<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/NCT03018080</url>
  </required_header>
  <id_info>
    <org_study_id>IRB00081370</org_study_id>
    <secondary_id>00019078</secondary_id>
    <secondary_id>LCI-BRE-H2N-PEPP-001</secondary_id>
    <nct_id>NCT03018080</nct_id>
  </id_info>
  <brief_title>Pilot Study of Paclitaxel Plus Pembrolizumab in Metastatic HER2-Negative Breast Cancer</brief_title>
  <acronym>PePPy</acronym>
  <official_title>LCI-BRE-H2N-PEPP-001: A Pilot Study of Paclitaxel Plus Pembrolizumab in Patients With Metastatic HER2-Negative Breast Cancer (The PePPy Trial)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Wake Forest University Health Sciences</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Merck Sharp &amp; Dohme LLC</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Wake Forest University Health Sciences</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The primary objective of this study is to assess the safety and feasibility of the following&#xD;
      two regimens: Cohort A) phased regimen of pembrolizumab in which paclitaxel is followed by&#xD;
      paclitaxel plus pembrolizumab and Cohort B) concurrent regimen of paclitaxel plus&#xD;
      pembrolizumab. The primary safety objective is to evaluate the overall grade 3 or 4&#xD;
      treatment-related adverse event rate for each cohort and compare them to relevant historical&#xD;
      controls.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is an open-label randomized pilot research study to determine if the study drug,&#xD;
      pembrolizumab, is safe to use in combination with a chemotherapy drug called paclitaxel. This&#xD;
      study will have the following two regimens: Cohort A) phased regimen of pembrolizumab in&#xD;
      which paclitaxel is followed by paclitaxel plus pembrolizumab and Cohort B) concurrent&#xD;
      regimen of paclitaxel plus pembrolizumab. A total of 40 evaluable subjects will be enrolled&#xD;
      over an enrollment period of 18-24 months. The study is planned to enroll approximately 20&#xD;
      evaluable subjects in each treatment cohort.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 12, 2017</start_date>
  <completion_date type="Actual">August 5, 2022</completion_date>
  <primary_completion_date type="Actual">July 29, 2021</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Participants With at Least One Grade 3 or 4 Treatment-related Adverse Event</measure>
    <time_frame>From enrollment to at least 30 days following cessation of study treatment. The median time on treatment was 5.5 months.</time_frame>
    <description>Grade 3 or 4 study treatment-related adverse events will be determined for each subject as a binary variable indicating whether or not the subject experienced at least one grade 3 or 4 study treatment-related adverse events according to the NCI Common Terminology for Adverse Events, version 4.0. An adverse event will be considered study treatment related if it is determined that the event is at least possibly related to either paclitaxel, pembrolizumab, or both.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Subjects With an Objective Response (Per RECIST V1.1)</measure>
    <time_frame>From enrollment to best response while on study treatment; subjects remained on treatment until disease progression or death or unacceptable toxicity (subjects were on treatment for a median of 5.5 months)</time_frame>
    <description>Objective response was determined for each subject as a binary variable indicating whether or not the subject achieved a best overall response of complete response (CR) or partial response (PR) as determined by RECIST 1.1 response criteria. A CR is indicated by disappearance of all target and non target lesions. A PR is indicated by &gt;=30% decrease in sum of longest diameter of target lesions with baseline as reference.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free Survival (PFS) Per RECIST 1.1</measure>
    <time_frame>From treatment start date to date of progression/death, or censored as described; assessed for approximately 2 years.</time_frame>
    <description>PFS is defined as the duration of time from treatment start date to first occurrence of either progressive disease (PD) or death. PD must be objectively determined per RECIST 1.1 criteria, where progression date is date of last assessment that identified PD. If subject died without documented PD, progression date will be death date. For surviving subjects who do not have PD, PFS will be censored at the date of last disease assessment. For subjects who received subsequent anti-cancer therapy prior to documented PD, PFS will be censored at the date of last disease assessment prior to commencement of subsequent therapy. Subjects who have an initial PFS event immediately following 2 or more consecutive missed assessments will be censored at date of last assessment prior to missed assessments.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>From date of treatment start to date of death, or censored as described; assessed for approximately 5 years.</time_frame>
    <description>OS is defined as the duration from treatment start date to the date of death from any cause. Subjects who are alive or lost to follow up at the time of the analysis will be censored at the last known date they were alive.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Subjects With Disease Control (Per RECIST V1.1)</measure>
    <time_frame>From enrollment to best response while on study treatment; subjects remained on treatment until disease progression or death or unacceptable toxicity (subjects were on treatment for a median of 5.5 months)</time_frame>
    <description>Disease control was determined for each subject as a binary variable indicating whether or not the subject achieved a best overall response of complete response (CR), partial response (PR), or stable disease (SD) as determined by RECIST 1.1 response criteria. A CR is indicated by disappearance of all target and non target lesions. A PR is indicated by &gt;=30% decrease in sum of longest diameter of target lesions with baseline as reference. SD is indicated by neither sufficient shrinkage to qualify for PR nor sufficient growth from nadir (&gt;=20%) to indicate progression.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Response (DoR)</measure>
    <time_frame>From date of response to date of progression/death, or censored as described above; assessed for approximately 2 years.</time_frame>
    <description>Duration of Response (DoR) is defined as the duration of time from the first assessment that determined a CR or PR to the date of the first occurrence of progressive disease or death. Progression events and the censoring mechanism for DoR will be the same as described for PFS. DoR will be determined for each subject using the RECIST 1.1 criteria.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">40</enrollment>
  <condition>Breast - Female</condition>
  <condition>Male Breast Cancer</condition>
  <arm_group>
    <arm_group_label>Arm A (Phased Pembrolizumab Regimen)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Paclitaxel will be given as an IV infusion over 60 minutes, on days 1 and 8 every 21 (+/- 3) days during Cycles 1 and 2. No pembrolizumab will be given during Cycles 1 and 2. Starting with cycle 3 and subsequent cycles, pembrolizumab will be given as an IV infusion over 30 minutes before paclitaxel on day 1 every 21 (+/- 3) days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm B (Concurrent Pembrolizumab Regimen)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Pembrolizumab will be given as an IV infusion on day 1 before paclitaxel every 21 (+/- 3) days. Paclitaxel will be given as an IV infusion over 60 minutes, on days 1 and 8 every 21 (+/- 3) days.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>IV (in the vein) on day 1 of a 21 day cycle</description>
    <arm_group_label>Arm A (Phased Pembrolizumab Regimen)</arm_group_label>
    <arm_group_label>Arm B (Concurrent Pembrolizumab Regimen)</arm_group_label>
    <other_name>Keytruda</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Paclitaxel</intervention_name>
    <description>IV (in the vein) on days 1 and 8 of a 21 day cycle</description>
    <arm_group_label>Arm A (Phased Pembrolizumab Regimen)</arm_group_label>
    <arm_group_label>Arm B (Concurrent Pembrolizumab Regimen)</arm_group_label>
    <other_name>Taxol</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria&#xD;
&#xD;
        Subjects must meet all of the following criteria:&#xD;
&#xD;
          1. Histologically or cytological confirmed diagnosis of HER2-negative metastatic breast&#xD;
             cancer or locally advanced disease not amenable to resection.&#xD;
&#xD;
               -  Available ER and PR status from tumor sample with either hormone receptor&#xD;
                  positive or negative tumor(s).&#xD;
&#xD;
               -  For subjects with hormone receptor-positive, HER2-negative metastatic breast&#xD;
                  cancer, they are eligible if they have already received or been intolerant to at&#xD;
                  least two lines of endocrine therapies (including the adjuvant and/or metastatic&#xD;
                  setting), or are appropriate candidates for chemotherapy (i.e. large burden of&#xD;
                  visceral disease).&#xD;
&#xD;
          2. Measurable disease by RECIST 1.1, or evaluable bone disease, i.e., bone lesions that&#xD;
             are lytic or mixed (i.e. lytic + sclerotic) in the absence of measurable lesion. Refer&#xD;
             to section 11 for the evaluation of measurable disease.&#xD;
&#xD;
          3. Male or female age ≥18 years.&#xD;
&#xD;
          4. ECOG performance status 0, 1 or 2.&#xD;
&#xD;
          5. Must have normal organ and marrow function as defined below:&#xD;
&#xD;
               -  Hematologic - Absolute neutrophil count ≥1,500/mcL&#xD;
&#xD;
                  - Platelets ≥75,000/mcL&#xD;
&#xD;
                  - Hemoglobin ≥ 9 g/dL&#xD;
&#xD;
               -  Renal&#xD;
&#xD;
                    -  Creatinine ≤ 1.5X ULN or&#xD;
&#xD;
                    -  Measured or calculated creatinine clearance (CrCl) ≥ 30 mL/min for subject&#xD;
                       with creatinine levels &gt; 1.5X ULN [CrCl should be calculated per&#xD;
                       institutional standard; GFR can also be used in place of creatinine or CrCl]&#xD;
&#xD;
               -  Hepatic&#xD;
&#xD;
                    -  Total bilirubin ≤1.5X ULN or for subjects with total bilirubin levels &gt;1.5X&#xD;
                       ULN, direct bilirubin ≤ULN&#xD;
&#xD;
                    -  AST(SGOT)/ALT(SGPT) ≤2.5X ULN&#xD;
&#xD;
               -  Coagulation&#xD;
&#xD;
                    -  PT and PTT ≤ 1.5X ULN; subjects receiving anticoagulant therapy are eligible&#xD;
                       if PT or PTT is within therapeutic range of intended use of anticoagulants&#xD;
                       per investigator discretion.&#xD;
&#xD;
                    -  INR ≤ 1.5; Patients receiving anticoagulant therapy are eligible if their&#xD;
                       INR is stable and within the recommended range for the desired level of&#xD;
                       anticoagulation per investigator discretion.&#xD;
&#xD;
          6. Female subjects of childbearing potential must have a negative serum or urine&#xD;
             pregnancy test within 14 days prior to receiving C1D1.&#xD;
&#xD;
          7. Female subjects of childbearing potential must be willing to use an adequate method of&#xD;
             birth control as outlined in Section 8.1.10, be surgically sterile, or abstain from&#xD;
             heterosexual activity for the course of the study and 120 days after the last dose of&#xD;
             study therapy. Subjects of childbearing potential are those who have not been&#xD;
             surgically sterilized or have not been free from menses for &gt; 1 year. Male subjects of&#xD;
             reproductive potential should agree to use an adequate method of contraception&#xD;
             starting with the first dose of study therapy and 120 days after the last dose of&#xD;
             study therapy. Abstinence is acceptable if this is the established and preferred&#xD;
             contraception for the subject.&#xD;
&#xD;
          8. Has completed the screening requirement of a core or punch biopsy of a tumor lesion&#xD;
             per Section 5 (bone tissue not acceptable). Biopsy of the breast tumor or other&#xD;
             regional areas is acceptable (i.e. lymph nodes, skin lesions).&#xD;
&#xD;
               -  Subjects who are unable to meet the screening requirement of a tumor biopsy due&#xD;
                  to inaccessible tumor, subject safety concern, or bone-only disease may submit an&#xD;
                  archived tumor specimen from primary tumor or metastatic biopsy collected within&#xD;
                  12 months from consent.&#xD;
&#xD;
               -  Subjects who decline tumor biopsy may submit archived tumor specimen as specified&#xD;
                  above (within 12 months from consent) only after Sponsor-Investigator approval.&#xD;
&#xD;
          9. Ability to understand and the willingness to sign the written informed consent&#xD;
             document.&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
        Subjects must not meet any of the following criteria:&#xD;
&#xD;
          1. Prior chemotherapy within 3 weeks, prior targeted small molecule therapy or radiation&#xD;
             therapy within 2 weeks, or prior anti-cancer monoclonal antibody (mAb) for direct&#xD;
             anti-neoplastic treatment within 4 weeks prior to Cycle 1 Day 1.&#xD;
&#xD;
          2. Not recovered (i.e., ≤ Grade 1) from adverse events due to agents previously&#xD;
             administered.&#xD;
&#xD;
             o Note: Subjects with ≤ Grade 2 neuropathy or alopecia of any grade are an exception&#xD;
             and may qualify for the study.&#xD;
&#xD;
          3. More than three prior lines of chemotherapy for HER2-negative metastatic disease or&#xD;
             for locally advanced disease that is not amenable to resection.&#xD;
&#xD;
             o Note: Non-Chemotherapy regimens do not count as prior lines (ex: hormonals,&#xD;
             biologics)&#xD;
&#xD;
          4. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 agent or with an&#xD;
             agent directed to another co-inhibitory T-cell receptor (e.g. CTLA-4, OX-40, CD137) or&#xD;
             has participated in Merck MK-3475 trial(s) and received MK-3475 as part of protocol&#xD;
             therapy.&#xD;
&#xD;
          5. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any&#xD;
             other form of immunosuppressive therapy within 7 days prior to Cycle 1 Day 1&#xD;
&#xD;
          6. Has had major surgery within 3 weeks prior to Cycle 1 Day 1.&#xD;
&#xD;
          7. Has received any other investigational agents within 4 weeks of Cycle 1 Day 1 of study&#xD;
             therapy.&#xD;
&#xD;
          8. Known active uncontrolled or symptomatic central nervous system (CNS) metastases&#xD;
             and/or carcinomatous meningitis as indicated by clinical symptoms, cerebral edema,&#xD;
             and/or progressive growth.&#xD;
&#xD;
             o Note: Subjects with treated CNS metastases are eligible if they are asymptomatic,&#xD;
             have no requirement for steroids, no requirement for anticonvulsants, and stable CNS&#xD;
             radiographic study showing no significant vasogenic edema ≥ 4 weeks since completion&#xD;
             of radiation and ≥ 2 weeks since discontinuation of steroids.&#xD;
&#xD;
          9. History of known allergic reaction to paclitaxel&#xD;
&#xD;
         10. Has a history or current evidence of any condition, therapy, or laboratory abnormality&#xD;
             that might interfere with the subject's participation for the full duration of the&#xD;
             trial, or is not in the best interest of the subject to participate, in the opinion of&#xD;
             the treating investigator.&#xD;
&#xD;
         11. Is pregnant or breastfeeding, or expecting to conceive or father children within the&#xD;
             projected duration of the trial, starting with the screening visit through 120 days&#xD;
             after the last dose of trial treatment. Pregnant women are excluded from this study&#xD;
             because paclitaxel is an agent with the potential for teratogenic or abortifacient&#xD;
             effects. Because there is an unknown but potential risk for adverse events in nursing&#xD;
             infants secondary to treatment of the mother with paclitaxel, breastfeeding should be&#xD;
             discontinued if the mother is treated with paclitaxel. These potential risks also&#xD;
             apply to pembrolizumab being used in this study.&#xD;
&#xD;
         12. Has a known history of Human Immunodeficiency Virus (HIV) or known acquired&#xD;
             immunodeficiency disorder (AIDS). HIV-positive patients on combination antiretroviral&#xD;
             therapy are ineligible because of the potential for pharmacokinetic interactions with&#xD;
             paclitaxel and pembrolizumab. In addition, these patients are at increased risk of&#xD;
             lethal infections when treated with marrow-suppressive therapy.&#xD;
&#xD;
         13. Has known active infection with hepatitis B or hepatitis C.&#xD;
&#xD;
         14. Has an active autoimmune disease that has required systemic treatment in past 2 years&#xD;
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive&#xD;
             drugs).&#xD;
&#xD;
             o Replacement therapy (i.e., thyroxine, insulin, or physiologic corticosteroid&#xD;
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a&#xD;
             form of systemic treatment.&#xD;
&#xD;
         15. Has a known additional malignancy that progressed or required active treatment within&#xD;
             the last 5 years.&#xD;
&#xD;
             o Note: Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma&#xD;
             of the skin that has undergone potentially curative therapy, or in situ cervical&#xD;
             cancer.&#xD;
&#xD;
         16. Has a history of (non-infectious) pneumonitis that required steroids or current&#xD;
             pneumonitis.&#xD;
&#xD;
         17. Has an active infection requiring systemic therapy.&#xD;
&#xD;
         18. Has known psychiatric or substance abuse disorders that would interfere with&#xD;
             cooperation with the requirements of the trial.&#xD;
&#xD;
         19. Has received a live vaccine within 30 days of Cycle 1 Day 1 of study therapy. o Note:&#xD;
             Seasonal influenza vaccines for injection are generally inactivated flu vaccines and&#xD;
             are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live&#xD;
             attenuated vaccines, and are not allowed.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Antoinette Tan, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Atrium Health (formerly Carolinas HealthCare System)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Levine Cancer Institute</name>
      <address>
        <city>Charlotte</city>
        <state>North Carolina</state>
        <zip>28204</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, Pusztai L, Pathiraja K, Aktan G, Cheng JD, Karantza V, Buisseret L. Pembrolizumab in Patients With Advanced Triple-Negative Breast Cancer: Phase Ib KEYNOTE-012 Study. J Clin Oncol. 2016 Jul 20;34(21):2460-7. doi: 10.1200/JCO.2015.64.8931. Epub 2016 May 2.</citation>
    <PMID>27138582</PMID>
  </reference>
  <results_reference>
    <citation>Tan AR, Chai SJ, Robinson MM, Hellner LB, Gavini N, Sulai N, Turner JD, Atlas J, Graham DL, Induru RR, Kadakia KC, Vallabhanei GD, Heeke AL, Foureau DM, Fisher JG. A pilot study of paclitaxel plus pembrolizumab in patients with metastatic HER2-negative breast cancer (PePPy). Cancer Research. 2022; 82(4_Supplement): P2-14-03</citation>
  </results_reference>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>January 10, 2017</study_first_submitted>
  <study_first_submitted_qc>January 10, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 11, 2017</study_first_posted>
  <results_first_submitted>July 29, 2022</results_first_submitted>
  <results_first_submitted_qc>September 15, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">October 13, 2022</results_first_posted>
  <last_update_submitted>July 26, 2023</last_update_submitted>
  <last_update_submitted_qc>July 26, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 4, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
    <mesh_term>Breast Neoplasms, Male</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Paclitaxel</mesh_term>
    <mesh_term>Pembrolizumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</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 13, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/80/NCT03018080/Prot_SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>June 9, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/80/NCT03018080/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Arm A (Phased Pembrolizumab Regimen)</title>
          <description>Paclitaxel will be given as an IV infusion over 60 minutes, on days 1 and 8 every 21 (+/- 3) days during Cycles 1 and 2. No pembrolizumab will be given during Cycles 1 and 2. Starting with cycle 3 and subsequent cycles, pembrolizumab will be given as an IV infusion over 30 minutes before paclitaxel on day 1 every 21 (+/- 3) days.&#xD;
Pembrolizumab: IV (in the vein) on day 1 of a 21 day cycle&#xD;
Paclitaxel: IV (in the vein) on days 1 and 8 of a 21 day cycle</description>
        </group>
        <group group_id="P2">
          <title>Arm B (Concurrent Pembrolizumab Regimen)</title>
          <description>Pembrolizumab will be given as an IV infusion on day 1 before paclitaxel every 21 (+/- 3) days. Paclitaxel will be given as an IV infusion over 60 minutes, on days 1 and 8 every 21 (+/- 3) days.&#xD;
Pembrolizumab: IV (in the vein) on day 1 of a 21 day cycle&#xD;
Paclitaxel: IV (in the vein) on days 1 and 8 of a 21 day cycle</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="21"/>
                <participants group_id="P2" count="19"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="12"/>
                <participants group_id="P2" count="19"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="12"/>
                <participants group_id="P2" count="19"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Arm A (Phased Pembrolizumab Regimen)</title>
          <description>Paclitaxel will be given as an IV infusion over 60 minutes, on days 1 and 8 every 21 (+/- 3) days during Cycles 1 and 2. No pembrolizumab will be given during Cycles 1 and 2. Starting with cycle 3 and subsequent cycles, pembrolizumab will be given as an IV infusion over 30 minutes before paclitaxel on day 1 every 21 (+/- 3) days.&#xD;
Pembrolizumab: IV (in the vein) on day 1 of a 21 day cycle&#xD;
Paclitaxel: IV (in the vein) on days 1 and 8 of a 21 day cycle</description>
        </group>
        <group group_id="B2">
          <title>Arm B (Concurrent Pembrolizumab Regimen)</title>
          <description>Pembrolizumab will be given as an IV infusion on day 1 before paclitaxel every 21 (+/- 3) days. Paclitaxel will be given as an IV infusion over 60 minutes, on days 1 and 8 every 21 (+/- 3) days.&#xD;
Pembrolizumab: IV (in the vein) on day 1 of a 21 day cycle&#xD;
Paclitaxel: IV (in the vein) on days 1 and 8 of a 21 day cycle</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="21"/>
            <count group_id="B2" value="19"/>
            <count group_id="B3" value="40"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="27"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="54" lower_limit="28" upper_limit="73"/>
                    <measurement group_id="B2" value="57" lower_limit="40" upper_limit="76"/>
                    <measurement group_id="B3" value="56.5" lower_limit="28" upper_limit="76"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="21"/>
                    <measurement group_id="B2" value="19"/>
                    <measurement group_id="B3" value="40"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="18"/>
                    <measurement group_id="B2" value="19"/>
                    <measurement group_id="B3" value="37"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                    <measurement group_id="B2" value="15"/>
                    <measurement group_id="B3" value="29"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="21"/>
                    <measurement group_id="B2" value="19"/>
                    <measurement group_id="B3" value="40"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>ECOG at Baseline</title>
          <description>Measure Description: ECOG Scale of Performance Status, developed by the Eastern Cooperative Oncology Group.&#xD;
(0) subject is fully active, able to carry on all predisease performance without restriction; (1) subject is restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (e.g., light house work, office work); (2) subject is ambulatory and capable of all self-care but unable to carry out any work activities (up and about more than 50% of waking hours)</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>0</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="17"/>
                  </measurement_list>
                </category>
                <category>
                  <title>1</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="13"/>
                    <measurement group_id="B3" value="21"/>
                  </measurement_list>
                </category>
                <category>
                  <title>2</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Hormone Receptor Status</title>
          <description>Hormone receptor (HR) status was determined based on tumor samples. Subject was HR positive if ER% or PR% were &gt;=10%. If ER% and PR% were &lt;10%, then subject was considered HR negative.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>HR Positive</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="20"/>
                  </measurement_list>
                </category>
                <category>
                  <title>HR Negative</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Prior Paclitaxel Exposure</title>
          <description>Indicates whether or not the subject had previously received paclitaxel in any setting.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Prior Paclitaxel</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="14"/>
                  </measurement_list>
                </category>
                <category>
                  <title>No Prior Paclitaxel</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="23"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Prior Docetaxel Exposure</title>
          <description>Indicates whether or not the subject had previously received docetaxel in any setting</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Prior Docetaxel</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="18"/>
                  </measurement_list>
                </category>
                <category>
                  <title>No Prior Docetaxel</title>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="20"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Number of Prior Metastatic Chemotherapy Lines</title>
          <description>Indicates the number of prior lines of chemotherapy that the subject received in the metastatic setting</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>0</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="18"/>
                  </measurement_list>
                </category>
                <category>
                  <title>1</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>2</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
                <category>
                  <title>3</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With at Least One Grade 3 or 4 Treatment-related Adverse Event</title>
        <description>Grade 3 or 4 study treatment-related adverse events will be determined for each subject as a binary variable indicating whether or not the subject experienced at least one grade 3 or 4 study treatment-related adverse events according to the NCI Common Terminology for Adverse Events, version 4.0. An adverse event will be considered study treatment related if it is determined that the event is at least possibly related to either paclitaxel, pembrolizumab, or both.</description>
        <time_frame>From enrollment to at least 30 days following cessation of study treatment. The median time on treatment was 5.5 months.</time_frame>
        <population>The evaluable population will consist of all randomized subjects who begin study therapy.</population>
        <group_list>
          <group group_id="O1">
            <title>Arm A (Phased Pembrolizumab Regimen)</title>
            <description>Paclitaxel will be given as an IV infusion over 60 minutes, on days 1 and 8 every 21 (+/- 3) days during Cycles 1 and 2. No pembrolizumab will be given during Cycles 1 and 2. Starting with cycle 3 and subsequent cycles, pembrolizumab will be given as an IV infusion over 30 minutes before paclitaxel on day 1 every 21 (+/- 3) days.&#xD;
Pembrolizumab: IV (in the vein) on day 1 of a 21 day cycle&#xD;
Paclitaxel: IV (in the vein) on days 1 and 8 of a 21 day cycle</description>
          </group>
          <group group_id="O2">
            <title>Arm B (Concurrent Pembrolizumab Regimen)</title>
            <description>Pembrolizumab will be given as an IV infusion on day 1 before paclitaxel every 21 (+/- 3) days. Paclitaxel will be given as an IV infusion over 60 minutes, on days 1 and 8 every 21 (+/- 3) days.&#xD;
Pembrolizumab: IV (in the vein) on day 1 of a 21 day cycle&#xD;
Paclitaxel: IV (in the vein) on days 1 and 8 of a 21 day cycle</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With at Least One Grade 3 or 4 Treatment-related Adverse Event</title>
          <description>Grade 3 or 4 study treatment-related adverse events will be determined for each subject as a binary variable indicating whether or not the subject experienced at least one grade 3 or 4 study treatment-related adverse events according to the NCI Common Terminology for Adverse Events, version 4.0. An adverse event will be considered study treatment related if it is determined that the event is at least possibly related to either paclitaxel, pembrolizumab, or both.</description>
          <population>The evaluable population will consist of all randomized subjects who begin study therapy.</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="21"/>
                <count group_id="O2" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                    <measurement group_id="O2" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>The reported grade 3/4 toxicity rate with weekly paclitaxel was 0.35. If it became evident that the grade 3/4 treatment-related toxicity rate on either arm convincingly exceeded 0.35, the study arm would have been halted. Convincing evidence of exceeding 0.35 was based on Bayesian methods and continuous monitoring, where the stopping rule would have held enrollment if the posterior probability at any point exceeded 0.50 or higher.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Estimation only.</non_inferiority_desc>
            <param_type>Rate</param_type>
            <param_value>0.238</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.082</ci_lower_limit>
            <ci_upper_limit>0.472</ci_upper_limit>
            <estimate_desc>Confidence interval estimated using the Clopper Pearson method.</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The reported grade 3/4 toxicity rate with weekly paclitaxel was 0.35. If it became evident that the grade 3/4 treatment-related toxicity rate on either arm convincingly exceeded 0.35, the study arm would have been halted. Convincing evidence of exceeding 0.35 was based on Bayesian methods and continuous monitoring, where the stopping rule would have held enrollment if the posterior probability at any point exceeded 0.50 or higher.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Estimation only.</non_inferiority_desc>
            <param_type>Rate</param_type>
            <param_value>0.316</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.126</ci_lower_limit>
            <ci_upper_limit>0.566</ci_upper_limit>
            <estimate_desc>Confidence interval estimated using the Clopper Pearson method.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Subjects With an Objective Response (Per RECIST V1.1)</title>
        <description>Objective response was determined for each subject as a binary variable indicating whether or not the subject achieved a best overall response of complete response (CR) or partial response (PR) as determined by RECIST 1.1 response criteria. A CR is indicated by disappearance of all target and non target lesions. A PR is indicated by &gt;=30% decrease in sum of longest diameter of target lesions with baseline as reference.</description>
        <time_frame>From enrollment to best response while on study treatment; subjects remained on treatment until disease progression or death or unacceptable toxicity (subjects were on treatment for a median of 5.5 months)</time_frame>
        <population>The evaluable population will consist of all randomized subjects who begin study therapy and have measurable disease at baseline.</population>
        <group_list>
          <group group_id="O1">
            <title>Arm A (Phased Pembrolizumab Regimen)</title>
            <description>Paclitaxel will be given as an IV infusion over 60 minutes, on days 1 and 8 every 21 (+/- 3) days during Cycles 1 and 2. No pembrolizumab will be given during Cycles 1 and 2. Starting with cycle 3 and subsequent cycles, pembrolizumab will be given as an IV infusion over 30 minutes before paclitaxel on day 1 every 21 (+/- 3) days.&#xD;
Pembrolizumab: IV (in the vein) on day 1 of a 21 day cycle&#xD;
Paclitaxel: IV (in the vein) on days 1 and 8 of a 21 day cycle</description>
          </group>
          <group group_id="O2">
            <title>Arm B (Concurrent Pembrolizumab Regimen)</title>
            <description>Pembrolizumab will be given as an IV infusion on day 1 before paclitaxel every 21 (+/- 3) days. Paclitaxel will be given as an IV infusion over 60 minutes, on days 1 and 8 every 21 (+/- 3) days.&#xD;
Pembrolizumab: IV (in the vein) on day 1 of a 21 day cycle&#xD;
Paclitaxel: IV (in the vein) on days 1 and 8 of a 21 day cycle</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Subjects With an Objective Response (Per RECIST V1.1)</title>
          <description>Objective response was determined for each subject as a binary variable indicating whether or not the subject achieved a best overall response of complete response (CR) or partial response (PR) as determined by RECIST 1.1 response criteria. A CR is indicated by disappearance of all target and non target lesions. A PR is indicated by &gt;=30% decrease in sum of longest diameter of target lesions with baseline as reference.</description>
          <population>The evaluable population will consist of all randomized subjects who begin study therapy and have measurable disease at baseline.</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="21"/>
                <count group_id="O2" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Estimation only</non_inferiority_desc>
            <param_type>Rate</param_type>
            <param_value>0.191</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.055</ci_lower_limit>
            <ci_upper_limit>0.419</ci_upper_limit>
            <estimate_desc>Confidence interval estimated using the Clopper Pearson method.</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Estimation only.</non_inferiority_desc>
            <param_type>Rate</param_type>
            <param_value>0.421</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.203</ci_lower_limit>
            <ci_upper_limit>0.665</ci_upper_limit>
            <estimate_desc>Confidence interval estimated using the Clopper Pearson method</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression-free Survival (PFS) Per RECIST 1.1</title>
        <description>PFS is defined as the duration of time from treatment start date to first occurrence of either progressive disease (PD) or death. PD must be objectively determined per RECIST 1.1 criteria, where progression date is date of last assessment that identified PD. If subject died without documented PD, progression date will be death date. For surviving subjects who do not have PD, PFS will be censored at the date of last disease assessment. For subjects who received subsequent anti-cancer therapy prior to documented PD, PFS will be censored at the date of last disease assessment prior to commencement of subsequent therapy. Subjects who have an initial PFS event immediately following 2 or more consecutive missed assessments will be censored at date of last assessment prior to missed assessments.</description>
        <time_frame>From treatment start date to date of progression/death, or censored as described; assessed for approximately 2 years.</time_frame>
        <population>The evaluable population for PFS consisted of all randomized subjects who begin study therapy</population>
        <group_list>
          <group group_id="O1">
            <title>Arm A (Phased Pembrolizumab Regimen)</title>
            <description>Paclitaxel will be given as an IV infusion over 60 minutes, on days 1 and 8 every 21 (+/- 3) days during Cycles 1 and 2. No pembrolizumab will be given during Cycles 1 and 2. Starting with cycle 3 and subsequent cycles, pembrolizumab will be given as an IV infusion over 30 minutes before paclitaxel on day 1 every 21 (+/- 3) days.&#xD;
Pembrolizumab: IV (in the vein) on day 1 of a 21 day cycle&#xD;
Paclitaxel: IV (in the vein) on days 1 and 8 of a 21 day cycle</description>
          </group>
          <group group_id="O2">
            <title>Arm B (Concurrent Pembrolizumab Regimen)</title>
            <description>Pembrolizumab will be given as an IV infusion on day 1 before paclitaxel every 21 (+/- 3) days. Paclitaxel will be given as an IV infusion over 60 minutes, on days 1 and 8 every 21 (+/- 3) days.&#xD;
Pembrolizumab: IV (in the vein) on day 1 of a 21 day cycle&#xD;
Paclitaxel: IV (in the vein) on days 1 and 8 of a 21 day cycle</description>
          </group>
        </group_list>
        <measure>
          <title>Progression-free Survival (PFS) Per RECIST 1.1</title>
          <description>PFS is defined as the duration of time from treatment start date to first occurrence of either progressive disease (PD) or death. PD must be objectively determined per RECIST 1.1 criteria, where progression date is date of last assessment that identified PD. If subject died without documented PD, progression date will be death date. For surviving subjects who do not have PD, PFS will be censored at the date of last disease assessment. For subjects who received subsequent anti-cancer therapy prior to documented PD, PFS will be censored at the date of last disease assessment prior to commencement of subsequent therapy. Subjects who have an initial PFS event immediately following 2 or more consecutive missed assessments will be censored at date of last assessment prior to missed assessments.</description>
          <population>The evaluable population for PFS consisted of all randomized subjects who begin study therapy</population>
          <units>Months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
                <count group_id="O2" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4.1" lower_limit="1.4" upper_limit="6.9"/>
                    <measurement group_id="O2" value="3.9" lower_limit="1.4" upper_limit="6.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Estimation only</non_inferiority_desc>
            <param_type>Median</param_type>
            <param_value>4.1</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.4</ci_lower_limit>
            <ci_upper_limit>6.9</ci_upper_limit>
            <estimate_desc>The Kaplan Meier method was used to estimate the median PFS(in months) for the population. The Greenwood method was used to estimate the confidence limits of the median progression free survival.</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Estimation only</non_inferiority_desc>
            <param_type>Median</param_type>
            <param_value>3.9</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.4</ci_lower_limit>
            <ci_upper_limit>6.8</ci_upper_limit>
            <estimate_desc>The Kaplan Meier method was used to estimate the median PFS(in months) for the population. The Greenwood method was used to estimate the confidence limits of the median progression free survival.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival (OS)</title>
        <description>OS is defined as the duration from treatment start date to the date of death from any cause. Subjects who are alive or lost to follow up at the time of the analysis will be censored at the last known date they were alive.</description>
        <time_frame>From date of treatment start to date of death, or censored as described; assessed for approximately 5 years.</time_frame>
        <population>The evaluable population consisted of all randomized subjects who begin study therapy.</population>
        <group_list>
          <group group_id="O1">
            <title>Arm A (Phased Pembrolizumab Regimen)</title>
            <description>Paclitaxel will be given as an IV infusion over 60 minutes, on days 1 and 8 every 21 (+/- 3) days during Cycles 1 and 2. No pembrolizumab will be given during Cycles 1 and 2. Starting with cycle 3 and subsequent cycles, pembrolizumab will be given as an IV infusion over 30 minutes before paclitaxel on day 1 every 21 (+/- 3) days.&#xD;
Pembrolizumab: IV (in the vein) on day 1 of a 21 day cycle&#xD;
Paclitaxel: IV (in the vein) on days 1 and 8 of a 21 day cycle</description>
          </group>
          <group group_id="O2">
            <title>Arm B (Concurrent Pembrolizumab Regimen)</title>
            <description>Pembrolizumab will be given as an IV infusion on day 1 before paclitaxel every 21 (+/- 3) days. Paclitaxel will be given as an IV infusion over 60 minutes, on days 1 and 8 every 21 (+/- 3) days.&#xD;
Pembrolizumab: IV (in the vein) on day 1 of a 21 day cycle&#xD;
Paclitaxel: IV (in the vein) on days 1 and 8 of a 21 day cycle</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival (OS)</title>
          <description>OS is defined as the duration from treatment start date to the date of death from any cause. Subjects who are alive or lost to follow up at the time of the analysis will be censored at the last known date they were alive.</description>
          <population>The evaluable population consisted of all randomized subjects who begin study therapy.</population>
          <units>Months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="21"/>
                <count group_id="O2" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="27.6" lower_limit="9.7" upper_limit="NA">Upper limit of the confidence interval is not reached due to censoring rate</measurement>
                    <measurement group_id="O2" value="9.0" lower_limit="6.8" upper_limit="14.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Estimation only</non_inferiority_desc>
            <param_type>Median</param_type>
            <param_value>27.6</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>9.7</ci_lower_limit>
            <ci_upper_limit_na_comment>Upper limit of the confidence interval is not reached due to censoring rate</ci_upper_limit_na_comment>
            <estimate_desc>The Kaplan Meier method was used to estimate median OS (in months). The Greenwood method was used to estimate confidence limits of median overall survival.</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Estimation only</non_inferiority_desc>
            <param_type>Median</param_type>
            <param_value>9.0</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>6.8</ci_lower_limit>
            <ci_upper_limit>14.0</ci_upper_limit>
            <estimate_desc>The Kaplan Meier method was used to estimate median OS (in months). The Greenwood method was used to estimate confidence limits of median overall survival.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Subjects With Disease Control (Per RECIST V1.1)</title>
        <description>Disease control was determined for each subject as a binary variable indicating whether or not the subject achieved a best overall response of complete response (CR), partial response (PR), or stable disease (SD) as determined by RECIST 1.1 response criteria. A CR is indicated by disappearance of all target and non target lesions. A PR is indicated by &gt;=30% decrease in sum of longest diameter of target lesions with baseline as reference. SD is indicated by neither sufficient shrinkage to qualify for PR nor sufficient growth from nadir (&gt;=20%) to indicate progression.</description>
        <time_frame>From enrollment to best response while on study treatment; subjects remained on treatment until disease progression or death or unacceptable toxicity (subjects were on treatment for a median of 5.5 months)</time_frame>
        <population>The evaluable population will consist of all randomized subjects who begin study therapy and have measurable disease at baseline.</population>
        <group_list>
          <group group_id="O1">
            <title>Arm A (Phased Pembrolizumab Regimen)</title>
            <description>Paclitaxel will be given as an IV infusion over 60 minutes, on days 1 and 8 every 21 (+/- 3) days during Cycles 1 and 2. No pembrolizumab will be given during Cycles 1 and 2. Starting with cycle 3 and subsequent cycles, pembrolizumab will be given as an IV infusion over 30 minutes before paclitaxel on day 1 every 21 (+/- 3) days.&#xD;
Pembrolizumab: IV (in the vein) on day 1 of a 21 day cycle&#xD;
Paclitaxel: IV (in the vein) on days 1 and 8 of a 21 day cycle</description>
          </group>
          <group group_id="O2">
            <title>Arm B (Concurrent Pembrolizumab Regimen)</title>
            <description>Pembrolizumab will be given as an IV infusion on day 1 before paclitaxel every 21 (+/- 3) days. Paclitaxel will be given as an IV infusion over 60 minutes, on days 1 and 8 every 21 (+/- 3) days.&#xD;
Pembrolizumab: IV (in the vein) on day 1 of a 21 day cycle&#xD;
Paclitaxel: IV (in the vein) on days 1 and 8 of a 21 day cycle</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Subjects With Disease Control (Per RECIST V1.1)</title>
          <description>Disease control was determined for each subject as a binary variable indicating whether or not the subject achieved a best overall response of complete response (CR), partial response (PR), or stable disease (SD) as determined by RECIST 1.1 response criteria. A CR is indicated by disappearance of all target and non target lesions. A PR is indicated by &gt;=30% decrease in sum of longest diameter of target lesions with baseline as reference. SD is indicated by neither sufficient shrinkage to qualify for PR nor sufficient growth from nadir (&gt;=20%) to indicate progression.</description>
          <population>The evaluable population will consist of all randomized subjects who begin study therapy and have measurable disease at baseline.</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="21"/>
                <count group_id="O2" value="19"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14"/>
                    <measurement group_id="O2" value="12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Estimation only.</non_inferiority_desc>
            <param_type>Rate</param_type>
            <param_value>0.667</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.430</ci_lower_limit>
            <ci_upper_limit>0.854</ci_upper_limit>
            <estimate_desc>Confidence interval estimated using the Clopper Pearson method</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Estimation only</non_inferiority_desc>
            <param_type>Rate</param_type>
            <param_value>0.632</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.384</ci_lower_limit>
            <ci_upper_limit>0.837</ci_upper_limit>
            <estimate_desc>Confidence interval estimated using the Clopper Pearson method</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Duration of Response (DoR)</title>
        <description>Duration of Response (DoR) is defined as the duration of time from the first assessment that determined a CR or PR to the date of the first occurrence of progressive disease or death. Progression events and the censoring mechanism for DoR will be the same as described for PFS. DoR will be determined for each subject using the RECIST 1.1 criteria.</description>
        <time_frame>From date of response to date of progression/death, or censored as described above; assessed for approximately 2 years.</time_frame>
        <population>The evaluable population consisted of all randomized subjects who begin study therapy and achieve objective response (CR or PR) on study treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>Arm A (Phased Pembrolizumab Regimen)</title>
            <description>Paclitaxel will be given as an IV infusion over 60 minutes, on days 1 and 8 every 21 (+/- 3) days during Cycles 1 and 2. No pembrolizumab will be given during Cycles 1 and 2. Starting with cycle 3 and subsequent cycles, pembrolizumab will be given as an IV infusion over 30 minutes before paclitaxel on day 1 every 21 (+/- 3) days.&#xD;
Pembrolizumab: IV (in the vein) on day 1 of a 21 day cycle&#xD;
Paclitaxel: IV (in the vein) on days 1 and 8 of a 21 day cycle</description>
          </group>
          <group group_id="O2">
            <title>Arm B (Concurrent Pembrolizumab Regimen)</title>
            <description>Pembrolizumab will be given as an IV infusion on day 1 before paclitaxel every 21 (+/- 3) days. Paclitaxel will be given as an IV infusion over 60 minutes, on days 1 and 8 every 21 (+/- 3) days.&#xD;
Pembrolizumab: IV (in the vein) on day 1 of a 21 day cycle&#xD;
Paclitaxel: IV (in the vein) on days 1 and 8 of a 21 day cycle</description>
          </group>
        </group_list>
        <measure>
          <title>Duration of Response (DoR)</title>
          <description>Duration of Response (DoR) is defined as the duration of time from the first assessment that determined a CR or PR to the date of the first occurrence of progressive disease or death. Progression events and the censoring mechanism for DoR will be the same as described for PFS. DoR will be determined for each subject using the RECIST 1.1 criteria.</description>
          <population>The evaluable population consisted of all randomized subjects who begin study therapy and achieve objective response (CR or PR) on study treatment.</population>
          <units>Months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
                <count group_id="O2" value="8"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.3" lower_limit="5.6" upper_limit="8.3"/>
                    <measurement group_id="O2" value="4.0" lower_limit="2.6" upper_limit="8.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Estimation only</non_inferiority_desc>
            <param_type>Median</param_type>
            <param_value>7.3</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>5.6</ci_lower_limit>
            <ci_upper_limit>8.3</ci_upper_limit>
            <estimate_desc>The Kaplan Meier method was used to estimate median duration of response (in months).&#xD;
The Greenwood method was used to estimate confidence limits of median duration of response.</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>Estimation only</non_inferiority_desc>
            <param_type>Median</param_type>
            <param_value>4.0</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>2.6</ci_lower_limit>
            <ci_upper_limit>8.3</ci_upper_limit>
            <estimate_desc>The Kaplan Meier method was used to estimate median duration of response (in months).&#xD;
The Greenwood method was used to estimate confidence limits of median duration of response.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Baseline, during treatment, and through 30 days after study treatment is discontinued, an average of 14 months.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Arm A (Phased Pembrolizumab Regimen)</title>
          <description>Paclitaxel will be given as an IV infusion over 60 minutes, on days 1 and 8 every 21 (+/- 3) days during Cycles 1 and 2. No pembrolizumab will be given during Cycles 1 and 2. Starting with cycle 3 and subsequent cycles, pembrolizumab will be given as an IV infusion over 30 minutes before paclitaxel on day 1 every 21 (+/- 3) days.&#xD;
Pembrolizumab: IV (in the vein) on day 1 of a 21 day cycle&#xD;
Paclitaxel: IV (in the vein) on days 1 and 8 of a 21 day cycle</description>
        </group>
        <group group_id="E2">
          <title>Arm B (Concurrent Pembrolizumab Regimen)</title>
          <description>Pembrolizumab will be given as an IV infusion on day 1 before paclitaxel every 21 (+/- 3) days. Paclitaxel will be given as an IV infusion over 60 minutes, on days 1 and 8 every 21 (+/- 3) days.&#xD;
Pembrolizumab: IV (in the vein) on day 1 of a 21 day cycle&#xD;
Paclitaxel: IV (in the vein) on days 1 and 8 of a 21 day cycle</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="12" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="19" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Gastrointestinal disorders - Other</sub_title>
                <description>Gastroenteritis</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Death NOS</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Hepatic failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Skin infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Enterocolitis infectious</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Hypoglycemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Cystitis noninfective</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Acute kidney injury</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </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="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Respiratory failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Stevens-Johnson syndrome</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="21" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="19" subjects_at_risk="19"/>
              </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="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial flutter</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Vertigo</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperthyroidism</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Hypothyroidism</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Conjunctivitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Eye disorders - Other</sub_title>
                <description>intermittent R eye sty</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Flashing lights</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Bloating</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Gastroesophageal reflux disease</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Gastrointestinal disorders - Other</sub_title>
                <description>Diverticulitis</description>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Edema face</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Edema limbs</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="11" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Gait disturbance</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Infusion related reaction</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Localized edema</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Malaise</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Hepatic pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Hepatobiliary disorders - Other</sub_title>
                <description>cholangitis</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </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="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Breast infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Device related infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Enterocolitis infectious</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Infections and infestations - Other</sub_title>
                <description>SHINGLES</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Laryngitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Lymph gland infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Mucosal infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Nail infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Papulopustular rash</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Sinusitis</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Skin infection</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Upper respiratory infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Vaginal infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Vulval infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </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="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Fracture</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Hip fracture</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Creatinine increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Lipase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Serum amylase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Hypocalcemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Hypomagnesemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Metabolism and nutrition disorders - Other</sub_title>
                <description>Vit B12 deficiency</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </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="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Bone pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Chest wall pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Muscle weakness lower limb</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Musculoskeletal and connective tissue disorder - Other</sub_title>
                <description>L jaw</description>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Musculoskeletal and connective tissue disorder - Other</sub_title>
                <description>restless leg</description>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Paresthesia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Peripheral sensory neuropathy</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="13" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Recurrent laryngeal nerve palsy</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Hallucinations</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Restlessness</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </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="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Urinary incontinence</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Urinary tract pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Urinary urgency</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Breast pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </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="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Hoarseness</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Hypoxia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Laryngeal hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Pneumonitis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Postnasal drip</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Productive cough</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Respiratory, thoracic and mediastinal disorders - Other</sub_title>
                <description>Chest congestion</description>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Sneezing</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Sore throat</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Wheezing</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </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="8" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Nail discoloration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Nail loss</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Nail ridging</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Palmar-plantar erythrodysesthesia syndrome</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Periorbital edema</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Rash acneiform</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - Other</sub_title>
                <description>dermatitis</description>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - Other</sub_title>
                <description>foreign body reaction</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - Other</sub_title>
                <description>ingrown toenail</description>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - Other</sub_title>
                <description>acne</description>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - Other</sub_title>
                <description>generalized rash</description>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Skin hyperpigmentation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Skin ulceration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Flushing</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Hot flashes</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Lymphedema</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="19"/>
              </event>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="21"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="19"/>
              </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>Chair of Biostatistics Department</name_or_title>
      <organization>Levine Cancer Institute</organization>
      <phone>9804422371</phone>
      <email>james.symanowski@atriumhealth.org</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03018080
org study id: IRB00081370
secondary id: 00019078
secondary id: LCI-BRE-H2N-PEPP-001
nct id: NCT03018080
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The primary objective of this study is to assess the safety and feasibility of the following
      two regimens: Cohort A) phased regimen of pembrolizumab in which paclitaxel is followed by
      paclitaxel plus pembrolizumab and Cohort B) concurrent regimen of paclitaxel plus
      pembrolizumab. The primary safety objective is to evaluate the overall grade 3 or 4
      treatment-related adverse event rate for each cohort and compare them to relevant historical
      controls.
This is an open-label randomized pilot research study to determine if the study drug,
      pembrolizumab, is safe to use in combination with a chemotherapy drug called paclitaxel. This
      study will have the following two regimens: Cohort A) phased regimen of pembrolizumab in
      which paclitaxel is followed by paclitaxel plus pembrolizumab and Cohort B) concurrent
      regimen of paclitaxel plus pembrolizumab. A total of 40 evaluable subjects will be enrolled
      over an enrollment period of 18-24 months. The study is planned to enroll approximately 20
      evaluable subjects in each treatment cohort.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of Participants With at Least One Grade 3 or 4 Treatment-related Adverse Event
time frame: From enrollment to at least 30 days following cessation of study treatment. The median time on treatment was 5.5 months.
description: Grade 3 or 4 study treatment-related adverse events will be determined for each subject as a binary variable indicating whether or not the subject experienced at least one grade 3 or 4 study treatment-related adverse events according to the NCI Common Terminology for Adverse Events, version 4.0. An adverse event will be considered study treatment related if it is determined that the event is at least possibly related to either paclitaxel, pembrolizumab, or both.
measure: Number of Subjects With an Objective Response (Per RECIST V1.1)
time frame: From enrollment to best response while on study treatment; subjects remained on treatment until disease progression or death or unacceptable toxicity (subjects were on treatment for a median of 5.5 months)
description: Objective response was determined for each subject as a binary variable indicating whether or not the subject achieved a best overall response of complete response (CR) or partial response (PR) as determined by RECIST 1.1 response criteria. A CR is indicated by disappearance of all target and non target lesions. A PR is indicated by >=30% decrease in sum of longest diameter of target lesions with baseline as reference.
measure: Progression-free Survival (PFS) Per RECIST 1.1
time frame: From treatment start date to date of progression/death, or censored as described; assessed for approximately 2 years.
description: PFS is defined as the duration of time from treatment start date to first occurrence of either progressive disease (PD) or death. PD must be objectively determined per RECIST 1.1 criteria, where progression date is date of last assessment that identified PD. If subject died without documented PD, progression date will be death date. For surviving subjects who do not have PD, PFS will be censored at the date of last disease assessment. For subjects who received subsequent anti-cancer therapy prior to documented PD, PFS will be censored at the date of last disease assessment prior to commencement of subsequent therapy. Subjects who have an initial PFS event immediately following 2 or more consecutive missed assessments will be censored at date of last assessment prior to missed assessments.
measure: Overall Survival (OS)
time frame: From date of treatment start to date of death, or censored as described; assessed for approximately 5 years.
description: OS is defined as the duration from treatment start date to the date of death from any cause. Subjects who are alive or lost to follow up at the time of the analysis will be censored at the last known date they were alive.
measure: Number of Subjects With Disease Control (Per RECIST V1.1)
time frame: From enrollment to best response while on study treatment; subjects remained on treatment until disease progression or death or unacceptable toxicity (subjects were on treatment for a median of 5.5 months)
description: Disease control was determined for each subject as a binary variable indicating whether or not the subject achieved a best overall response of complete response (CR), partial response (PR), or stable disease (SD) as determined by RECIST 1.1 response criteria. A CR is indicated by disappearance of all target and non target lesions. A PR is indicated by >=30% decrease in sum of longest diameter of target lesions with baseline as reference. SD is indicated by neither sufficient shrinkage to qualify for PR nor sufficient growth from nadir (>=20%) to indicate progression.
measure: Duration of Response (DoR)
time frame: From date of response to date of progression/death, or censored as described above; assessed for approximately 2 years.
description: Duration of Response (DoR) is defined as the duration of time from the first assessment that determined a CR or PR to the date of the first occurrence of progressive disease or death. Progression events and the censoring mechanism for DoR will be the same as described for PFS. DoR will be determined for each subject using the RECIST 1.1 criteria.
arm group label: Arm A (Phased Pembrolizumab Regimen)
arm group type: Experimental
description: Paclitaxel will be given as an IV infusion over 60 minutes, on days 1 and 8 every 21 (+/- 3) days during Cycles 1 and 2. No pembrolizumab will be given during Cycles 1 and 2. Starting with cycle 3 and subsequent cycles, pembrolizumab will be given as an IV infusion over 30 minutes before paclitaxel on day 1 every 21 (+/- 3) days.
arm group label: Arm B (Concurrent Pembrolizumab Regimen)
arm group type: Experimental
description: Pembrolizumab will be given as an IV infusion on day 1 before paclitaxel every 21 (+/- 3) days. Paclitaxel will be given as an IV infusion over 60 minutes, on days 1 and 8 every 21 (+/- 3) days.
intervention type: Drug
intervention name: Pembrolizumab
description: IV (in the vein) on day 1 of a 21 day cycle
arm group label: Arm A (Phased Pembrolizumab Regimen)
arm group label: Arm B (Concurrent Pembrolizumab Regimen)
other name: Keytruda
intervention type: Drug
intervention name: Paclitaxel
description: IV (in the vein) on days 1 and 8 of a 21 day cycle
arm group label: Arm A (Phased Pembrolizumab Regimen)
arm group label: Arm B (Concurrent Pembrolizumab Regimen)
other name: Taxol
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Antoinette Tan, MD
role: Principal Investigator
affiliation: Atrium Health (formerly Carolinas HealthCare System)
facility: 
country: United States
citation: Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, Pusztai L, Pathiraja K, Aktan G, Cheng JD, Karantza V, Buisseret L. Pembrolizumab in Patients With Advanced Triple-Negative Breast Cancer: Phase Ib KEYNOTE-012 Study. J Clin Oncol. 2016 Jul 20;34(21):2460-7. doi: 10.1200/JCO.2015.64.8931. Epub 2016 May 2.
PMID: 27138582
citation: Tan AR, Chai SJ, Robinson MM, Hellner LB, Gavini N, Sulai N, Turner JD, Atlas J, Graham DL, Induru RR, Kadakia KC, Vallabhanei GD, Heeke AL, Foureau DM, Fisher JG. A pilot study of paclitaxel plus pembrolizumab in patients with metastatic HER2-negative breast cancer (PePPy). Cancer Research. 2022; 82(4_Supplement): P2-14-03
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Breast Neoplasms, Male
mesh term: Paclitaxel
mesh term: Pembrolizumab
sharing ipd: Undecided
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 