<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/NCT02971956</url>
  </required_header>
  <id_info>
    <org_study_id>16-293</org_study_id>
    <nct_id>NCT02971956</nct_id>
  </id_info>
  <brief_title>Pembrolizumab in Refractory Advanced Esophageal Cancer</brief_title>
  <official_title>A Phase II Study of Pembrolizumab in Refractory Advanced Esophageal Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Dana-Farber Cancer Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Merck Sharp &amp; Dohme LLC</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Dana-Farber Cancer Institute</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This research study is studying a targeted therapy as a possible treatment for advanced&#xD;
      esophageal cancer.&#xD;
&#xD;
      The study intervention involved in this study is:&#xD;
&#xD;
      -Pembrolizumab&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This research study is a Phase II clinical trial. Phase II clinical trials test the safety&#xD;
      and effectiveness of an investigational drug to learn whether the drug works in treating a&#xD;
      specific disease. &quot;Investigational&quot; means that the drug is being studied.&#xD;
&#xD;
      The FDA (the U.S. Food and Drug Administration) has not approved Pembrolizumab for the&#xD;
      participant specific disease but it has been approved for other uses.&#xD;
&#xD;
      Pembrolizumab, also known as KEYTRUDA or MK-3475, is approved in the USA and several other&#xD;
      countries to treat other types of diseases.&#xD;
&#xD;
      The goal of this research study is to&#xD;
&#xD;
      -Evaluate the safety and efficacy of pembrolizumab in participants with advanced esophageal&#xD;
      cancer that have not responded to standard treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 18, 2017</start_date>
  <completion_date type="Actual">May 13, 2020</completion_date>
  <primary_completion_date type="Actual">July 23, 2019</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Overall Response Rate (ORR)</measure>
    <time_frame>Disease was evaluated each cycle on treatment; Treatment continued until disease progression or unacceptable toxicity. Treatment duration was a median of 2.1 months with a maximum of 14.9 months.</time_frame>
    <description>The objective response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Median Progression-free Survival (PFS)</measure>
    <time_frame>Disease was evaluated each cycle on treatment and in long-term follow-up every 12 weeks for up to 5 years. Maximum follow-up in this study cohort was 28.9 months</time_frame>
    <description>Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) or death. Per RECIST 1.1 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median Overall Survival (OS)</measure>
    <time_frame>Disease was evaluated each cycle on treatment and in long-term follow-up every 12 weeks for up to 5 years. Maximum follow-up in this study cohort was 38.7 months.</time_frame>
    <description>OS based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Patients Experiencing Grade 3-4 Treatment-Related Toxicity</measure>
    <time_frame>Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Median treatment duration for this study cohort was 2.1 months with maximum of 14.9 months.</time_frame>
    <description>All grade 3-4 adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv4 as reported on case report forms were counted. Outcome defined as the number of patients experiencing at least one treatment-related grade 3-4 AE of any type during the time of observation.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">50</enrollment>
  <condition>Esophageal Cancer</condition>
  <condition>Squamous Cell Esophagus Cancer</condition>
  <condition>Adenocarcinoma Esophagus</condition>
  <arm_group>
    <arm_group_label>Pembrolizumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>Immune checkpoint inhibitor</description>
    <arm_group_label>Pembrolizumab</arm_group_label>
    <other_name>Keytruda</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically confirmed, measurable, unresectable adenocarcinoma or squamous cell&#xD;
             carcinoma of the esophagus. For the purposes of this study, undifferentiated&#xD;
             carcinomas or adenosquamous carcinomas will be categorized as adenocarcinomas.&#xD;
&#xD;
          -  The primary tumor must originate in the esophagus. Tumors that involve the GE junction&#xD;
             must meet Sievert Type 1 criteria: &quot;Adenocarcinoma of the distal oesophagus which&#xD;
             usually arises from an area with specialized intestinal metaplasia of the oesophagus&#xD;
             (i.e. Barrett's oesophagus) and which may infiltrate the oesophagogastric junction&#xD;
             from above.&quot; For the purposes of this protocol, this will be interpreted as: greater&#xD;
             than 50% of the tumor must be above the GE junction or, alternatively, the tumor must&#xD;
             involve the GE junction and arise in the setting of biopsy-documented Barrett's&#xD;
             esophagus (specialized intestinal metaplasia).&#xD;
&#xD;
          -  Patients must have received at least one prior therapy for unresectable disease.&#xD;
             Patients with recurrence within 6 months of completion of neoadjuvant or adjuvant&#xD;
             therapy may be considered as having received one prior therapy for unresectable&#xD;
             disease.&#xD;
&#xD;
          -  Be willing and able to provide written informed consent/assent for the trial.&#xD;
&#xD;
          -  Be ≥ 18 years of age on day of signing informed consent.&#xD;
&#xD;
          -  Have measurable disease based on irRECIST.&#xD;
&#xD;
          -  Be willing to provide tissue from a newly obtained biopsy of a tumor lesion, most&#xD;
             commonly an EGD biopsy from the esophagus. Newly-obtained is defined as a specimen&#xD;
             obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1. Subjects&#xD;
             for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject&#xD;
             safety concern) may submit an archived specimen only upon agreement from the Sponsor.&#xD;
             Please note, patients may not initiate therapy until the biopsy specimen is received&#xD;
             at the Dana-Farber Cancer Institute.&#xD;
&#xD;
          -  The first 15 patients with adenocarcinoma will be offered an optional tumor biopsy&#xD;
             (typically EGD biopsy) at 8 weeks. Starting with adenocarcinoma patient #16, patients&#xD;
             must have an accessible tumor and must agree to tumor biopsy at 8 weeks; this will&#xD;
             continue to be mandatory until a total of 20 patients have undergone biopsy at 8&#xD;
             weeks.&#xD;
&#xD;
          -  Have a performance status of 0 or 1 on the ECOG Performance Scale (Appendix A).&#xD;
&#xD;
          -  Female subject of childbearing potential must have a negative urine or serum pregnancy&#xD;
             within 72 hours prior to receiving the first dose of study medication. If the urine&#xD;
             test is positive or cannot be confirmed as negative, a serum pregnancy test will be&#xD;
             required.&#xD;
&#xD;
          -  Female subjects of childbearing potential must be willing to use 2 methods of birth&#xD;
             control or be surgically sterile, or abstain from heterosexual activity for the course&#xD;
             of the study through 120 days after the last dose of study medication (Reference&#xD;
             Section 6.3.2). Subjects of childbearing potential are those who have not been&#xD;
             surgically sterilized or have not been free from menses for &gt; 1 year.&#xD;
&#xD;
          -  Male subjects must agree to use an adequate method of contraception starting with the&#xD;
             first dose of study therapy through 120 days after the last dose of study therapy.&#xD;
&#xD;
          -  Demonstrate adequate organ function as defined below, all screening labs should be&#xD;
             performed within 10 days of treatment initiation.&#xD;
&#xD;
        Hematological&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) ≥1,500 /mcL&#xD;
&#xD;
          -  Platelets ≥80,000 / mcL&#xD;
&#xD;
          -  Hemoglobin ≥8.5 g/dL or ≥5.6 mmol/L&#xD;
&#xD;
             -Renal&#xD;
&#xD;
          -  Serum creatinine ≤1.5 X upper limit of normal (ULN) OR Measured creatinine clearance&#xD;
             ≥60 mL/min for subject with creatinine levels &gt; 1.5 X institutional ULN (GFR can also&#xD;
             be used in place of creatinine or CrCL) Creatinine clearance should be calculated per&#xD;
             institutional standard.&#xD;
&#xD;
             -Hepatic&#xD;
&#xD;
          -  Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total&#xD;
             bilirubin levels &gt; 1.5 ULN&#xD;
&#xD;
          -  AST (SGOT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases&#xD;
&#xD;
          -  ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases&#xD;
&#xD;
          -  Albumin &gt; 2.8 mg/dL&#xD;
&#xD;
             -Coagulation&#xD;
&#xD;
          -  International Normalized Ratio (INR) OR Prothrombin Time (PT) ≤1.5 X ULN unless&#xD;
             subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic&#xD;
             range of intended use of anticoagulants&#xD;
&#xD;
          -  Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving&#xD;
             anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use&#xD;
             of anticoagulants&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any&#xD;
             other form of immunosuppressive therapy within 7 days prior to the first dose of trial&#xD;
             treatment. Subjects requiring systemic steroids are excluded from the trial. The use&#xD;
             of physiologic doses of corticosteroids may be approved after discussion with the&#xD;
             sponsor.&#xD;
&#xD;
          -  Has a known history of active TB (Bacillus Tuberculosis)&#xD;
&#xD;
          -  Hypersensitivity to pembrolizumab or any of its excipients.&#xD;
&#xD;
          -  Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study&#xD;
             Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events&#xD;
             due to agents administered more than 4 weeks earlier.&#xD;
&#xD;
          -  Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy&#xD;
             within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at&#xD;
             baseline) from adverse events due to a previously administered agent.&#xD;
&#xD;
               -  Note: Subjects with ≤ Grade 2 neuropathy and alopecia are an exception to this&#xD;
                  criterion and may qualify for the study.&#xD;
&#xD;
               -  Note: If subject received major surgery, they must wait ≥ 3 weeks prior to&#xD;
                  starting study treatment. They must have recovered adequately from the toxicity&#xD;
                  and/or complications from the intervention prior to starting therapy.&#xD;
&#xD;
          -  Has a known additional malignancy that is progressing or requires active treatment.&#xD;
             Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the&#xD;
             skin that has undergone potentially curative therapy or in situ cervical cancer.&#xD;
&#xD;
          -  Has known active central nervous system (CNS) metastases and/or carcinomatous&#xD;
             meningitis. Subjects with previously treated brain metastases may participate provided&#xD;
             they are stable (without evidence of progression by imaging for at least four weeks&#xD;
             prior to the first dose of trial treatment and any neurologic symptoms have returned&#xD;
             to baseline), have no evidence of new or enlarging brain metastases, and are not using&#xD;
             steroids for at least 7 days prior to trial treatment. This exception does not include&#xD;
             carcinomatous meningitis which is excluded regardless of clinical stability.&#xD;
&#xD;
          -  Has active autoimmune disease that has required systemic treatment in the past 2 years&#xD;
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive&#xD;
             drugs). Replacement therapy (eg., 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;
          -  Has an active infection requiring systemic therapy.&#xD;
&#xD;
          -  Patients that require supplemental oxygen are excluded.&#xD;
&#xD;
          -  Has a history or current evidence of any condition, therapy, or laboratory abnormality&#xD;
             that might confound the results of the trial, interfere with the subject's&#xD;
             participation for the full duration of the trial, or is not in the best interest of&#xD;
             the subject to participate, in the opinion of the treating investigator.&#xD;
&#xD;
          -  Has known psychiatric or substance abuse disorders that would interfere with&#xD;
             cooperation with the requirements of the trial.&#xD;
&#xD;
          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the&#xD;
             projected duration of the trial, starting with the pre-screening or screening visit&#xD;
             through 120 days after the last dose of trial treatment.&#xD;
&#xD;
          -  Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.&#xD;
&#xD;
          -  Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).&#xD;
&#xD;
          -  Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA&#xD;
             [qualitative] is detected).&#xD;
&#xD;
          -  Has received a live vaccine within 30 days of planned start of study therapy.&#xD;
&#xD;
             --Note: Seasonal influenza vaccines for injection are generally inactivated flu&#xD;
             vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are&#xD;
             live attenuated vaccines, and are not allowed.&#xD;
&#xD;
          -  Has a history of (non-infectious) pneumonitis that required steroids or current&#xD;
             pneumonitis.&#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>Peter C. Enzinger, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Dana-Farber Cancer Institute</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Massachusetts General Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Beth Israel Deaconess Medical Center</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dana Farber Cancer Institute</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>November 21, 2016</study_first_submitted>
  <study_first_submitted_qc>November 21, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 23, 2016</study_first_posted>
  <results_first_submitted>January 18, 2022</results_first_submitted>
  <results_first_submitted_qc>April 7, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">April 8, 2022</results_first_posted>
  <last_update_submitted>August 11, 2023</last_update_submitted>
  <last_update_submitted_qc>August 11, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 6, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Dana-Farber Cancer Institute</investigator_affiliation>
    <investigator_full_name>Peter Enzinger, MD</investigator_full_name>
    <investigator_title>Peter C. Enzinger MD</investigator_title>
  </responsible_party>
  <keyword>Esophageal Cancer</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Esophageal Neoplasms</mesh_term>
    <mesh_term>Esophageal Squamous Cell Carcinoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pembrolizumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>February 26, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/56/NCT02971956/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>from January 2017 to October 2018</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Pembrolizumab</title>
          <description>Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="49"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="49"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Pembrolizumab</title>
          <description>Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="49"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age, Customized</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="64" lower_limit="34" upper_limit="80"/>
                  </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="39"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>White</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="44"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Black or African American</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Asian</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Other</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>More than one race</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="49"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Overall Response Rate (ORR)</title>
        <description>The objective response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.</description>
        <time_frame>Disease was evaluated each cycle on treatment; Treatment continued until disease progression or unacceptable toxicity. Treatment duration was a median of 2.1 months with a maximum of 14.9 months.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Pembrolizumab</title>
            <description>Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Response Rate (ORR)</title>
          <description>The objective response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.</description>
          <units>proportion of participant</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="49"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.08" lower_limit="0.023" upper_limit="0.196"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Median Progression-free Survival (PFS)</title>
        <description>Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) or death. Per RECIST 1.1 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.</description>
        <time_frame>Disease was evaluated each cycle on treatment and in long-term follow-up every 12 weeks for up to 5 years. Maximum follow-up in this study cohort was 28.9 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Pembrolizumab</title>
            <description>Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Median Progression-free Survival (PFS)</title>
          <description>Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) or death. Per RECIST 1.1 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.</description>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="49"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.8" lower_limit="1.8" upper_limit="2.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Median Overall Survival (OS)</title>
        <description>OS based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive.</description>
        <time_frame>Disease was evaluated each cycle on treatment and in long-term follow-up every 12 weeks for up to 5 years. Maximum follow-up in this study cohort was 38.7 months.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Pembrolizumab</title>
            <description>Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Median Overall Survival (OS)</title>
          <description>OS based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive.</description>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="49"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5.8" lower_limit="4.0" upper_limit="9.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Patients Experiencing Grade 3-4 Treatment-Related Toxicity</title>
        <description>All grade 3-4 adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv4 as reported on case report forms were counted. Outcome defined as the number of patients experiencing at least one treatment-related grade 3-4 AE of any type during the time of observation.</description>
        <time_frame>Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Median treatment duration for this study cohort was 2.1 months with maximum of 14.9 months.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Pembrolizumab</title>
            <description>Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Patients Experiencing Grade 3-4 Treatment-Related Toxicity</title>
          <description>All grade 3-4 adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv4 as reported on case report forms were counted. Outcome defined as the number of patients experiencing at least one treatment-related grade 3-4 AE of any type during the time of observation.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="49"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Median treatment duration for this study cohort was 2.1 months with maximum of 14.9 months. All-Cause Mortality was evaluated each cycle on treatment and in long-term follow-up every 12 weeks for up to 5 years. Maximum follow-up in this study cohort was 38.7 months.</time_frame>
      <desc>Serious adverse events (AEs) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher per CTCAEv4. All remaining events regardless of treatment attribution were classified as Other AEs. Maximum grade toxicity by type for a patient over time was calculated. No further data is available to specify classification of other beyond the general term.</desc>
      <group_list>
        <group group_id="E1">
          <title>Pembrolizumab</title>
          <description>Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.</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="49" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Cardiac arrest</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Eye disorders - Other</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Duodenal hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Dysphagia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Nervous system disorders - Other</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </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="49"/>
              </event>
              <event>
                <sub_title>Hypoxia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Pneumonitis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Respiratory failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </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="46" subjects_at_risk="49"/>
              </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="32" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Blood and lymphatic system disorders - Other</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Chest pain - cardiac</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Palpitations</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Sinus tachycardia</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Endocrine disorders - Other</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Hyperthyroidism</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Hypothyroidism</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Eye disorders - Other</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Vitreous hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal distension</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Ascites</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="17" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="14" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Duodenal hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Dysphagia</sub_title>
                <counts group_id="E1" subjects_affected="18" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Esophageal hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Esophageal pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Esophageal perforation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Fecal incontinence</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Gastric hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Gastritis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Gastrointestinal disorders - Other</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Gastrointestinal pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="20" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Obstruction gastric</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Pancreatitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="12" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Death NOS</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Edema limbs</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="40" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Gait disturbance</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>General disorders and administration site conditions - Other</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Localized edema</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Abdominal infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Bronchial infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Activated partial thromboplastin time prolonged</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" subjects_affected="26" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="20" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Creatinine increased</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Investigations - Other</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Lipase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" subjects_affected="12" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Weight gain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Acidosis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" subjects_affected="21" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Hypercalcemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" subjects_affected="31" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Hyperkalemia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Hypernatremia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" subjects_affected="31" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Hypocalcemia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Hypomagnesemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" subjects_affected="24" subjects_at_risk="49"/>
              </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="4" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Arthritis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Bone pain</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Chest wall pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Muscle weakness left-sided</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Musculoskeletal and connective tissue disorder - Other</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Neck pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Ataxia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Memory impairment</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Nervous system disorders - Other</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Peripheral motor neuropathy</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Peripheral sensory neuropathy</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Tremor</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Confusion</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Hematuria</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Proteinuria</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Renal and urinary disorders - Other</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="21" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="17" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Hypoxia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Pneumonitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Respiratory, thoracic and mediastinal disorders - Other</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Tracheal fistula</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="49"/>
              </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="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Hyperhidrosis</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Rash acneiform</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - Other</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="29" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Vascular disorders - Other</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="49"/>
              </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>Peter C. Enzinger MD</name_or_title>
      <organization>Dana-Farber Cancer Institute</organization>
      <phone>(877) 442-3324</phone>
      <email>Peter_Enzinger@dfci.harvard.edu</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02971956
org study id: 16-293
nct id: NCT02971956
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This research study is studying a targeted therapy as a possible treatment for advanced
      esophageal cancer.

      The study intervention involved in this study is:

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

      The FDA (the U.S. Food and Drug Administration) has not approved Pembrolizumab for the
      participant specific disease but it has been approved for other uses.

      Pembrolizumab, also known as KEYTRUDA or MK-3475, is approved in the USA and several other
      countries to treat other types of diseases.

      The goal of this research study is to

      -Evaluate the safety and efficacy of pembrolizumab in participants with advanced esophageal
      cancer that have not responded to standard treatment.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall Response Rate (ORR)
time frame: Disease was evaluated each cycle on treatment; Treatment continued until disease progression or unacceptable toxicity. Treatment duration was a median of 2.1 months with a maximum of 14.9 months.
description: The objective response rate (ORR) was defined as the proportion of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.
measure: Median Progression-free Survival (PFS)
time frame: Disease was evaluated each cycle on treatment and in long-term follow-up every 12 weeks for up to 5 years. Maximum follow-up in this study cohort was 28.9 months
description: Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) or death. Per RECIST 1.1 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.
measure: Median Overall Survival (OS)
time frame: Disease was evaluated each cycle on treatment and in long-term follow-up every 12 weeks for up to 5 years. Maximum follow-up in this study cohort was 38.7 months.
description: OS based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive.
measure: Number of Patients Experiencing Grade 3-4 Treatment-Related Toxicity
time frame: Assessed each cycle throughout treatment from time of first dose and up to day 30 post-treatment. Median treatment duration for this study cohort was 2.1 months with maximum of 14.9 months.
description: All grade 3-4 adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv4 as reported on case report forms were counted. Outcome defined as the number of patients experiencing at least one treatment-related grade 3-4 AE of any type during the time of observation.
arm group label: Pembrolizumab
arm group type: Experimental
description: Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.
intervention type: Drug
intervention name: Pembrolizumab
description: Immune checkpoint inhibitor
arm group label: Pembrolizumab
other name: Keytruda
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Peter C. Enzinger, MD
role: Principal Investigator
affiliation: Dana-Farber Cancer Institute
facility: 
facility: 
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Dana-Farber Cancer Institute
investigator full name: Peter Enzinger, MD
investigator title: Peter C. Enzinger MD
mesh term: Esophageal Neoplasms
mesh term: Esophageal Squamous Cell Carcinoma
mesh term: Pembrolizumab
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 