; &lt;0.5 x 10e9/L</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of Palbociclib Dose Reduction</measure>
    <time_frame>Through the completion of treatment (estimated to be 24 months)</time_frame>
    <description>-Percentage of participants who have a palbociclib dose reduction during treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of Palbociclib Dose Interruption</measure>
    <time_frame>Through the completion of treatment (estimated to be 24 months)</time_frame>
    <description>-Percentage of participants who have a palbociclib dose interruption during treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of Palbociclib Discontinuation</measure>
    <time_frame>Through the completion of treatment (estimated to be 24 months)</time_frame>
    <description>-Percentage of participants who discontinue palbociclib</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse Event Profile of Palbociclib</measure>
    <time_frame>Through the 30 day follow-up (estimated to be 25 months)</time_frame>
    <description>-The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free Survival (PFS)</measure>
    <time_frame>1 year</time_frame>
    <description>PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.&#xD;
At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Response Rate (Complete Response + Partial Response)</measure>
    <time_frame>Time of progression (estimated to be 24 months)</time_frame>
    <description>Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm, dDisappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (&lt;10 mm short axis).&#xD;
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Benefit Rate (Complete Response + Partial Response + Stable Disease) for at Least 6 Months)</measure>
    <time_frame>Time of progression (estimated to be 24 months)</time_frame>
    <description>Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm, dDisappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (&lt;10 mm short axis).&#xD;
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters&#xD;
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">55</enrollment>
  <condition>Breast Cancer</condition>
  <condition>Breast Carcinoma</condition>
  <condition>Cancer of Breast</condition>
  <condition>Malignant Tumor of Breast</condition>
  <arm_group>
    <arm_group_label>Palbociclib + letrozole or + fulvestrant</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Palbociclib should be taken by mouth with food on a 5 days on/2 days off schedule (meaning: on Days 1-5, 8-12, 15-19, and 22-26 of each 28-day cycle).&#xD;
Patients who are receiving letrozole will take it daily by mouth, every day of each 28-day cycle.&#xD;
Patients who are receiving fulvestrant will receive it as two intramuscular injections (one into each buttock) on Days 1 and 15 of Cycle 1 and then on Day 1 of each cycle thereafter.&#xD;
Goserelin is given as a subcutaneous injection every 28 days. It is preferred to be given on Day 1 of each cycle, but it may be administered on any day of the treatment cycle to accommodate its specific Q28-day cycle. It will be given to pre- or peri-menopausal women only.&#xD;
Optional research biopsy at baseline and progression&#xD;
Blood for research at baseline, cycle 1 day 15, cycle 2 day 1, every 2-3 months (to coincide with imaging studies), and time of progression</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Palbociclib</intervention_name>
    <description>Palbociclib at a dose of 125 mg should be taken by mouth with food on a 5 days on/2 days off schedule</description>
    <arm_group_label>Palbociclib + letrozole or + fulvestrant</arm_group_label>
    <other_name>Ibrance</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Letrozole</intervention_name>
    <description>Patients who are receiving letrozole will take it daily by mouth, every day of each 28-day cycle, at a dose of 2.5 mg.</description>
    <arm_group_label>Palbociclib + letrozole or + fulvestrant</arm_group_label>
    <other_name>Femara</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fulvestrant</intervention_name>
    <description>Patients who are receiving fulvestrant will receive it at a dose of 500 mg as two 5 mL intramuscular injections (one into each buttock) on Days 1 and 15 of Cycle 1 and then on Day 1 of each cycle thereafter.</description>
    <arm_group_label>Palbociclib + letrozole or + fulvestrant</arm_group_label>
    <other_name>Faslodex</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Optional research biopsy</intervention_name>
    <description>Patients may consent to paired tumor biopsies at baseline and time of progression.</description>
    <arm_group_label>Palbociclib + letrozole or + fulvestrant</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Goserelin</intervention_name>
    <description>Goserelin is given as a subcutaneous injection every 28 days. It is preferred to be given on Day 1 of each cycle, but it may be administered on any day of the treatment cycle to accommodate its specific Q28-day cycle. It will be given to pre- and peri-menopausal women only.</description>
    <arm_group_label>Palbociclib + letrozole or + fulvestrant</arm_group_label>
    <other_name>Zoladex</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Research blood draw</intervention_name>
    <description>-Blood will be drawn at the following time points for serum, plasma, cfDNA, and germline DNA (only at baseline):&#xD;
Baseline&#xD;
C1D15&#xD;
C2D1&#xD;
Every 2-3 months thereafter (to coincide with imaging studies)&#xD;
Time of progression</description>
    <arm_group_label>Palbociclib + letrozole or + fulvestrant</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Circulating tumor cell blood draw</intervention_name>
    <description>-Baseline, cycle 2 day 1, post 2 or 3 months of therapy (to coincide with first tumor imaging), and progression</description>
    <arm_group_label>Palbociclib + letrozole or + fulvestrant</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Tumor biopsy (optional)</intervention_name>
    <description>-Baseline and progression</description>
    <arm_group_label>Palbociclib + letrozole or + fulvestrant</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically confirmed metastatic ER+ and/or PR+ and HER2- breast cancer who are&#xD;
             candidates for palbociclib in combination with either letrozole or fulvestrant per&#xD;
             treating physician.&#xD;
&#xD;
          -  Presence of measurable or non-measurable disease by RECIST 1.1 criteria.&#xD;
&#xD;
          -  One prior systemic therapy in the metastatic setting is allowed, but patients who have&#xD;
             not had any prior systemic therapies in the metastatic setting are also eligible.&#xD;
&#xD;
             *Note: patients who were started on endocrine therapy monotherapy as their 1st line or&#xD;
             2nd line systemic therapy in the metastatic setting for no more than 28 days and&#xD;
             without clinical progression prior to the initiation of the study drug therapy are&#xD;
             allowed to enroll on the study as their 1st line or 2nd line therapy, respectively.&#xD;
&#xD;
          -  At least 18 years of age.&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2&#xD;
&#xD;
          -  Normal bone marrow and organ function as defined below:&#xD;
&#xD;
               -  Absolute neutrophil count ≥ 1,500/mcl&#xD;
&#xD;
               -  Platelets ≥ 100,000/mcl&#xD;
&#xD;
          -  Total bilirubin ≤ institutional upper limit of normal (IULN) or total bilirubin ≤ 3.0&#xD;
             x IULN with direct bilirubin within normal range in patients with documented Gilbert's&#xD;
             syndrome&#xD;
&#xD;
          -  AST(SGOT)/ALT(SGPT) ≤ 1.5 x IULN (up to 5 x IULN in patients with liver disease)&#xD;
&#xD;
          -  Creatinine ≤ IULN OR creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with serum&#xD;
             creatinine levels above institutional normal (calculated by Creatinine Clearance&#xD;
             Estimate by Cockcroft-Gault Equation)&#xD;
&#xD;
          -  Pre- or post-menopausal women are allowed. If pre- or peri-menopausal, concurrent&#xD;
             ovarian suppression for pre- or peri-menopausal women is required.&#xD;
&#xD;
          -  Women of childbearing potential must agree to use adequate contraception (hormonal or&#xD;
             barrier method of birth control, abstinence) prior to study entry and for the duration&#xD;
             of study participation. Should a woman become pregnant or suspect she is pregnant&#xD;
             while participating in this study, she must inform her treating physician immediately.&#xD;
&#xD;
          -  Able to swallow and retain oral medication.&#xD;
&#xD;
          -  Washout of at least 3 weeks from prior chemotherapy or targeted therapy that induces&#xD;
             myelosuppression and recovery of treatment related adverse events to grade 1 or less,&#xD;
             with the exception of alopecia, is required prior to the start of palbociclib.&#xD;
&#xD;
          -  Ability to understand and willingness to sign an Institutional Review Board (IRB)&#xD;
             approved written informed consent document (or that of legally authorized&#xD;
             representative, if applicable).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior therapy with any CDK inhibitor.&#xD;
&#xD;
          -  Currently receiving any other investigational agents.&#xD;
&#xD;
          -  Currently receiving exogenous estrogen replacement (topical vaginal estrogen therapy&#xD;
             is allowed).&#xD;
&#xD;
          -  Known brain metastases. Patients with known brain metastases must be excluded from&#xD;
             this clinical trial because of their poor prognosis which could affect the evaluation&#xD;
             of all-cycle adverse events.&#xD;
&#xD;
          -  A history of allergic reactions attributed to compounds of similar chemical or&#xD;
             biologic composition to palbociclib or other agents used in the study.&#xD;
&#xD;
          -  Receiving any medications or substances that are potent inhibitors or inducers of&#xD;
             CYP3A isoenzymes within 7 days prior to registration.&#xD;
&#xD;
          -  Clinically significant history of liver disease.&#xD;
&#xD;
          -  A condition that would interfere with enteric absorption.&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac&#xD;
             arrhythmia.&#xD;
&#xD;
          -  Pregnant and/or breastfeeding. Women of childbearing potential must have a negative&#xD;
             pregnancy test within 7 days of study entry.&#xD;
&#xD;
          -  Known HIV-positivity on combination antiretroviral therapy because of the potential&#xD;
             for pharmacokinetic interactions with palbociclib. In addition, these patients are at&#xD;
             increased risk of lethal infections when treated with marrow-suppressive therapy.&#xD;
             Appropriate studies will be undertaken in patients receiving combination&#xD;
             antiretroviral therapy when indicated.&#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>Cynthia X Ma, M.D., Ph.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Washington University School of Medicine</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Washington University School of Medicine</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Nebraska</name>
      <address>
        <city>Lincoln</city>
        <state>Nebraska</state>
        <zip>68588</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.siteman.wustl.edu</url>
    <description>Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine</description>
  </link>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>December 19, 2016</study_first_submitted>
  <study_first_submitted_qc>December 28, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 2, 2017</study_first_posted>
  <results_first_submitted>February 19, 2021</results_first_submitted>
  <results_first_submitted_qc>February 19, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">March 15, 2021</results_first_posted>
  <last_update_submitted>April 5, 2023</last_update_submitted>
  <last_update_submitted_qc>April 5, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 7, 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>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Letrozole</mesh_term>
    <mesh_term>Fulvestrant</mesh_term>
    <mesh_term>Palbociclib</mesh_term>
    <mesh_term>Goserelin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>April 12, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/79/NCT03007979/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Palbociclib + Letrozole or + Fulvestrant</title>
          <description>Palbociclib should be taken by mouth with food on a 5 days on/2 days off schedule (meaning: on Days 1-5, 8-12, 15-19, and 22-26 of each 28-day cycle).&#xD;
Patients who are receiving letrozole will take it daily by mouth, every day of each 28-day cycle.&#xD;
Patients who are receiving fulvestrant will receive it as two intramuscular injections (one into each buttock) on Days 1 and 15 of Cycle 1 and then on Day 1 of each cycle thereafter.&#xD;
Goserelin is given as a subcutaneous injection every 28 days. It is preferred to be given on Day 1 of each cycle, but it may be administered on any day of the treatment cycle to accommodate its specific Q28-day cycle. It will be given to pre- or peri-menopausal women only.&#xD;
Optional research biopsy at baseline and progression&#xD;
Blood for research at baseline, cycle 1 day 15, cycle 2 day 1, every 2-3 months (to coincide with imaging studies), and time of progression</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="55"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="54"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Deemed not eligible prior to starting palbociclib</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Palbociclib + Letrozole or + Fulvestrant</title>
          <description>Palbociclib should be taken by mouth with food on a 5 days on/2 days off schedule (meaning: on Days 1-5, 8-12, 15-19, and 22-26 of each 28-day cycle).&#xD;
Patients who are receiving letrozole will take it daily by mouth, every day of each 28-day cycle.&#xD;
Patients who are receiving fulvestrant will receive it as two intramuscular injections (one into each buttock) on Days 1 and 15 of Cycle 1 and then on Day 1 of each cycle thereafter.&#xD;
Goserelin is given as a subcutaneous injection every 28 days. It is preferred to be given on Day 1 of each cycle, but it may be administered on any day of the treatment cycle to accommodate its specific Q28-day cycle. It will be given to pre- or peri-menopausal women only.&#xD;
Optional research biopsy at baseline and progression&#xD;
Blood for research at baseline, cycle 1 day 15, cycle 2 day 1, every 2-3 months (to coincide with imaging studies), and time of progression</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="55"/>
          </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="61" lower_limit="34" upper_limit="86"/>
                  </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="55"/>
                  </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>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="55"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="45"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="55"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Rate of Grade 3 or Higher Neutropenia</title>
        <description>The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.&#xD;
Grade 3 neutropenia: &lt;1000-500/mm^3; &lt;1.0-0.5 x 10e9/L&#xD;
Grade 4 neutropenia: &lt;500/mm^3; &lt;0.5 x 10e9/L</description>
        <time_frame>Through the first 29 days of treatment</time_frame>
        <population>The following participants were not evaluable for this outcome measure: 4 participants did not take palbociclib dose as per protocol and were without dose-limiting toxicity; 2 participants withdrew in cycle 1, and 1 participant went off treatment in cycle 1 due to adverse events unrelated to the study.</population>
        <group_list>
          <group group_id="O1">
            <title>Palbociclib + Letrozole or + Fulvestrant</title>
            <description>Palbociclib should be taken by mouth with food on a 5 days on/2 days off schedule (meaning: on Days 1-5, 8-12, 15-19, and 22-26 of each 28-day cycle).&#xD;
Patients who are receiving letrozole will take it daily by mouth, every day of each 28-day cycle.&#xD;
Patients who are receiving fulvestrant will receive it as two intramuscular injections (one into each buttock) on Days 1 and 15 of Cycle 1 and then on Day 1 of each cycle thereafter.&#xD;
Goserelin is given as a subcutaneous injection every 28 days. It is preferred to be given on Day 1 of each cycle, but it may be administered on any day of the treatment cycle to accommodate its specific Q28-day cycle. It will be given to pre- or peri-menopausal women only.&#xD;
Optional research biopsy at baseline and progression&#xD;
Blood for research at baseline, cycle 1 day 15, cycle 2 day 1, every 2-3 months (to coincide with imaging studies), and time of progression</description>
          </group>
        </group_list>
        <measure>
          <title>Rate of Grade 3 or Higher Neutropenia</title>
          <description>The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.&#xD;
Grade 3 neutropenia: &lt;1000-500/mm^3; &lt;1.0-0.5 x 10e9/L&#xD;
Grade 4 neutropenia: &lt;500/mm^3; &lt;0.5 x 10e9/L</description>
          <population>The following participants were not evaluable for this outcome measure: 4 participants did not take palbociclib dose as per protocol and were without dose-limiting toxicity; 2 participants withdrew in cycle 1, and 1 participant went off treatment in cycle 1 due to adverse events unrelated to the study.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="47"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Rate of Grade 3 or Higher Neutropenia</title>
        <description>The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.&#xD;
Grade 3 neutropenia: &lt;1000-500/mm^3; &lt;1.0-0.5 x 10e9/L&#xD;
Grade 4 neutropenia: &lt;500/mm^3; &lt;0.5 x 10e9/L</description>
        <time_frame>Through 30 day follow-up (estimated to be 25 months)</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Rate of Palbociclib Dose Reduction</title>
        <description>-Percentage of participants who have a palbociclib dose reduction during treatment</description>
        <time_frame>Through the completion of treatment (estimated to be 24 months)</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Rate of Palbociclib Dose Interruption</title>
        <description>-Percentage of participants who have a palbociclib dose interruption during treatment</description>
        <time_frame>Through the completion of treatment (estimated to be 24 months)</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Rate of Palbociclib Discontinuation</title>
        <description>-Percentage of participants who discontinue palbociclib</description>
        <time_frame>Through the completion of treatment (estimated to be 24 months)</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Adverse Event Profile of Palbociclib</title>
        <description>-The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.</description>
        <time_frame>Through the 30 day follow-up (estimated to be 25 months)</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression-free Survival (PFS)</title>
        <description>PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.&#xD;
At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).</description>
        <time_frame>1 year</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Response Rate (Complete Response + Partial Response)</title>
        <description>Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm, dDisappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (&lt;10 mm short axis).&#xD;
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters</description>
        <time_frame>Time of progression (estimated to be 24 months)</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Clinical Benefit Rate (Complete Response + Partial Response + Stable Disease) for at Least 6 Months)</title>
        <description>Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm, dDisappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (&lt;10 mm short axis).&#xD;
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters&#xD;
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.</description>
        <time_frame>Time of progression (estimated to be 24 months)</time_frame>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse events were collected from start of treatment through 30 days following completion of treatment.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Palbociclib + Letrozole or + Fulvestrant</title>
          <description>Palbociclib should be taken by mouth with food on a 5 days on/2 days off schedule (meaning: on Days 1-5, 8-12, 15-19, and 22-26 of each 28-day cycle).&#xD;
Patients who are receiving letrozole will take it daily by mouth, every day of each 28-day cycle.&#xD;
Patients who are receiving fulvestrant will receive it as two intramuscular injections (one into each buttock) on Days 1 and 15 of Cycle 1 and then on Day 1 of each cycle thereafter.&#xD;
Goserelin is given as a subcutaneous injection every 28 days. It is preferred to be given on Day 1 of each cycle, but it may be administered on any day of the treatment cycle to accommodate its specific Q28-day cycle. It will be given to pre- or peri-menopausal women only.&#xD;
Optional research biopsy at baseline and progression&#xD;
Blood for research at baseline, cycle 1 day 15, cycle 2 day 1, every 2-3 months (to coincide with imaging studies), and time of progression</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Asystole</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Generalized weakness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Failure to thrive</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Intracranial hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Acute kidney injury</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Cellulitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Superficial thrombophlebitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="54" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" subjects_affected="41" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Gout</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Chest pain - cardiac</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Heart failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Mitral valve disease</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Tinnitus</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Vertigo</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Vestibular schwannoma</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Hypothyroidism</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Blurred vision</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Cataract</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Dry eye</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Eye lid pain/soreness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Photophobia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Red eye</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Watering eyes</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Broken tooth</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>C. difficile</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="17" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="28" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Dry lips</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Dysphagia</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Gastric ulcer</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Gastroesophageal reflux disease</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Gingival pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Gout</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Hematochezia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Hemorrhoidal hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Hemorrhoids</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" subjects_affected="14" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="31" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Oral dysesthesia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Oral pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Stomach pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Toothache</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Ulcerative colitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Body aches</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Breast pain</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Buttock pain</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" subjects_affected="12" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Cold sensitivity</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Common cold</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Dilation of appendix with periappendiceal fat stranding seen on CT</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Edema face</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Edema limbs</sub_title>
                <counts group_id="E1" subjects_affected="17" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Edema trunk</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="45" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Flu-like symptoms</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Gait disturbance</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Hyperhidrosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Itchy scalp</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Mole pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="19" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Peeling lips</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Right arm numbness</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Right thumb bump</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Sciatic pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Tick bite</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Allergic reaction</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Acute bronchitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Bronchitis</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>COVID-19</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Extremity infection</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Otitis media</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Paronychia - infection right middle</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Pharyngitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Respiratory syncytial virus (RSV)</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Sinusitis</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Skin infection</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Tooth infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Upper respiratory infection</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Yeast infection under right breast</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Bruising</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Bug bite</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Burn - left hand</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Fracture</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Head injury - upper left occipital swelling</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Left hand puncture wound</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Radiation recall reaction (dermatologic)</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Snake bite</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Spinal fracture</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Wrist fracture</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Activated partial thromboplastin time prolonged</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Creatinine increased</sub_title>
                <counts group_id="E1" subjects_affected="18" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Hemoglobin increased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>INR increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" subjects_affected="39" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Lymphocyte count increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" subjects_affected="47" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" subjects_affected="18" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Weight gain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>White blood cell count decreased</sub_title>
                <counts group_id="E1" subjects_affected="49" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" subjects_affected="22" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Hypercalcemia</sub_title>
                <counts group_id="E1" subjects_affected="19" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Hyperkalemia</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Hypernatremia</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Hypocalcemia</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Hypoglycemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Hypomagnesemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" subjects_affected="17" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="24" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Arthritis</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="29" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Bilateral leg pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Bone pain</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Chest wall pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Flank pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Hand cramps</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Hip pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Knee pain</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Left sided flank pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Leg stiffness</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Muscle cramp</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Muscle spasm</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Muscle weakness lower limb</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Neck pain</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Osteonecrosis of jaw</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Osteopenia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Right arm pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Sacroliac joint pain</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Shoulder pain</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Sternum pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Acoustic neuroma</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="22" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Facial nerve disorder</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="24" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Paresthesia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Peripheral motor neuropathy</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Peripheral sensory neuropathy</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Right arm numbness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Sinus pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Spasticity</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>ADHD</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="14" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Confusion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Hallucinations</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="21" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Mood swings</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Urinary frequency</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Urinary retention</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Urine discoloration</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Vaginal discharge</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Vaginal dryness</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Vaginal itch</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Allergic rhinitis</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Asthma</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="23" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="17" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Hoarseness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Laryngeal inflammation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Nasal drainage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Nasal dryness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Postnasal drip</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Productive cough</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Rhinovirus</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Sleep apnea</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Sore throat</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Voice alteration</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" subjects_affected="23" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Blister</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Brittle nail</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Erythema multiforme</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Erythema right breast</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Eye lid pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Hyperhidrosis</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Itchy skin</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Nail loss</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Nodule</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Open cutaneous area left breast</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Oral fissure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Peeling skin palms of hands</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Psoriasis</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Rash acneiform</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Rash maculopapular</sub_title>
                <counts group_id="E1" subjects_affected="12" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Skin bumps</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Skin hypopigmentation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Sores bilateral nares</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Stomach rash</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Tender nail bed</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hot flashes</sub_title>
                <counts group_id="E1" subjects_affected="28" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="47" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Lymphedema</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="54"/>
              </event>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="54"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

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


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03007979
org study id: 201612098
nct id: NCT03007979
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
The investigators propose to conduct a study to test an alternative dosing schedule of
      palbociclib. With the current three-week on and one week off schedule, a significant number
      of patients develop grade 3 or higher degree of neutropenia and require dose reduction and
      sometimes discontinuation. This potentially compromises the efficacy of the drug. In
      addition, as the half-life of palbociclib is 27 hours, 1 week break with the standard 3 weeks
      on and 1 week off dosing schedule could potentially lead to recovery of Rb phosphorylation
      during the off week. Hence, the investigators propose a 5 days on and 2 days off schedule
      each week without any weeks off drug. Although the cumulative doses each 28-day cycle is
      roughly the same with this schedule compared to conventional dosing, the bone marrow is not
      exposed to the drug continuously for 21 days and rather gets frequent breaks from therapy.
      The investigators hypothesize that the 5 days on and 2 days off schedule is more tolerable
      with less frequent high grade neutropenia and dose interruption/reduction. In addition, this
      schedule also provides for a more continuous drug delivery to the patient since there is not
      a week's break in therapy, which could ultimately prove to be more efficacious.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Rate of Grade 3 or Higher Neutropenia
time frame: Through the first 29 days of treatment
description: The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.
Grade 3 neutropenia: <1000-500/mm^3; <1.0-0.5 x 10e9/L
Grade 4 neutropenia: <500/mm^3; <0.5 x 10e9/L
measure: Rate of Grade 3 or Higher Neutropenia
time frame: Through 30 day follow-up (estimated to be 25 months)
description: The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.
Grade 3 neutropenia: <1000-500/mm^3; <1.0-0.5 x 10e9/L
Grade 4 neutropenia: <500/mm^3; <0.5 x 10e9/L
measure: Rate of Palbociclib Dose Reduction
time frame: Through the completion of treatment (estimated to be 24 months)
description: -Percentage of participants who have a palbociclib dose reduction during treatment
measure: Rate of Palbociclib Dose Interruption
time frame: Through the completion of treatment (estimated to be 24 months)
description: -Percentage of participants who have a palbociclib dose interruption during treatment
measure: Rate of Palbociclib Discontinuation
time frame: Through the completion of treatment (estimated to be 24 months)
description: -Percentage of participants who discontinue palbociclib
measure: Adverse Event Profile of Palbociclib
time frame: Through the 30 day follow-up (estimated to be 25 months)
description: -The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.
measure: Progression-free Survival (PFS)
time frame: 1 year
description: PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.
At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).
measure: Overall Response Rate (Complete Response + Partial Response)
time frame: Time of progression (estimated to be 24 months)
description: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm, dDisappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis).
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters
measure: Clinical Benefit Rate (Complete Response + Partial Response + Stable Disease) for at Least 6 Months)
time frame: Time of progression (estimated to be 24 months)
description: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm, dDisappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis).
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
arm group label: Palbociclib + letrozole or + fulvestrant
arm group type: Experimental
description: Palbociclib should be taken by mouth with food on a 5 days on/2 days off schedule (meaning: on Days 1-5, 8-12, 15-19, and 22-26 of each 28-day cycle).
Patients who are receiving letrozole will take it daily by mouth, every day of each 28-day cycle.
Patients who are receiving fulvestrant will receive it as two intramuscular injections (one into each buttock) on Days 1 and 15 of Cycle 1 and then on Day 1 of each cycle thereafter.
Goserelin is given as a subcutaneous injection every 28 days. It is preferred to be given on Day 1 of each cycle, but it may be administered on any day of the treatment cycle to accommodate its specific Q28-day cycle. It will be given to pre- or peri-menopausal women only.
Optional research biopsy at baseline and progression
Blood for research at baseline, cycle 1 day 15, cycle 2 day 1, every 2-3 months (to coincide with imaging studies), and time of progression
intervention type: Drug
intervention name: Palbociclib
description: Palbociclib at a dose of 125 mg should be taken by mouth with food on a 5 days on/2 days off schedule
arm group label: Palbociclib + letrozole or + fulvestrant
other name: Ibrance
intervention type: Drug
intervention name: Letrozole
description: Patients who are receiving letrozole will take it daily by mouth, every day of each 28-day cycle, at a dose of 2.5 mg.
arm group label: Palbociclib + letrozole or + fulvestrant
other name: Femara
intervention type: Drug
intervention name: Fulvestrant
description: Patients who are receiving fulvestrant will receive it at a dose of 500 mg as two 5 mL intramuscular injections (one into each buttock) on Days 1 and 15 of Cycle 1 and then on Day 1 of each cycle thereafter.
arm group label: Palbociclib + letrozole or + fulvestrant
other name: Faslodex
intervention type: Procedure
intervention name: Optional research biopsy
description: Patients may consent to paired tumor biopsies at baseline and time of progression.
arm group label: Palbociclib + letrozole or + fulvestrant
intervention type: Drug
intervention name: Goserelin
description: Goserelin is given as a subcutaneous injection every 28 days. It is preferred to be given on Day 1 of each cycle, but it may be administered on any day of the treatment cycle to accommodate its specific Q28-day cycle. It will be given to pre- and peri-menopausal women only.
arm group label: Palbociclib + letrozole or + fulvestrant
other name: Zoladex
intervention type: Procedure
intervention name: Research blood draw
description: -Blood will be drawn at the following time points for serum, plasma, cfDNA, and germline DNA (only at baseline):
Baseline
C1D15
C2D1
Every 2-3 months thereafter (to coincide with imaging studies)
Time of progression
arm group label: Palbociclib + letrozole or + fulvestrant
intervention type: Procedure
intervention name: Circulating tumor cell blood draw
description: -Baseline, cycle 2 day 1, post 2 or 3 months of therapy (to coincide with first tumor imaging), and progression
arm group label: Palbociclib + letrozole or + fulvestrant
intervention type: Procedure
intervention name: Tumor biopsy (optional)
description: -Baseline and progression
arm group label: Palbociclib + letrozole or + fulvestrant
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Cynthia X Ma, M.D., Ph.D.
role: Principal Investigator
affiliation: Washington University School of Medicine
facility: 
facility: 
country: United States
url: http://www.siteman.wustl.edu
description: Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Letrozole
mesh term: Fulvestrant
mesh term: Palbociclib
mesh term: Goserelin
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 