<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/NCT03025880</url>
  </required_header>
  <id_info>
    <org_study_id>GEICAM/2015-04</org_study_id>
    <secondary_id>2016-001779-54</secondary_id>
    <nct_id>NCT03025880</nct_id>
  </id_info>
  <brief_title>Trial to Evaluate Efficacy and Safety of Pembrolizumab and Gemcitabine in HER2-negative ABC</brief_title>
  <acronym>PANGEA</acronym>
  <official_title>A Multicenter Phase II Trial to Evaluate the Efficacy and Safety of Pembrolizumab and Gemcitabine in Patients With HER2-negative Advanced Breast Cancer (ABC) &quot;PANGEA-Breast&quot;</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Spanish Breast Cancer Research Group</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Merck Sharp &amp; Dohme LLC</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Spanish Breast Cancer Research Group</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Study Design and Treatment:&#xD;
&#xD;
      This is a multicenter phase II trial, with an initial exploratory run-in-phase, to evaluate&#xD;
      the efficacy and safety of pembrolizumab in combination with gemcitabine in patients with&#xD;
      HER2-negative ABC that have previously received anthracyclines and taxanes (unless clinically&#xD;
      contraindicated). In hormone receptor positive patients, previous treatment with 2 or more&#xD;
      lines of hormone therapy will also be required. Patients must have at least one measurable&#xD;
      lesion that can be accurately assessed at baseline and is suitable for repeated assessment by&#xD;
      CT, MRI or plan X-ray. Approximately 53 patients (up to a maximum of 65 patients depending on&#xD;
      the results of the run-in-phase) will be included in this trial.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study Design and Treatment (continuation):&#xD;
&#xD;
      The study will include two cohorts of patients: i) Triple Negative and ii) Luminal A+B, with&#xD;
      an approximate 1:1 distribution between both groups.&#xD;
&#xD;
      A safety dose testing or &quot;run-in-phase&quot;, with a 6+6 design, in which toxicity will be&#xD;
      evaluated within the first cycle, will be performed since pembrolizumab in combination with&#xD;
      gemcitabine has not been previously tested. Initially 6 patients will be included in the&#xD;
      study at dose level 0 (gemcitabine at a dose of 1,250mg/m2 as an IV infusion on day 1 and 8&#xD;
      of each 21-day cycle and pembrolizumab at a dose of 200mg as an IV infusion on day 1 of each&#xD;
      21-day cycle):&#xD;
&#xD;
        -  If ≤ 2 patients experience Dose Limiting Toxicity (DLT), 6 additional patients will be&#xD;
           included at the current dose level. If there is a confirmation of this dose to be safe&#xD;
           (≤ 3 patients experiencing DLT), this will be considered the RP2D and it will be used&#xD;
           for the following recruited patients.&#xD;
&#xD;
        -  If ≥ 3 patients experience DLT within the first 6 patients, or ≥ 4 within the first 12&#xD;
           patients included at dose level 0, a de-escalation to dose level -1 (gemcitabine at a&#xD;
           dose of 1,000mg/m2 as an IV infusion on day 1 and 8 of each 21-day cycle and&#xD;
           pembrolizumab at a dose of 200mg as an IV infusion on day 1 of each 21-day cycle) will&#xD;
           be performed. In this case, a group of 12 additional patients will be included at dose&#xD;
           level -1, if ≥ 4 experience DLT, this combination will be considered too toxic and the&#xD;
           study will be stopped. If ≤ 3 experience DLT with this combination, this will be&#xD;
           considered the RP2D and it will be used for the following recruited patients.&#xD;
&#xD;
      Initially 3 patients will be allowed for inclusion simultaneously. These 3 patients will be&#xD;
      followed closely during the first cycle to observe the occurrence of any DLT. At the times&#xD;
      these 3 patients are completing the first cycle, the next 3 patients will be included one by&#xD;
      one, until the first cohort is completed.&#xD;
&#xD;
      If none of these 6 patients have a DLT, up to 4 patients will be allowed for inclusion from&#xD;
      the second cohort of 6 patients; they will follow the same procedure as in the first cohort.&#xD;
      If one of these patients from the second cohort has a DLT, the inclusion will be in smaller&#xD;
      groups (with a maximum number of 4 patients with DLT) and following the same procedure as in&#xD;
      the first cohort of 6 patients.&#xD;
&#xD;
      An internal committee will periodically review the safety data in order to take the decision&#xD;
      to maintain or decrease the dose level. This internal committee will consist of the chief&#xD;
      investigator, the Spanish Breast Cancer Research Group Scientific Director and the study&#xD;
      statistician. The meetings will be performed by teleconference to take these decisions as&#xD;
      quickly as possible once the last patient finishes the first cycle of treatment. Other&#xD;
      meetings will be considered ad-hoc whenever necessary (i.e when new DLTs appear).&#xD;
&#xD;
      Patients included in the run-in-phase at the same dose than that in the phase II will be&#xD;
      considered for the phase II analysis.&#xD;
&#xD;
      Study Drug/Medication:&#xD;
&#xD;
      Eligible patients will be enrolled and treated with:&#xD;
&#xD;
      Pembrolizumab at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day&#xD;
      cycle.&#xD;
&#xD;
      in combination with Gemcitabine at a dose of 1,250mg/m2 or 1,000mg/m2 (this dose will be&#xD;
      explored in combination with pembrolizumab in the initial exploratory run-in-phase if&#xD;
      necessary) as an intravenous (IV) infusion on day 1 and 8 of each 21-day cycle.&#xD;
&#xD;
      Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression,&#xD;
      clinical progression (under investigator criteria), unacceptable toxicity, death or&#xD;
      withdrawal of consent, whichever occurs first. Patients completing 24 months of uninterrupted&#xD;
      treatment with pembrolizumab or 35 administrations of study medication will stop&#xD;
      pembrolizumab treatment (though may continue with gemcitabine). Subjects who stop&#xD;
      pembrolizumab after 24 months may be eligible for up to one year of additional pembrolizumab&#xD;
      treatment if they progress after stopping it.&#xD;
&#xD;
      An initial exploratory run-in-phase will be performed to test the safety of the combination&#xD;
      and determine the Recommended Phase II Dose (RP2D) of gemcitabine in combination with fixed&#xD;
      doses of pembrolizumab.&#xD;
&#xD;
      Primary Objective:&#xD;
&#xD;
        -  Run-in-phase: To determine the Recommended Phase II Dose (RP2D) of gemcitabine in&#xD;
           combination with fixed doses of pembrolizumab.&#xD;
&#xD;
        -  Phase II: To assess the efficacy of pembrolizumab in combination with gemcitabine in&#xD;
           terms of Objective Response Rate (ORR) in patients with HER2-negative ABC.&#xD;
&#xD;
      Primary End-point:&#xD;
&#xD;
        -  Run-in-phase: To determine the incidence rate of Dose Limiting Toxicity (DLT) within the&#xD;
           first cycle of the combination.&#xD;
&#xD;
        -  Phase II: Objective Response Rate (ORR) is defined as Complete Response (CR) plus&#xD;
           Partial Response (PR) according to Response Evaluation Criteria in Solid Tumours&#xD;
           (RECIST) version 1.1.&#xD;
&#xD;
      Secondary Objectives:&#xD;
&#xD;
      The following secondary objectives will be studied:&#xD;
&#xD;
        -  To assess other efficacy measures of the combination in patients included in the phase&#xD;
           II (including those in the run-in-phase at the same dose that in the phase II).&#xD;
&#xD;
        -  To determine safety and tolerability of the combination in all patients included in the&#xD;
           study.&#xD;
&#xD;
      Secondary End-points:&#xD;
&#xD;
      The following secondary end-points will be studied:&#xD;
&#xD;
        -  Efficacy:&#xD;
&#xD;
             -  Progression-Free Survival (PFS) assessed according to RECIST version 1.1 by the&#xD;
                investigator.&#xD;
&#xD;
             -  Clinical Benefit Rate (CBR) defined as Complete Response (CR) plus Partial Response&#xD;
                (PR) plus Stable Disease (SD) lasting ≥ 24 weeks according to RECIST version 1.1.&#xD;
&#xD;
             -  Response Duration (RD) assessed according to RECIST version 1.1.&#xD;
&#xD;
             -  Overall Survival (OS). With special interest on long term responders (i.e. alive&#xD;
                and without disease progression after 24 months of study treatment).&#xD;
&#xD;
        -  Safety will be assessed by standard clinical and laboratory tests (haematology, serum&#xD;
           chemistry). Adverse Events (AE) grade will be defined by the NCI CTCAE (National Cancer&#xD;
           Institute Common Terminology Criteria for Adverse Events) version 4.0.&#xD;
&#xD;
      Exploratory Objectives:&#xD;
&#xD;
      The following exploratory objectives will be studied in all patients included in the study&#xD;
      unless otherwise specified:&#xD;
&#xD;
        -  To assess other efficacy measures of the combination based on immune-related (ir)&#xD;
           response criteria in patients included in the phase II (including those in the&#xD;
           run-in-phase at the same dose that in the phase II).&#xD;
&#xD;
        -  To search for tumour tissue and peripheral blood biomarkers of clinical activity.&#xD;
&#xD;
        -  To compare biomarkers data from cohorts of healthy volunteers (if available) with data&#xD;
           from patients included in the study.&#xD;
&#xD;
      Exploratory End-points:&#xD;
&#xD;
      The following exploratory end-points will be studied:&#xD;
&#xD;
        -  Efficacy:&#xD;
&#xD;
             -  ORR is defined as immune-related Complete Response (irCR) plus immune-related&#xD;
                Partial Response (irPR) according to immune-related RECIST (irRECIST).&#xD;
&#xD;
             -  Progression-Free Survival (PFS) assessed according to irRECIST by the investigator.&#xD;
&#xD;
             -  Clinical Benefit Rate (CBR) defined as irCR plus irPR plus immune-related Stable&#xD;
                Disease (irSD) lasting ≥ 24 weeks according to irRECIST.&#xD;
&#xD;
             -  Response Duration (RD) assessed according to irRECIST.&#xD;
&#xD;
        -  A set of immune biomarkers will be analysed and correlated with evolution of the disease&#xD;
           and efficacy of pembrolizumab in combination with gemcitabine (ORR and other efficacy&#xD;
           end-points: PFS, CBR and RD), paying special attention to long term responders.&#xD;
&#xD;
        -  This set of immune biomarkers will be compared with those from healthy volunteers (if&#xD;
           available).&#xD;
&#xD;
      Study population:&#xD;
&#xD;
      Patients with HER2-negative advanced breast cancer.&#xD;
&#xD;
      Justification of Sample size determination:&#xD;
&#xD;
      A Simon's minimax two-stage design will be employed with the possibility of stopping early&#xD;
      due to lack of response. Results from previous studies showed that gemcitabine produced a&#xD;
      response rate of around 20%, this will be our expected H0. With the combination of&#xD;
      pembrolizumab and gemcitabine, we expect to increase this rate to 35% what will be our H1 (an&#xD;
      absolute increase of 15%), with an alpha error of 0.05 and a statistical power of 80%, we&#xD;
      will need to include 53 evaluable patients in this trial. The first stage will include 31&#xD;
      evaluable patients, if at least 7 present a response, recruitment will continue to include&#xD;
      the 53 evaluable patients. The null hypothesis of H0=20% will be rejected if 16 or more&#xD;
      responses are observed in 53 patients.&#xD;
&#xD;
      Statistical Analyses:&#xD;
&#xD;
      Demographics and Baseline Characteristics: Standard descriptive statistics, such as the mean,&#xD;
      median, range and proportion, will be used to summarize the patient sample and to estimate&#xD;
      parameters of interest.&#xD;
&#xD;
      Safety Analyses: AEs and Serious Adverse Events (SAE) will be reported in frequency tables&#xD;
      (overall and by intensity). The safety analysis will be performed in the population that has&#xD;
      received at least one dose of any of the study drugs/medications.&#xD;
&#xD;
      Efficacy Analyses: All efficacy endpoints will be evaluated in the Per-protocol and Intent to&#xD;
      treat (ITT) populations.&#xD;
&#xD;
      Biomarker analysis:The biomarker analysis will be exploratory and descriptive. For continuous&#xD;
      variables, mean, standard deviation, median, minimum and maximum values will be provided.&#xD;
      Categorical variables will be summarized by numbers and proportions. Biomarker endpoints will&#xD;
      be evaluated in all patients enrolled in the study with available samples.&#xD;
&#xD;
      Study Duration:&#xD;
&#xD;
      The end date of study is date of last patient´s death or the date when there is sufficient&#xD;
      data to achieve the primary and secondary objectives and all patients have ended the study&#xD;
      treatment, whichever comes first.&#xD;
&#xD;
      Performing exploratory objectives will be independent of the date of the end of the study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 28, 2017</start_date>
  <completion_date type="Actual">July 22, 2021</completion_date>
  <primary_completion_date type="Actual">June 3, 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>Number of Participants With Dose Limiting Toxicity (DLT) Within the First Cycle</measure>
    <time_frame>Up to cycle 1</time_frame>
    <description>DLT was defined as the occurrence of any of the following adverse events (AE) or abnormal laboratory value (graded according to the NCI Common Terminology Criteria for AE (CTCAE) version 4.0), assessed as possibly, probably or definitively related to study drug/medication, occurring within the first cycle of study treatment: any Grade 4 thrombocytopenia or neutropenia lasting &gt; 7 days; episcleritis, uveitis, or iritis of Grade 2 or higher, any Grade 4 toxicity, any Grade 3 toxicity EXCLUDING: nausea, vomiting, or diarrhea controlled by medical intervention within 72 hours, grade 3 rash in the absence of desquamation, no mucosal involvement, does not require steroids, and resolves to Grade 1 by the next scheduled dose of pembrolizumab, transient Grade 3 Aspartate Transaminase (AST) or Alanine Transaminase (ALT) elevation, defined as no more than 3 days with or without steroid use, discontinuation or delay of more than 2 weeks of any study drug/medication due to treatment-related AE.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Recommended Phase II Dose (RP2D) of Gemcitabine in Combination With Pembrolizumab</measure>
    <time_frame>Up to cycle 1</time_frame>
    <description>The RP2D was decided by the internal committee taken into consideration the information obtained in the study and based on the number of DLT.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Objective Response Rate (ORR)</measure>
    <time_frame>Through study treatment, and average of 3 months</time_frame>
    <description>Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1). ORR is defined as the percentage of patients with a Complete Response (CR) or Partial Response (PR) out of the patients from the efficacy population. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an &gt;=30% decrease in the sum of the longest diameter of target lesions.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression-Free Survival (PFS)</measure>
    <time_frame>Through study treatment, and average of 3 months</time_frame>
    <description>Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1). PFS is defined as the time from enrollment to the first documented progression disease (PD), or death from any cause, whichever occurs first. PD is defined using RECIST, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Benefit Rate (CBR)</measure>
    <time_frame>Through study treatment, and average of 3 months</time_frame>
    <description>Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. CBR was defined as the percentage of patients with a Complete Response (CR) or Partial Response (PR) plus stable disease (SD) out of the efficacy population. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an &gt;=30% decrease in the sum of the longest diameter of target lesions; SD is defined as a failure to meet criteria for CR or PR in the absence of progressive disease. Overall Response (OR) = CR + PR.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical Benefit Rate (CBR) at Least 24 Weeks</measure>
    <time_frame>24 weeks</time_frame>
    <description>Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. CBR was defined as the percentage of patients with a Complete Response (CR) or Partial Response (PR) plus stable disease (SD) lasting at least 24 months out of the efficacy population. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an &gt;=30% decrease in the sum of the longest diameter of target lesions; SD is defined as a failure to meet criteria for CR or PR in the absence of progressive disease lasting at least 24 months. Overall Response (OR) = CR + PR.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Response Duration (RD)</measure>
    <time_frame>Through study treatment, and average of 3 months</time_frame>
    <description>Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. RD was defined as the time from the first documentation of objective tumor response (complete response (CR) or partial response (PR)) to the first documented progressive disease (PD), or to death due to any cause, whichever occurs first. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an &gt;=30% decrease in the sum of the longest diameter of target lesions; PD is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>Up to 2 years</time_frame>
    <description>OS is defined as the time from the date of enrollment to the date of death from any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The Number of Participants Who Experienced Adverse Events (AE) Related to Study Treatment</measure>
    <time_frame>Through study treatment, and average of 3 months</time_frame>
    <description>Safety assessments were performed at baseline and during the study: Vital signs assessments (blood pressure, pulse and body temperature), Laboratory assessments (hemoglobin, platelet count, White Blood Cell (WBC), Absolute Neutrophil Count (ANC) and Absolute Lymphocyte Count (ALC), albumin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, serum creatinine, creatinine clearance (for patients with creatinine levels &gt; 1.5 x ULN), glucose and urea, International Normalized Ratio (INR)/ Prothrombin time (PT) and activated partial thromboplastin time (aPTT), total or free triiodothyronine (T3 or FT3), free thyroxine (FT4) and Thyroid-stimulating hormone (TSH)) and Urinalysis. A baseline standard 12-lead electrocardiogram (ECG) was mandatory. AEs were graded according to NCI-CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 4.03.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immune-related Objective Response Rate (irORR)</measure>
    <time_frame>Through study treatment, and average of 3 months</time_frame>
    <description>Tumor response was assessed using Immune-Related Response Evaluation Criteria In Solid Tumors Criteria (irRECIST v 1.0). irORR is defined as the percentage of patients with a Immune-Related Complete Response (irCR) or Immune-Related Partial Response (irPR) out of the patients from the efficacy population. Per irRECIST, irCR is defined as the disappearance of all measurable and non-measurable lesions, and lymph nodes must decrease to &lt; 10 mm in short axis; irPR is defined as an &gt;=30% decrease in total measured tumor burden relative to baseline; Immune-Related Overall Response (irOR) = irCR + irPR.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immune-related Progression-Free Survival (irPFS)</measure>
    <time_frame>Through study treatment, and average of 3 months</time_frame>
    <description>Tumor response was assessed using Immune-Related Response Evaluation Criteria In Solid Tumors Criteria (irRECIST v 1.0). irPFS was defined as the time from enrollment to the first documented progressive disease (PD), or death from any cause, whichever occurs first. PD is defined by irRECIST, as a 20% increase and minimum 5 mm absolute increase in total measured tumor burden compared with nadir, or a measurable increase in a non-target lesion, or the appearance of new lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immune Related Clinical Benefit Rate (irCBR)</measure>
    <time_frame>Through study treatment, and average of 3 months</time_frame>
    <description>Tumor response was assessed using Immune-Related Response Evaluation Criteria In Solid Tumors Criteria (irRECIST v 1.0). irCBR was defined as the percentage of patients with a Immune Related Complete Response (irCR) or Immune Related Partial Response (irPR) plus Immune Related Stable Disease (irSD) out of the efficacy population. Per irRECIST, irCR is defined as the disappearance of all measurable and non-measurable lesions, and lymph nodes must decrease to &lt; 10 mm in short axis; irPR is defined as an &gt;=30% decrease in total measured tumor burden relative to baseline; irSD is defined as a failure to meet criteria for irCR or irPR in the absence of progressive disease.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immune Related Clinical Benefit Rate (irCBR) at Least 24 Weeks</measure>
    <time_frame>Through study treatment, and average of 3 months</time_frame>
    <description>Tumor response was assessed using Immune-Related Response Evaluation Criteria In Solid Tumors Criteria (irRECIST v 1.0). irCBR was defined as the percentage of patients with a Immune Related Complete Response (irCR) or Immune Related Partial Response (irPR) plus Immune Related stable disease (irSD) lasting at least 24 months out of the efficacy population. Per irRECIST, irCR is defined as the disappearance of all measurable and non-measurable lesions, and lymph nodes must decrease to &lt; 10 mm in short axis; irPR is defined as an &gt;=30% decrease in total measured tumor burden relative to baseline; irSD is defined as a failure to meet criteria for irCR or irPR in the absence of progressive disease at least 24 weeks.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immune Related Response Duration (irRD)</measure>
    <time_frame>Through study treatment, and average of 3 months</time_frame>
    <description>Tumor response was assessed using Immune-Related Response Evaluation Criteria In Solid Tumors Criteria (irRECIST v 1.0). irRD was defined as the time from the first documentation of objective tumor response (immune related complete response (irCR) or immune related partial response (irPR)) to the first documented immune related progressive disease (irPD), or to death due to any cause, whichever occurs first. Per RECIST, irCR is defined as the disappearance of all measurable and non-measurable lesions, and lymph nodes must decrease to &lt; 10 mm in short axis; irPR is defined as an &gt;=30% decrease in total measured tumor burden relative to baseline; irPD is defined as a 20% increase and minimum 5 mm absolute increase in total measured tumor burden compared with nadir, or a measurable increase in a non-target lesion, or the appearance of new lesions.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">36</enrollment>
  <condition>Advanced Breast Cancer</condition>
  <arm_group>
    <arm_group_label>Single arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Eligible patients will be enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 or 1,000mg/m2 (this dose will be explored in combination with P in the initial exploratory run-in-phase if necessary) as a IV infusion on day 1 and 8 of each 21-day cycle.&#xD;
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first. An initial exploratory run-in-phase will be performed to test the safety of the combination and determine the Recommended Phase II Dose (RP2D) of G in combination with fixed doses of P.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>Pembrolizumab at a dose of 200mg as an intravenous (IV) 30 minutes infusion on day 1 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first. Patients completing 24 months of uninterrupted treatment with pembrolizumab or 35 administrations of study medication will stop pembrolizumab treatment (though may continue with gemcitabine). Subjects who stop pembrolizumab after 24 months may be eligible for up to one year of additional pembrolizumab treatment if they progress after stopping it.</description>
    <arm_group_label>Single arm</arm_group_label>
    <other_name>Keytruda</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Gemcitabine</intervention_name>
    <description>Gemcitabine at a dose of 1,250mg/m2 as an intravenous (IV) 60 minutes infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.</description>
    <arm_group_label>Single arm</arm_group_label>
    <other_name>Gemzar</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. The patient has signed and dated the informed consent document and it has been&#xD;
             obtained before conducting any procedure specifically for the study.&#xD;
&#xD;
          2. Female ≥ 18 years of age on day of signing informed consent.&#xD;
&#xD;
          3. Histological/cytological confirmation of breast cancer with evidence of advanced&#xD;
             disease, not amenable to resection or radiation therapy with curative intent.&#xD;
&#xD;
          4. Documented luminal A, luminal B (HER2-negative) or triple negative disease by&#xD;
             immunohistochemistry (IHQ) and/or in situ hybridization (FISH/CISH/SISH) based on&#xD;
             local testing on the most recent tumour biopsy defined as follows:&#xD;
&#xD;
             Luminal A: tumour with positive oestrogen receptor (ER) status (≥1% of tumour cells&#xD;
             with ER expression) and HER2-negative status (IHQ score 0/1+ or negative by in situ&#xD;
             hybridization defined as a HER2/chromosome enumeration probe 17 (CEP17) ratio &lt; 2 or&#xD;
             for single probe assessment a HER2 copy number &lt; 4) and high progesterone receptor&#xD;
             (PgR) (≥ 20% of tumour cells with PgR expression) and low Ki67 (&lt; 14%).&#xD;
&#xD;
             Luminal B (HER2-negative): tumour with positive ER status (≥1% of tumour cells with ER&#xD;
             expression) and HER2-negative status (IHQ score 0/1+ or negative by in situ&#xD;
             hybridization defined as a HER2/CEP17 ratio &lt; 2 or for single probe assessment a HER2&#xD;
             copy number &lt; 4) and either low or negative PgR (&lt; 20% of tumour cells with PgR&#xD;
             expression) and/or high Ki67 (≥ 14%).&#xD;
&#xD;
             Triple negative: tumour with negative hormone receptor status (&lt;1% of tumour cells&#xD;
             with ER and PgR expression) and HER2-negative status (IHQ score 0/1+ or negative by in&#xD;
             situ hybridization defined as a HER2/CEP17 ratio &lt; 2 or for single probe assessment a&#xD;
             HER2 copy number &lt; 4).&#xD;
&#xD;
          5. Have at least one unidimensionally measurable lesion by RECIST 1.1.&#xD;
&#xD;
          6. Patient agrees to the collection of a metastatic tumor sample (biopsy) at the time of&#xD;
             inclusion and at progression (whenever possible).&#xD;
&#xD;
          7. Have a performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group&#xD;
             (ECOG) Performance Scale.&#xD;
&#xD;
          8. Demonstrate adequate organ function as follows (all screening labs should be performed&#xD;
             within 7 days of study treatment initiation):&#xD;
&#xD;
             Bone marrow:&#xD;
&#xD;
             Absolute Neutrophil Count (ANC) ≥ 1,500/mm3 (1.5x109/l) Platelets ≥ 100,000/mm3&#xD;
             (100x109/l) Hemoglobin ≥ 9g/dl or ≥ 5.6 mmol/l without transfusion or erythropoietin&#xD;
             (EPO) dependency (within 7 days of assessment)&#xD;
&#xD;
             Hepatic:&#xD;
&#xD;
             Serum total bilirubin ≤ 1.5 x Upper Limit of Normal (ULN) Alkaline Phosphatase ≤ 2.5 x&#xD;
             ULN Aspartate aminotransferase (AST) (SGOT) and Alanine aminotransferase (ALT) (SGPT)&#xD;
             ≤ 2.5 x ULN or ≤ 5 x ULN for patients with liver metastases Albumin ≥ 2.5 g/dl&#xD;
&#xD;
             Renal:&#xD;
&#xD;
             Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 60 ml/min for patients with&#xD;
             creatinine levels &gt; 1.5 x ULN&#xD;
&#xD;
             Coagulation:&#xD;
&#xD;
             International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 x ULN unless&#xD;
             patient 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 patient is receiving&#xD;
             anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use&#xD;
             of anticoagulants.&#xD;
&#xD;
          9. Prior treatment with anthracyclines and taxanes (unless clinically contraindicated)&#xD;
             and two or more prior lines of hormone therapy in hormone receptor positive disease.&#xD;
&#xD;
         10. At least 3 months life expectancy.&#xD;
&#xD;
         11. Patient of childbearing potential should have a negative urine or serum pregnancy&#xD;
             within 72 hours prior to receiving the first dose of study drug/medication. If the&#xD;
             urine test is positive or cannot be confirmed as negative, a serum pregnancy test will&#xD;
             be required.&#xD;
&#xD;
         12. Patients of childbearing potential (see section 4.4. for definition) must be willing&#xD;
             to use an adequate method of contraception as outlined in Section 4.4. -&#xD;
             Contraception, for the course of the study through 120 days after the last dose of&#xD;
             study medication.&#xD;
&#xD;
             Note: Abstinence is acceptable if this is the usual lifestyle and preferred&#xD;
             contraception for the subject.&#xD;
&#xD;
         13. Willingness and ability to comply with scheduled visits, treatment plan, laboratory&#xD;
             tests and other study procedures.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. HER2-positive disease by immunohistochemistry or in situ hybridation (FISH-SISH-CISH).&#xD;
&#xD;
          2. Patient is currently participating or has participated in a study of an&#xD;
             investigational agent and received study therapy or used an investigational device&#xD;
             within 4 weeks of the first dose of study drug/medication.&#xD;
&#xD;
          3. 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;
          4. 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: Patients with ≤ grade 2 neuropathy are an exception to this criterion and&#xD;
                  may qualify for the study.&#xD;
&#xD;
               -  Note: If patient received major surgery, they must have recovered adequately from&#xD;
                  the toxicity and/or complications from the intervention prior to starting&#xD;
                  therapy.&#xD;
&#xD;
          5. Has received prior therapy with an anti-Programmed death-1 (PD), anti-PD-L1, or&#xD;
             anti-PD-L2 agent.&#xD;
&#xD;
          6. Has received a live vaccine within 30 days of planned start of study therapy.&#xD;
&#xD;
             o 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;
          7. Has hypersensitivity to pembrolizumab, gemcitabine or any of theirs excipients.&#xD;
&#xD;
          8. Has known active central nervous system (CNS) metastases and/or carcinomatous&#xD;
             meningitis. Patients 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 all 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;
          9. 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 study&#xD;
             drug/medication.&#xD;
&#xD;
         10. Has an active autoimmune disease that has required systemic treatment in the past 2&#xD;
             years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive&#xD;
             drugs). Replacement therapy (e.g., 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;
         11. Has a current or prior malignancy within the previous 5 years (other than breast&#xD;
             cancer or adequately treated basal cell or squamous cell carcinoma of the skin or&#xD;
             in-situ carcinoma of the cervix).&#xD;
&#xD;
         12. Has a history of (non-infectious) pneumonitis that required steroids or current&#xD;
             pneumonitis.&#xD;
&#xD;
         13. Has an active infection requiring systemic therapy.&#xD;
&#xD;
         14. Has a known history of active Tuberculosis Bacillus (TB) or Human Immunodeficiency&#xD;
             Virus (HIV) (HIV 1/2 antibodies) or a known active Hepatitis B (e.g., HBsAg reactive)&#xD;
             or Hepatitis C (e.g., hepatitis C virus (HCV) RNA [qualitative] is detected).&#xD;
&#xD;
         15. 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 patient's&#xD;
             participation for the full duration of the trial, or is not in the best interest of&#xD;
             the patient to participate, in the opinion of the treating investigator.&#xD;
&#xD;
         16. Has known psychiatric or substance abuse disorders that would interfere with&#xD;
             cooperation with the requirements of the trial.&#xD;
&#xD;
         17. Patient is pregnant or breastfeeding, or expecting to conceive within the projected&#xD;
             duration of the trial, starting with the baseline visit through 120 days after the&#xD;
             last dose of trial treatment.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Study Director</last_name>
    <role>Study Director</role>
    <affiliation>Hospital Universitario Virgen Macarena</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Institut Català d'Oncologia. Hospital Universitario Germans Trias i Pujol</name>
      <address>
        <city>Badalona</city>
        <state>Barcelona</state>
        <zip>08916</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario de Canarias</name>
      <address>
        <city>La Laguna</city>
        <state>Canarias</state>
        <zip>38320</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Virgen de la Arrixaca</name>
      <address>
        <city>El Palmar</city>
        <state>Murcia</state>
        <zip>30120</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clínica Universitaria de Navarra</name>
      <address>
        <city>Pamplona</city>
        <state>Navarra</state>
        <zip>31008</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centro Oncológico de Galicia</name>
      <address>
        <city>A Coruña</city>
        <zip>15009</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Ramón y Cajal</name>
      <address>
        <city>Madrid</city>
        <zip>28034</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Clínico Universitario San Carlos</name>
      <address>
        <city>Madrid</city>
        <zip>28040</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Virgen de la Macarena</name>
      <address>
        <city>Sevilla</city>
        <zip>41009</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Clínico Universitario de Zaragoza &quot;Lozano Blesa&quot;</name>
      <address>
        <city>Zaragoza</city>
        <zip>50009</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
  <link>
    <url>http://www.geicam.org/</url>
    <description>GEICAM is a Spanish Breast Cancer Research Group</description>
  </link>
  <results_reference>
    <citation>de la Cruz-Merino L, Gion M, Cruz J, Alonso-Romero JL, Quiroga V, Moreno F, Andres R, Santisteban M, Ramos M, Holgado E, Cortes J, Lopez-Miranda E, Cortes A, Henao F, Palazon-Carrion N, Rodriguez LM, Ceballos I, Soto A, Puertes A, Casas M, Benito S, Chiesa M, Bezares S, Caballero R, Jimenez-Cortegana C, Sanchez-Margalet V, Rojo F. Pembrolizumab in combination with gemcitabine for patients with HER2-negative advanced breast cancer: GEICAM/2015-04 (PANGEA-Breast) study. BMC Cancer. 2022 Dec 3;22(1):1258. doi: 10.1186/s12885-022-10363-3.</citation>
    <PMID>36463104</PMID>
  </results_reference>
  <results_reference>
    <citation>de la Cruz-Merino L, Gion M, Cruz-Jurado J, Quiroga V, Andres R, Moreno F, Alonso-Romero JL, Ramos M, Holgado E, Cortes J, Lopez-Miranda E, Henao-Carrasco F, Palazon-Carrion N, Rodriguez LM, Ceballos I, Casas M, Benito S, Chiesa M, Bezares S, Caballero R, Jimenez-Cortegana C, Sanchez-Margalet V, Rojo F. Pembrolizumab Plus Gemcitabine in the Subset of Triple-Negative Advanced Breast Cancer Patients in the GEICAM/2015-04 (PANGEA-Breast) Study. Cancers (Basel). 2021 Oct 29;13(21):5432. doi: 10.3390/cancers13215432.</citation>
    <PMID>34771596</PMID>
  </results_reference>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>January 11, 2017</study_first_submitted>
  <study_first_submitted_qc>January 19, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 20, 2017</study_first_posted>
  <results_first_submitted>February 3, 2022</results_first_submitted>
  <results_first_submitted_qc>April 12, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">January 10, 2023</results_first_posted>
  <last_update_submitted>March 3, 2023</last_update_submitted>
  <last_update_submitted_qc>March 3, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 3, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Advanced Breast Cancer</keyword>
  <keyword>Pembrolizumab</keyword>
  <keyword>HER2-negative</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Gemcitabine</mesh_term>
    <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</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>March 19, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/80/NCT03025880/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>March 26, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/80/NCT03025880/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Fourteen patients were enrolled at the Run-in phase, receiving at least one cycle of the combination. All patients were included at Dose Level (DL) 0. Twenty-two patients were included at the phase II.</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Run-in Phase Dose Level 0</title>
          <description>Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) or 1,000mg/m2 (Dose Level -1) as a IV infusion on day 1 and 8 of each 21-day cycle.&#xD;
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.&#xD;
An initial exploratory run-in-phase will be performed to test the safety of the combination and determine the Recommended Phase II Dose (RP2D) of G in combination with fixed doses of P.</description>
        </group>
        <group group_id="P2">
          <title>Phase II</title>
          <description>Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle.&#xD;
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="14"/>
                <participants group_id="P2" count="22"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="14"/>
                <participants group_id="P2" count="22"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Progressive Disease</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>Run-in Phase Dose Level 0</title>
          <description>Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) or 1,000mg/m2 (Dose Level -1) as a IV infusion on day 1 and 8 of each 21-day cycle.&#xD;
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.&#xD;
An initial exploratory run-in-phase will be performed to test the safety of the combination and determine the Recommended Phase II Dose (RP2D) of G in combination with fixed doses of P.</description>
        </group>
        <group group_id="B2">
          <title>Phase II</title>
          <description>Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle.&#xD;
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.</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="14"/>
            <count group_id="B2" value="22"/>
            <count group_id="B3" value="36"/>
          </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="14"/>
                    <measurement group_id="B2" value="19"/>
                    <measurement group_id="B3" value="33"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="48.5" spread="8"/>
                    <measurement group_id="B2" value="56" spread="12.19"/>
                    <measurement group_id="B3" value="51.5" spread="10.9"/>
                  </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="14"/>
                    <measurement group_id="B2" value="22"/>
                    <measurement group_id="B3" value="36"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_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="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </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="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                    <measurement group_id="B2" value="22"/>
                    <measurement group_id="B3" value="36"/>
                  </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>Spain</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                    <measurement group_id="B2" value="22"/>
                    <measurement group_id="B3" value="36"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Menopause Status</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Postmenopausal</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="16"/>
                    <measurement group_id="B3" value="26"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Premenopausal</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Eastern Cooperative Oncology Group (ECOG) status</title>
          <description>ECOG score runs from 0 to 5, with 0 denoting perfect health and 5 death. 0 - Asymptomatic&#xD;
- Symptomatic but completely ambulatory&#xD;
- Symptomatic, &lt;50% in bed during the day&#xD;
- Symptomatic, &gt;50% in bed, but not bedbound&#xD;
- Bedbound&#xD;
- Death</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>ECOG 0</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="16"/>
                    <measurement group_id="B3" value="23"/>
                  </measurement_list>
                </category>
                <category>
                  <title>ECOG 1</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="12"/>
                  </measurement_list>
                </category>
                <category>
                  <title>ECOG 2</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_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Type of Disease for Cohort Purposes</title>
          <description>Luminal A: estrogen-receptor (ER) and/or progesterone-receptor (PR) positive, Human Epidermal Growth Factor Receptor 2 (HER2) negative, low levels of Ki67. Luminal A are low-grade, tend to grow slowly and have the best prognosis.&#xD;
Luminal B: ER and/or PR positive, and HER2 positive or HER2 negative with high levels of Ki67. Luminal B grow faster than luminal A and their prognosis is worse.&#xD;
Triple-negative (TN): negative for ER, PR, and HER2. Is more aggressive and have poorer prognosis than Luminal due to there are fewer targeted medicines that treat TN.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Triple negative</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="21"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Luminal A+B</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ki67 cut-off 20%</title>
          <description>Ki67 is a protein found in the nucleus of cells when they divide. Ki67 determines the proliferation rate. Tumors with high proliferation rates (&gt; 20%) have a worse prognosis.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Ki67 &lt;20%</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Ki67 &gt;=20%</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>Ki67 Not Available/Not Done</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Histopathologic Type</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Ductal</title>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="20"/>
                    <measurement group_id="B3" value="33"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Lobular</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>
                  <title>Other: Squamous Invasive Cancer</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>
          <title>Histologic Grade</title>
          <description>Cancer cells are given a Grade (G) when they are removed from the breast and checked under a microscope. The G is based on how much the cancer cells look like normal cells.&#xD;
G1 or well differentiated (score 3, 4, or 5): cells are slower-growing, and look more like normal breast tissue.&#xD;
G2 or moderately differentiated (score 6, 7): cells are growing at a speed of and look like cells somewhere between G1 and 3.&#xD;
G3 or poorly differentiated (score 8, 9): cells look very different from normal and will probably grow and spread faster.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Grade 1</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>
                  <title>Grade 2</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="14"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Grade 3</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="16"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown</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>Not done</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Dose Limiting Toxicity (DLT) Within the First Cycle</title>
        <description>DLT was defined as the occurrence of any of the following adverse events (AE) or abnormal laboratory value (graded according to the NCI Common Terminology Criteria for AE (CTCAE) version 4.0), assessed as possibly, probably or definitively related to study drug/medication, occurring within the first cycle of study treatment: any Grade 4 thrombocytopenia or neutropenia lasting &gt; 7 days; episcleritis, uveitis, or iritis of Grade 2 or higher, any Grade 4 toxicity, any Grade 3 toxicity EXCLUDING: nausea, vomiting, or diarrhea controlled by medical intervention within 72 hours, grade 3 rash in the absence of desquamation, no mucosal involvement, does not require steroids, and resolves to Grade 1 by the next scheduled dose of pembrolizumab, transient Grade 3 Aspartate Transaminase (AST) or Alanine Transaminase (ALT) elevation, defined as no more than 3 days with or without steroid use, discontinuation or delay of more than 2 weeks of any study drug/medication due to treatment-related AE.</description>
        <time_frame>Up to cycle 1</time_frame>
        <population>There was no need to explore the Dose Level -1 (Pembrolizumab 200mg intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine 1,000mg/m2 as a IV infusion on day 1 and 8 of each 21-day cycle.</population>
        <group_list>
          <group group_id="O1">
            <title>Run-in Phase Dose Level 0</title>
            <description>Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) as a IV infusion on day 1 and 8 of each 21-day cycle.&#xD;
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Dose Limiting Toxicity (DLT) Within the First Cycle</title>
          <description>DLT was defined as the occurrence of any of the following adverse events (AE) or abnormal laboratory value (graded according to the NCI Common Terminology Criteria for AE (CTCAE) version 4.0), assessed as possibly, probably or definitively related to study drug/medication, occurring within the first cycle of study treatment: any Grade 4 thrombocytopenia or neutropenia lasting &gt; 7 days; episcleritis, uveitis, or iritis of Grade 2 or higher, any Grade 4 toxicity, any Grade 3 toxicity EXCLUDING: nausea, vomiting, or diarrhea controlled by medical intervention within 72 hours, grade 3 rash in the absence of desquamation, no mucosal involvement, does not require steroids, and resolves to Grade 1 by the next scheduled dose of pembrolizumab, transient Grade 3 Aspartate Transaminase (AST) or Alanine Transaminase (ALT) elevation, defined as no more than 3 days with or without steroid use, discontinuation or delay of more than 2 weeks of any study drug/medication due to treatment-related AE.</description>
          <population>There was no need to explore the Dose Level -1 (Pembrolizumab 200mg intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine 1,000mg/m2 as a IV infusion on day 1 and 8 of each 21-day cycle.</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="14"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Recommended Phase II Dose (RP2D) of Gemcitabine in Combination With Pembrolizumab</title>
        <description>The RP2D was decided by the internal committee taken into consideration the information obtained in the study and based on the number of DLT.</description>
        <time_frame>Up to cycle 1</time_frame>
        <population>Run in phase population</population>
        <group_list>
          <group group_id="O1">
            <title>Run-in Phase Dose Level 0</title>
            <description>Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) as a IV infusion on day 1 and 8 of each 21-day cycle.&#xD;
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.</description>
          </group>
        </group_list>
        <measure>
          <title>Recommended Phase II Dose (RP2D) of Gemcitabine in Combination With Pembrolizumab</title>
          <description>The RP2D was decided by the internal committee taken into consideration the information obtained in the study and based on the number of DLT.</description>
          <population>Run in phase population</population>
          <units>mg/m2</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="14"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1250"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Objective Response Rate (ORR)</title>
        <description>Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1). ORR is defined as the percentage of patients with a Complete Response (CR) or Partial Response (PR) out of the patients from the efficacy population. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an &gt;=30% decrease in the sum of the longest diameter of target lesions.</description>
        <time_frame>Through study treatment, and average of 3 months</time_frame>
        <population>Efficacy population: patients that had measurable disease, had received at least one dose of study treatment and had at least one tumor response assessment (unless progression or death or unacceptable toxicity before the first tumor response assessment) and without certain major protocol deviations according to the protocol deviation manual.</population>
        <group_list>
          <group group_id="O1">
            <title>Run-in Phase Dose Level 0</title>
            <description>Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) as a IV infusion on day 1 and 8 of each 21-day cycle.&#xD;
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.</description>
          </group>
          <group group_id="O2">
            <title>Phase II</title>
            <description>Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle.&#xD;
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.</description>
          </group>
          <group group_id="O3">
            <title>Run-in Phase Plus Phase II</title>
            <description>Patients included in the run-in-phase at the same dose that in the phase II (DL0) were included on the analysis.</description>
          </group>
        </group_list>
        <measure>
          <title>Objective Response Rate (ORR)</title>
          <description>Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1). ORR is defined as the percentage of patients with a Complete Response (CR) or Partial Response (PR) out of the patients from the efficacy population. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an &gt;=30% decrease in the sum of the longest diameter of target lesions.</description>
          <population>Efficacy population: patients that had measurable disease, had received at least one dose of study treatment and had at least one tumor response assessment (unless progression or death or unacceptable toxicity before the first tumor response assessment) and without certain major protocol deviations according to the protocol deviation manual.</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="13"/>
                <count group_id="O2" value="20"/>
                <count group_id="O3" value="33"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="5"/>
                    <measurement group_id="O3" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression-Free Survival (PFS)</title>
        <description>Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1). PFS is defined as the time from enrollment to the first documented progression disease (PD), or death from any cause, whichever occurs first. PD is defined using RECIST, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions</description>
        <time_frame>Through study treatment, and average of 3 months</time_frame>
        <population>Efficacy population</population>
        <group_list>
          <group group_id="O1">
            <title>Run-in Phase Dose Level 0</title>
            <description>Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) as a IV infusion on day 1 and 8 of each 21-day cycle.&#xD;
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.</description>
          </group>
          <group group_id="O2">
            <title>Phase II</title>
            <description>Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle.&#xD;
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.</description>
          </group>
          <group group_id="O3">
            <title>Run-in Phase Plus Phase II</title>
            <description>Patients included in the run-in-phase at the same dose that in the phase II (DL0) were included on the analysis.</description>
          </group>
        </group_list>
        <measure>
          <title>Progression-Free Survival (PFS)</title>
          <description>Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1). PFS is defined as the time from enrollment to the first documented progression disease (PD), or death from any cause, whichever occurs first. PD is defined using RECIST, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions</description>
          <population>Efficacy population</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="13"/>
                <count group_id="O2" value="20"/>
                <count group_id="O3" value="33"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.1" lower_limit="0.9" upper_limit="5.4"/>
                    <measurement group_id="O2" value="2.6" lower_limit="1.9" upper_limit="6.1"/>
                    <measurement group_id="O3" value="3.1" lower_limit="2" upper_limit="4.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Clinical Benefit Rate (CBR)</title>
        <description>Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. CBR was defined as the percentage of patients with a Complete Response (CR) or Partial Response (PR) plus stable disease (SD) out of the efficacy population. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an &gt;=30% decrease in the sum of the longest diameter of target lesions; SD is defined as a failure to meet criteria for CR or PR in the absence of progressive disease. Overall Response (OR) = CR + PR.</description>
        <time_frame>Through study treatment, and average of 3 months</time_frame>
        <population>Efficacy population</population>
        <group_list>
          <group group_id="O1">
            <title>Run-in Phase Dose Level 0</title>
            <description>Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) as a IV infusion on day 1 and 8 of each 21-day cycle.&#xD;
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.</description>
          </group>
          <group group_id="O2">
            <title>Phase II</title>
            <description>Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle.&#xD;
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.</description>
          </group>
          <group group_id="O3">
            <title>Run-in Phase Plus Phase II</title>
            <description>Patients included in the run-in-phase at the same dose that in the phase II (DL0) were included on the analysis.</description>
          </group>
        </group_list>
        <measure>
          <title>Clinical Benefit Rate (CBR)</title>
          <description>Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. CBR was defined as the percentage of patients with a Complete Response (CR) or Partial Response (PR) plus stable disease (SD) out of the efficacy population. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an &gt;=30% decrease in the sum of the longest diameter of target lesions; SD is defined as a failure to meet criteria for CR or PR in the absence of progressive disease. Overall Response (OR) = CR + PR.</description>
          <population>Efficacy population</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="13"/>
                <count group_id="O2" value="20"/>
                <count group_id="O3" value="33"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7"/>
                    <measurement group_id="O2" value="10"/>
                    <measurement group_id="O3" value="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Clinical Benefit Rate (CBR) at Least 24 Weeks</title>
        <description>Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. CBR was defined as the percentage of patients with a Complete Response (CR) or Partial Response (PR) plus stable disease (SD) lasting at least 24 months out of the efficacy population. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an &gt;=30% decrease in the sum of the longest diameter of target lesions; SD is defined as a failure to meet criteria for CR or PR in the absence of progressive disease lasting at least 24 months. Overall Response (OR) = CR + PR.</description>
        <time_frame>24 weeks</time_frame>
        <population>Efficacy population</population>
        <group_list>
          <group group_id="O1">
            <title>Run-in Phase Dose Level 0</title>
            <description>Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) as a IV infusion on day 1 and 8 of each 21-day cycle.&#xD;
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.</description>
          </group>
          <group group_id="O2">
            <title>Phase II</title>
            <description>Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle.&#xD;
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.</description>
          </group>
          <group group_id="O3">
            <title>Run-in Phase Plus Phase II</title>
            <description>Patients included in the run-in-phase at the same dose that in the phase II (DL0) were included on the analysis.</description>
          </group>
        </group_list>
        <measure>
          <title>Clinical Benefit Rate (CBR) at Least 24 Weeks</title>
          <description>Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. CBR was defined as the percentage of patients with a Complete Response (CR) or Partial Response (PR) plus stable disease (SD) lasting at least 24 months out of the efficacy population. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an &gt;=30% decrease in the sum of the longest diameter of target lesions; SD is defined as a failure to meet criteria for CR or PR in the absence of progressive disease lasting at least 24 months. Overall Response (OR) = CR + PR.</description>
          <population>Efficacy population</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="13"/>
                <count group_id="O2" value="20"/>
                <count group_id="O3" value="33"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="5"/>
                    <measurement group_id="O3" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Response Duration (RD)</title>
        <description>Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. RD was defined as the time from the first documentation of objective tumor response (complete response (CR) or partial response (PR)) to the first documented progressive disease (PD), or to death due to any cause, whichever occurs first. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an &gt;=30% decrease in the sum of the longest diameter of target lesions; PD is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions</description>
        <time_frame>Through study treatment, and average of 3 months</time_frame>
        <population>There were only 5 Partial Responses on the phase II population.</population>
        <group_list>
          <group group_id="O1">
            <title>Run-in Phase Dose Level 0</title>
            <description>Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) as a IV infusion on day 1 and 8 of each 21-day cycle.&#xD;
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.</description>
          </group>
          <group group_id="O2">
            <title>Phase II</title>
            <description>Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle.&#xD;
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.</description>
          </group>
          <group group_id="O3">
            <title>Run-in Phase Plus Phase II</title>
            <description>Patients included in the run-in-phase at the same dose that in the phase II (DL0) were included on the analysis.</description>
          </group>
        </group_list>
        <measure>
          <title>Response Duration (RD)</title>
          <description>Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. RD was defined as the time from the first documentation of objective tumor response (complete response (CR) or partial response (PR)) to the first documented progressive disease (PD), or to death due to any cause, whichever occurs first. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an &gt;=30% decrease in the sum of the longest diameter of target lesions; PD is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions</description>
          <population>There were only 5 Partial Responses on the phase II population.</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="0"/>
                <count group_id="O2" value="5"/>
                <count group_id="O3" value="5"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O2" value="4.3" lower_limit="2.3" upper_limit="7.4"/>
                    <measurement group_id="O3" value="4.3" lower_limit="2.3" upper_limit="7.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival (OS)</title>
        <description>OS is defined as the time from the date of enrollment to the date of death from any cause.</description>
        <time_frame>Up to 2 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Run-in Phase Dose Level 0</title>
            <description>Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) as a IV infusion on day 1 and 8 of each 21-day cycle.&#xD;
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.</description>
          </group>
          <group group_id="O2">
            <title>Phase II</title>
            <description>Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle.&#xD;
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.</description>
          </group>
          <group group_id="O3">
            <title>Run-in Phase Plus Phase II</title>
            <description>Patients included in the run-in-phase at the same dose that in the phase II (DL0) were included on the analysis.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival (OS)</title>
          <description>OS is defined as the time from the date of enrollment to the date of death from any cause.</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="13"/>
                <count group_id="O2" value="20"/>
                <count group_id="O3" value="33"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.1" lower_limit="1.3" upper_limit="11.7"/>
                    <measurement group_id="O2" value="10.1" lower_limit="7.3" upper_limit="17.7"/>
                    <measurement group_id="O3" value="8.7" lower_limit="6.5" upper_limit="11.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>The Number of Participants Who Experienced Adverse Events (AE) Related to Study Treatment</title>
        <description>Safety assessments were performed at baseline and during the study: Vital signs assessments (blood pressure, pulse and body temperature), Laboratory assessments (hemoglobin, platelet count, White Blood Cell (WBC), Absolute Neutrophil Count (ANC) and Absolute Lymphocyte Count (ALC), albumin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, serum creatinine, creatinine clearance (for patients with creatinine levels &gt; 1.5 x ULN), glucose and urea, International Normalized Ratio (INR)/ Prothrombin time (PT) and activated partial thromboplastin time (aPTT), total or free triiodothyronine (T3 or FT3), free thyroxine (FT4) and Thyroid-stimulating hormone (TSH)) and Urinalysis. A baseline standard 12-lead electrocardiogram (ECG) was mandatory. AEs were graded according to NCI-CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 4.03.</description>
        <time_frame>Through study treatment, and average of 3 months</time_frame>
        <population>Safety population: patients who were enrolled and had have received at least one dose of the study treatment.</population>
        <group_list>
          <group group_id="O1">
            <title>Run-in Phase Dose Level 0</title>
            <description>Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) or 1,000mg/m2 (Dose Level -1) as a IV infusion on day 1 and 8 of each 21-day cycle.&#xD;
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.&#xD;
An initial exploratory run-in-phase will be performed to test the safety of the combination and determine the Recommended Phase II Dose (RP2D) of G in combination with fixed doses of P.</description>
          </group>
          <group group_id="O2">
            <title>Phase II</title>
            <description>Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle.&#xD;
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.</description>
          </group>
        </group_list>
        <measure>
          <title>The Number of Participants Who Experienced Adverse Events (AE) Related to Study Treatment</title>
          <description>Safety assessments were performed at baseline and during the study: Vital signs assessments (blood pressure, pulse and body temperature), Laboratory assessments (hemoglobin, platelet count, White Blood Cell (WBC), Absolute Neutrophil Count (ANC) and Absolute Lymphocyte Count (ALC), albumin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, serum creatinine, creatinine clearance (for patients with creatinine levels &gt; 1.5 x ULN), glucose and urea, International Normalized Ratio (INR)/ Prothrombin time (PT) and activated partial thromboplastin time (aPTT), total or free triiodothyronine (T3 or FT3), free thyroxine (FT4) and Thyroid-stimulating hormone (TSH)) and Urinalysis. A baseline standard 12-lead electrocardiogram (ECG) was mandatory. AEs were graded according to NCI-CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 4.03.</description>
          <population>Safety population: patients who were enrolled and had have received at least one dose of the study treatment.</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="14"/>
                <count group_id="O2" value="22"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8"/>
                    <measurement group_id="O2" value="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Immune-related Objective Response Rate (irORR)</title>
        <description>Tumor response was assessed using Immune-Related Response Evaluation Criteria In Solid Tumors Criteria (irRECIST v 1.0). irORR is defined as the percentage of patients with a Immune-Related Complete Response (irCR) or Immune-Related Partial Response (irPR) out of the patients from the efficacy population. Per irRECIST, irCR is defined as the disappearance of all measurable and non-measurable lesions, and lymph nodes must decrease to &lt; 10 mm in short axis; irPR is defined as an &gt;=30% decrease in total measured tumor burden relative to baseline; Immune-Related Overall Response (irOR) = irCR + irPR.</description>
        <time_frame>Through study treatment, and average of 3 months</time_frame>
        <population>Efficacy population: patients that had measurable disease, had received at least one dose of study treatment and had at least one tumor response assessment (unless progression or death or unacceptable toxicity before the first tumor response assessment) and without certain major protocol deviations according to the protocol deviation manual.</population>
        <group_list>
          <group group_id="O1">
            <title>Run-in Phase Dose Level 0</title>
            <description>Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) as a IV infusion on day 1 and 8 of each 21-day cycle.&#xD;
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.</description>
          </group>
          <group group_id="O2">
            <title>Phase II</title>
            <description>Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle.&#xD;
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.</description>
          </group>
          <group group_id="O3">
            <title>Run-in Phase Plus Phase II</title>
            <description>Patients included in the run-in-phase at the same dose that in the phase II (DL0) were included on the analysis.</description>
          </group>
        </group_list>
        <measure>
          <title>Immune-related Objective Response Rate (irORR)</title>
          <description>Tumor response was assessed using Immune-Related Response Evaluation Criteria In Solid Tumors Criteria (irRECIST v 1.0). irORR is defined as the percentage of patients with a Immune-Related Complete Response (irCR) or Immune-Related Partial Response (irPR) out of the patients from the efficacy population. Per irRECIST, irCR is defined as the disappearance of all measurable and non-measurable lesions, and lymph nodes must decrease to &lt; 10 mm in short axis; irPR is defined as an &gt;=30% decrease in total measured tumor burden relative to baseline; Immune-Related Overall Response (irOR) = irCR + irPR.</description>
          <population>Efficacy population: patients that had measurable disease, had received at least one dose of study treatment and had at least one tumor response assessment (unless progression or death or unacceptable toxicity before the first tumor response assessment) and without certain major protocol deviations according to the protocol deviation manual.</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="13"/>
                <count group_id="O2" value="20"/>
                <count group_id="O3" value="33"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="5"/>
                    <measurement group_id="O3" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Immune-related Progression-Free Survival (irPFS)</title>
        <description>Tumor response was assessed using Immune-Related Response Evaluation Criteria In Solid Tumors Criteria (irRECIST v 1.0). irPFS was defined as the time from enrollment to the first documented progressive disease (PD), or death from any cause, whichever occurs first. PD is defined by irRECIST, as a 20% increase and minimum 5 mm absolute increase in total measured tumor burden compared with nadir, or a measurable increase in a non-target lesion, or the appearance of new lesions.</description>
        <time_frame>Through study treatment, and average of 3 months</time_frame>
        <population>Efficacy population</population>
        <group_list>
          <group group_id="O1">
            <title>Run-in Phase Dose Level 0</title>
            <description>Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) as a IV infusion on day 1 and 8 of each 21-day cycle.&#xD;
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.</description>
          </group>
          <group group_id="O2">
            <title>Phase II</title>
            <description>Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle.&#xD;
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.</description>
          </group>
          <group group_id="O3">
            <title>Run-in Phase Plus Phase II</title>
            <description>Patients included in the run-in-phase at the same dose that in the phase II (DL0) were included on the analysis.</description>
          </group>
        </group_list>
        <measure>
          <title>Immune-related Progression-Free Survival (irPFS)</title>
          <description>Tumor response was assessed using Immune-Related Response Evaluation Criteria In Solid Tumors Criteria (irRECIST v 1.0). irPFS was defined as the time from enrollment to the first documented progressive disease (PD), or death from any cause, whichever occurs first. PD is defined by irRECIST, as a 20% increase and minimum 5 mm absolute increase in total measured tumor burden compared with nadir, or a measurable increase in a non-target lesion, or the appearance of new lesions.</description>
          <population>Efficacy population</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="13"/>
                <count group_id="O2" value="20"/>
                <count group_id="O3" value="33"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.1" lower_limit="1.3" upper_limit="7.7"/>
                    <measurement group_id="O2" value="2.6" lower_limit="1.9" upper_limit="6.1"/>
                    <measurement group_id="O3" value="3.1" lower_limit="2.0" upper_limit="5.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Immune Related Clinical Benefit Rate (irCBR)</title>
        <description>Tumor response was assessed using Immune-Related Response Evaluation Criteria In Solid Tumors Criteria (irRECIST v 1.0). irCBR was defined as the percentage of patients with a Immune Related Complete Response (irCR) or Immune Related Partial Response (irPR) plus Immune Related Stable Disease (irSD) out of the efficacy population. Per irRECIST, irCR is defined as the disappearance of all measurable and non-measurable lesions, and lymph nodes must decrease to &lt; 10 mm in short axis; irPR is defined as an &gt;=30% decrease in total measured tumor burden relative to baseline; irSD is defined as a failure to meet criteria for irCR or irPR in the absence of progressive disease.</description>
        <time_frame>Through study treatment, and average of 3 months</time_frame>
        <population>Efficacy population</population>
        <group_list>
          <group group_id="O1">
            <title>Run-in Phase Dose Level 0</title>
            <description>Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) as a IV infusion on day 1 and 8 of each 21-day cycle.&#xD;
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.</description>
          </group>
          <group group_id="O2">
            <title>Phase II</title>
            <description>Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle.&#xD;
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.</description>
          </group>
          <group group_id="O3">
            <title>Run-in Phase Plus Phase II</title>
            <description>Patients included in the run-in-phase at the same dose that in the phase II (DL0) were included on the analysis.</description>
          </group>
        </group_list>
        <measure>
          <title>Immune Related Clinical Benefit Rate (irCBR)</title>
          <description>Tumor response was assessed using Immune-Related Response Evaluation Criteria In Solid Tumors Criteria (irRECIST v 1.0). irCBR was defined as the percentage of patients with a Immune Related Complete Response (irCR) or Immune Related Partial Response (irPR) plus Immune Related Stable Disease (irSD) out of the efficacy population. Per irRECIST, irCR is defined as the disappearance of all measurable and non-measurable lesions, and lymph nodes must decrease to &lt; 10 mm in short axis; irPR is defined as an &gt;=30% decrease in total measured tumor burden relative to baseline; irSD is defined as a failure to meet criteria for irCR or irPR in the absence of progressive disease.</description>
          <population>Efficacy population</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="13"/>
                <count group_id="O2" value="20"/>
                <count group_id="O3" value="33"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7"/>
                    <measurement group_id="O2" value="11"/>
                    <measurement group_id="O3" value="18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Immune Related Clinical Benefit Rate (irCBR) at Least 24 Weeks</title>
        <description>Tumor response was assessed using Immune-Related Response Evaluation Criteria In Solid Tumors Criteria (irRECIST v 1.0). irCBR was defined as the percentage of patients with a Immune Related Complete Response (irCR) or Immune Related Partial Response (irPR) plus Immune Related stable disease (irSD) lasting at least 24 months out of the efficacy population. Per irRECIST, irCR is defined as the disappearance of all measurable and non-measurable lesions, and lymph nodes must decrease to &lt; 10 mm in short axis; irPR is defined as an &gt;=30% decrease in total measured tumor burden relative to baseline; irSD is defined as a failure to meet criteria for irCR or irPR in the absence of progressive disease at least 24 weeks.</description>
        <time_frame>Through study treatment, and average of 3 months</time_frame>
        <population>Efficacy population</population>
        <group_list>
          <group group_id="O1">
            <title>Run-in Phase Dose Level 0</title>
            <description>Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) as a IV infusion on day 1 and 8 of each 21-day cycle.&#xD;
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.</description>
          </group>
          <group group_id="O2">
            <title>Phase II</title>
            <description>Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle.&#xD;
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.</description>
          </group>
          <group group_id="O3">
            <title>Run-in Phase Plus Phase II</title>
            <description>Patients included in the run-in-phase at the same dose that in the phase II (DL0) were included on the analysis.</description>
          </group>
        </group_list>
        <measure>
          <title>Immune Related Clinical Benefit Rate (irCBR) at Least 24 Weeks</title>
          <description>Tumor response was assessed using Immune-Related Response Evaluation Criteria In Solid Tumors Criteria (irRECIST v 1.0). irCBR was defined as the percentage of patients with a Immune Related Complete Response (irCR) or Immune Related Partial Response (irPR) plus Immune Related stable disease (irSD) lasting at least 24 months out of the efficacy population. Per irRECIST, irCR is defined as the disappearance of all measurable and non-measurable lesions, and lymph nodes must decrease to &lt; 10 mm in short axis; irPR is defined as an &gt;=30% decrease in total measured tumor burden relative to baseline; irSD is defined as a failure to meet criteria for irCR or irPR in the absence of progressive disease at least 24 weeks.</description>
          <population>Efficacy population</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="13"/>
                <count group_id="O2" value="20"/>
                <count group_id="O3" value="33"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="5"/>
                    <measurement group_id="O3" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Immune Related Response Duration (irRD)</title>
        <description>Tumor response was assessed using Immune-Related Response Evaluation Criteria In Solid Tumors Criteria (irRECIST v 1.0). irRD was defined as the time from the first documentation of objective tumor response (immune related complete response (irCR) or immune related partial response (irPR)) to the first documented immune related progressive disease (irPD), or to death due to any cause, whichever occurs first. Per RECIST, irCR is defined as the disappearance of all measurable and non-measurable lesions, and lymph nodes must decrease to &lt; 10 mm in short axis; irPR is defined as an &gt;=30% decrease in total measured tumor burden relative to baseline; irPD is defined as a 20% increase and minimum 5 mm absolute increase in total measured tumor burden compared with nadir, or a measurable increase in a non-target lesion, or the appearance of new lesions.</description>
        <time_frame>Through study treatment, and average of 3 months</time_frame>
        <population>There were only 5 Partial Responses on the phase II population.</population>
        <group_list>
          <group group_id="O1">
            <title>Run-in Phase Dose Level 0</title>
            <description>Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) as a IV infusion on day 1 and 8 of each 21-day cycle.&#xD;
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.</description>
          </group>
          <group group_id="O2">
            <title>Phase II</title>
            <description>Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle.&#xD;
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.</description>
          </group>
          <group group_id="O3">
            <title>Run-in Phase Plus Phase II</title>
            <description>Patients included in the run-in-phase at the same dose that in the phase II (DL0) were included on the analysis.</description>
          </group>
        </group_list>
        <measure>
          <title>Immune Related Response Duration (irRD)</title>
          <description>Tumor response was assessed using Immune-Related Response Evaluation Criteria In Solid Tumors Criteria (irRECIST v 1.0). irRD was defined as the time from the first documentation of objective tumor response (immune related complete response (irCR) or immune related partial response (irPR)) to the first documented immune related progressive disease (irPD), or to death due to any cause, whichever occurs first. Per RECIST, irCR is defined as the disappearance of all measurable and non-measurable lesions, and lymph nodes must decrease to &lt; 10 mm in short axis; irPR is defined as an &gt;=30% decrease in total measured tumor burden relative to baseline; irPD is defined as a 20% increase and minimum 5 mm absolute increase in total measured tumor burden compared with nadir, or a measurable increase in a non-target lesion, or the appearance of new lesions.</description>
          <population>There were only 5 Partial Responses on the phase II population.</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="0"/>
                <count group_id="O2" value="5"/>
                <count group_id="O3" value="5"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O2" value="4.3" lower_limit="2.3" upper_limit="7.4"/>
                    <measurement group_id="O3" value="4.3" lower_limit="2.3" upper_limit="7.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>AEs have been recorded through study treatment, an average of 3 months, and deaths have been recorded through study treatment and up to 2 years of follow up.</time_frame>
      <desc>AE were reported after Informed Consent Document (ICD) and before study drugs until approximately 30 days following the discontinuation of study treatment.</desc>
      <group_list>
        <group group_id="E1">
          <title>Run-in Phase Dose Level 0</title>
          <description>Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Dose Level 0) as a IV infusion on day 1 and 8 of each 21-day cycle.&#xD;
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.</description>
        </group>
        <group group_id="E2">
          <title>Phase II</title>
          <description>Eligible patients were enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 (Recommended Phase II Dose (RP2D) from the run-in phase) as a IV infusion on day 1 and 8 of each 21-day cycle.&#xD;
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>NCI CTC-AE v 4.03</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="14"/>
                <counts group_id="E2" subjects_affected="19" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="14"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Abdominal pain upper</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Oedema peripheral</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperbilirubinaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Abdominal sepsis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Bacterial pyelonephritis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Cellulitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Respiratory tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Anemia Grade 2 and Platelet cound decreased Grade 2</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Pancytopenia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Intraabdominal bleeding</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>Tumour pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Neurological decompensation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>NCI CTC-AE v 4.03</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="14" subjects_at_risk="14"/>
                <counts group_id="E2" subjects_affected="21" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anaemia</sub_title>
                <counts group_id="E1" events="136" subjects_affected="13" subjects_at_risk="14"/>
                <counts group_id="E2" events="218" subjects_affected="21" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Tachycardia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="14"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Hypothyroidism</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="14"/>
                <counts group_id="E2" events="7" subjects_affected="6" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" events="11" subjects_affected="2" subjects_at_risk="14"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Abdominal pain upper</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Asthenia</sub_title>
                <counts group_id="E1" events="9" subjects_affected="7" subjects_at_risk="14"/>
                <counts group_id="E2" events="21" subjects_affected="14" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Pyrexia</sub_title>
                <counts group_id="E1" events="8" subjects_affected="4" subjects_at_risk="14"/>
                <counts group_id="E2" events="7" subjects_affected="6" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="14"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="53" subjects_affected="7" subjects_at_risk="14"/>
                <counts group_id="E2" events="28" subjects_affected="15" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="19" subjects_affected="8" subjects_at_risk="14"/>
                <counts group_id="E2" events="18" subjects_affected="11" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="24" subjects_affected="9" subjects_at_risk="14"/>
                <counts group_id="E2" events="33" subjects_affected="11" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" events="30" subjects_affected="9" subjects_at_risk="14"/>
                <counts group_id="E2" events="34" subjects_affected="13" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="101" subjects_affected="13" subjects_at_risk="14"/>
                <counts group_id="E2" events="89" subjects_affected="12" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>White blood cell count decreased</sub_title>
                <counts group_id="E1" events="82" subjects_affected="11" subjects_at_risk="14"/>
                <counts group_id="E2" events="68" subjects_affected="18" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" events="46" subjects_affected="10" subjects_at_risk="14"/>
                <counts group_id="E2" events="51" subjects_affected="14" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>INR increased</sub_title>
                <counts group_id="E1" events="5" subjects_affected="2" subjects_at_risk="14"/>
                <counts group_id="E2" events="33" subjects_affected="8" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="14"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Lymphocyte count increased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Weight decreased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="14"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" events="30" subjects_affected="10" subjects_at_risk="14"/>
                <counts group_id="E2" events="21" subjects_affected="9" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" events="15" subjects_affected="7" subjects_at_risk="14"/>
                <counts group_id="E2" events="23" subjects_affected="4" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Hypoglycemia</sub_title>
                <counts group_id="E1" events="6" subjects_affected="3" subjects_at_risk="14"/>
                <counts group_id="E2" events="4" subjects_affected="2" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="14"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Musculoskeletal chest pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Albuminuria</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnoea</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="14"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Rash</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Pain of skin</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="14"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="14"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E2" events="7" subjects_affected="4" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Hot flush</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="14"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Scientific Director / Medical Lead / Project Manager</name_or_title>
      <organization>Spanish Breast Cancer Research Group</organization>
      <phone>+34916592870</phone>
      <email>geicam@geicam.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/NCT03025880
org study id: GEICAM/2015-04
secondary id: 2016-001779-54
nct id: NCT03025880
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
Study Design and Treatment:

      This is a multicenter phase II trial, with an initial exploratory run-in-phase, to evaluate
      the efficacy and safety of pembrolizumab in combination with gemcitabine in patients with
      HER2-negative ABC that have previously received anthracyclines and taxanes (unless clinically
      contraindicated). In hormone receptor positive patients, previous treatment with 2 or more
      lines of hormone therapy will also be required. Patients must have at least one measurable
      lesion that can be accurately assessed at baseline and is suitable for repeated assessment by
      CT, MRI or plan X-ray. Approximately 53 patients (up to a maximum of 65 patients depending on
      the results of the run-in-phase) will be included in this trial.
Study Design and Treatment (continuation):

      The study will include two cohorts of patients: i) Triple Negative and ii) Luminal A+B, with
      an approximate 1:1 distribution between both groups.

      A safety dose testing or "run-in-phase", with a 6+6 design, in which toxicity will be
      evaluated within the first cycle, will be performed since pembrolizumab in combination with
      gemcitabine has not been previously tested. Initially 6 patients will be included in the
      study at dose level 0 (gemcitabine at a dose of 1,250mg/m2 as an IV infusion on day 1 and 8
      of each 21-day cycle and pembrolizumab at a dose of 200mg as an IV infusion on day 1 of each
      21-day cycle):

        -  If ≤ 2 patients experience Dose Limiting Toxicity (DLT), 6 additional patients will be
           included at the current dose level. If there is a confirmation of this dose to be safe
           (≤ 3 patients experiencing DLT), this will be considered the RP2D and it will be used
           for the following recruited patients.

        -  If ≥ 3 patients experience DLT within the first 6 patients, or ≥ 4 within the first 12
           patients included at dose level 0, a de-escalation to dose level -1 (gemcitabine at a
           dose of 1,000mg/m2 as an IV infusion on day 1 and 8 of each 21-day cycle and
           pembrolizumab at a dose of 200mg as an IV infusion on day 1 of each 21-day cycle) will
           be performed. In this case, a group of 12 additional patients will be included at dose
           level -1, if ≥ 4 experience DLT, this combination will be considered too toxic and the
           study will be stopped. If ≤ 3 experience DLT with this combination, this will be
           considered the RP2D and it will be used for the following recruited patients.

      Initially 3 patients will be allowed for inclusion simultaneously. These 3 patients will be
      followed closely during the first cycle to observe the occurrence of any DLT. At the times
      these 3 patients are completing the first cycle, the next 3 patients will be included one by
      one, until the first cohort is completed.

      If none of these 6 patients have a DLT, up to 4 patients will be allowed for inclusion from
      the second cohort of 6 patients; they will follow the same procedure as in the first cohort.
      If one of these patients from the second cohort has a DLT, the inclusion will be in smaller
      groups (with a maximum number of 4 patients with DLT) and following the same procedure as in
      the first cohort of 6 patients.

      An internal committee will periodically review the safety data in order to take the decision
      to maintain or decrease the dose level. This internal committee will consist of the chief
      investigator, the Spanish Breast Cancer Research Group Scientific Director and the study
      statistician. The meetings will be performed by teleconference to take these decisions as
      quickly as possible once the last patient finishes the first cycle of treatment. Other
      meetings will be considered ad-hoc whenever necessary (i.e when new DLTs appear).

      Patients included in the run-in-phase at the same dose than that in the phase II will be
      considered for the phase II analysis.

      Study Drug/Medication:

      Eligible patients will be enrolled and treated with:

      Pembrolizumab at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day
      cycle.

      in combination with Gemcitabine at a dose of 1,250mg/m2 or 1,000mg/m2 (this dose will be
      explored in combination with pembrolizumab in the initial exploratory run-in-phase if
      necessary) as an intravenous (IV) infusion on day 1 and 8 of each 21-day cycle.

      Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression,
      clinical progression (under investigator criteria), unacceptable toxicity, death or
      withdrawal of consent, whichever occurs first. Patients completing 24 months of uninterrupted
      treatment with pembrolizumab or 35 administrations of study medication will stop
      pembrolizumab treatment (though may continue with gemcitabine). Subjects who stop
      pembrolizumab after 24 months may be eligible for up to one year of additional pembrolizumab
      treatment if they progress after stopping it.

      An initial exploratory run-in-phase will be performed to test the safety of the combination
      and determine the Recommended Phase II Dose (RP2D) of gemcitabine in combination with fixed
      doses of pembrolizumab.

      Primary Objective:

        -  Run-in-phase: To determine the Recommended Phase II Dose (RP2D) of gemcitabine in
           combination with fixed doses of pembrolizumab.

        -  Phase II: To assess the efficacy of pembrolizumab in combination with gemcitabine in
           terms of Objective Response Rate (ORR) in patients with HER2-negative ABC.

      Primary End-point:

        -  Run-in-phase: To determine the incidence rate of Dose Limiting Toxicity (DLT) within the
           first cycle of the combination.

        -  Phase II: Objective Response Rate (ORR) is defined as Complete Response (CR) plus
           Partial Response (PR) according to Response Evaluation Criteria in Solid Tumours
           (RECIST) version 1.1.

      Secondary Objectives:

      The following secondary objectives will be studied:

        -  To assess other efficacy measures of the combination in patients included in the phase
           II (including those in the run-in-phase at the same dose that in the phase II).

        -  To determine safety and tolerability of the combination in all patients included in the
           study.

      Secondary End-points:

      The following secondary end-points will be studied:

        -  Efficacy:

             -  Progression-Free Survival (PFS) assessed according to RECIST version 1.1 by the
                investigator.

             -  Clinical Benefit Rate (CBR) defined as Complete Response (CR) plus Partial Response
                (PR) plus Stable Disease (SD) lasting ≥ 24 weeks according to RECIST version 1.1.

             -  Response Duration (RD) assessed according to RECIST version 1.1.

             -  Overall Survival (OS). With special interest on long term responders (i.e. alive
                and without disease progression after 24 months of study treatment).

        -  Safety will be assessed by standard clinical and laboratory tests (haematology, serum
           chemistry). Adverse Events (AE) grade will be defined by the NCI CTCAE (National Cancer
           Institute Common Terminology Criteria for Adverse Events) version 4.0.

      Exploratory Objectives:

      The following exploratory objectives will be studied in all patients included in the study
      unless otherwise specified:

        -  To assess other efficacy measures of the combination based on immune-related (ir)
           response criteria in patients included in the phase II (including those in the
           run-in-phase at the same dose that in the phase II).

        -  To search for tumour tissue and peripheral blood biomarkers of clinical activity.

        -  To compare biomarkers data from cohorts of healthy volunteers (if available) with data
           from patients included in the study.

      Exploratory End-points:

      The following exploratory end-points will be studied:

        -  Efficacy:

             -  ORR is defined as immune-related Complete Response (irCR) plus immune-related
                Partial Response (irPR) according to immune-related RECIST (irRECIST).

             -  Progression-Free Survival (PFS) assessed according to irRECIST by the investigator.

             -  Clinical Benefit Rate (CBR) defined as irCR plus irPR plus immune-related Stable
                Disease (irSD) lasting ≥ 24 weeks according to irRECIST.

             -  Response Duration (RD) assessed according to irRECIST.

        -  A set of immune biomarkers will be analysed and correlated with evolution of the disease
           and efficacy of pembrolizumab in combination with gemcitabine (ORR and other efficacy
           end-points: PFS, CBR and RD), paying special attention to long term responders.

        -  This set of immune biomarkers will be compared with those from healthy volunteers (if
           available).

      Study population:

      Patients with HER2-negative advanced breast cancer.

      Justification of Sample size determination:

      A Simon's minimax two-stage design will be employed with the possibility of stopping early
      due to lack of response. Results from previous studies showed that gemcitabine produced a
      response rate of around 20%, this will be our expected H0. With the combination of
      pembrolizumab and gemcitabine, we expect to increase this rate to 35% what will be our H1 (an
      absolute increase of 15%), with an alpha error of 0.05 and a statistical power of 80%, we
      will need to include 53 evaluable patients in this trial. The first stage will include 31
      evaluable patients, if at least 7 present a response, recruitment will continue to include
      the 53 evaluable patients. The null hypothesis of H0=20% will be rejected if 16 or more
      responses are observed in 53 patients.

      Statistical Analyses:

      Demographics and Baseline Characteristics: Standard descriptive statistics, such as the mean,
      median, range and proportion, will be used to summarize the patient sample and to estimate
      parameters of interest.

      Safety Analyses: AEs and Serious Adverse Events (SAE) will be reported in frequency tables
      (overall and by intensity). The safety analysis will be performed in the population that has
      received at least one dose of any of the study drugs/medications.

      Efficacy Analyses: All efficacy endpoints will be evaluated in the Per-protocol and Intent to
      treat (ITT) populations.

      Biomarker analysis:The biomarker analysis will be exploratory and descriptive. For continuous
      variables, mean, standard deviation, median, minimum and maximum values will be provided.
      Categorical variables will be summarized by numbers and proportions. Biomarker endpoints will
      be evaluated in all patients enrolled in the study with available samples.

      Study Duration:

      The end date of study is date of last patient´s death or the date when there is sufficient
      data to achieve the primary and secondary objectives and all patients have ended the study
      treatment, whichever comes first.

      Performing exploratory objectives will be independent of the date of the end of the study.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of Participants With Dose Limiting Toxicity (DLT) Within the First Cycle
time frame: Up to cycle 1
description: DLT was defined as the occurrence of any of the following adverse events (AE) or abnormal laboratory value (graded according to the NCI Common Terminology Criteria for AE (CTCAE) version 4.0), assessed as possibly, probably or definitively related to study drug/medication, occurring within the first cycle of study treatment: any Grade 4 thrombocytopenia or neutropenia lasting > 7 days; episcleritis, uveitis, or iritis of Grade 2 or higher, any Grade 4 toxicity, any Grade 3 toxicity EXCLUDING: nausea, vomiting, or diarrhea controlled by medical intervention within 72 hours, grade 3 rash in the absence of desquamation, no mucosal involvement, does not require steroids, and resolves to Grade 1 by the next scheduled dose of pembrolizumab, transient Grade 3 Aspartate Transaminase (AST) or Alanine Transaminase (ALT) elevation, defined as no more than 3 days with or without steroid use, discontinuation or delay of more than 2 weeks of any study drug/medication due to treatment-related AE.
measure: Recommended Phase II Dose (RP2D) of Gemcitabine in Combination With Pembrolizumab
time frame: Up to cycle 1
description: The RP2D was decided by the internal committee taken into consideration the information obtained in the study and based on the number of DLT.
measure: Objective Response Rate (ORR)
time frame: Through study treatment, and average of 3 months
description: Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1). ORR is defined as the percentage of patients with a Complete Response (CR) or Partial Response (PR) out of the patients from the efficacy population. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an >=30% decrease in the sum of the longest diameter of target lesions.
measure: Progression-Free Survival (PFS)
time frame: Through study treatment, and average of 3 months
description: Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1). PFS is defined as the time from enrollment to the first documented progression disease (PD), or death from any cause, whichever occurs first. PD is defined using RECIST, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
measure: Clinical Benefit Rate (CBR)
time frame: Through study treatment, and average of 3 months
description: Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. CBR was defined as the percentage of patients with a Complete Response (CR) or Partial Response (PR) plus stable disease (SD) out of the efficacy population. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an >=30% decrease in the sum of the longest diameter of target lesions; SD is defined as a failure to meet criteria for CR or PR in the absence of progressive disease. Overall Response (OR) = CR + PR.
measure: Clinical Benefit Rate (CBR) at Least 24 Weeks
time frame: 24 weeks
description: Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. CBR was defined as the percentage of patients with a Complete Response (CR) or Partial Response (PR) plus stable disease (SD) lasting at least 24 months out of the efficacy population. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an >=30% decrease in the sum of the longest diameter of target lesions; SD is defined as a failure to meet criteria for CR or PR in the absence of progressive disease lasting at least 24 months. Overall Response (OR) = CR + PR.
measure: Response Duration (RD)
time frame: Through study treatment, and average of 3 months
description: Tumor response was assessed using Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) criteria. RD was defined as the time from the first documentation of objective tumor response (complete response (CR) or partial response (PR)) to the first documented progressive disease (PD), or to death due to any cause, whichever occurs first. Per RECIST, CR is defined as the disappearance of all target lesions; PR is defined as an >=30% decrease in the sum of the longest diameter of target lesions; PD is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
measure: Overall Survival (OS)
time frame: Up to 2 years
description: OS is defined as the time from the date of enrollment to the date of death from any cause.
measure: The Number of Participants Who Experienced Adverse Events (AE) Related to Study Treatment
time frame: Through study treatment, and average of 3 months
description: Safety assessments were performed at baseline and during the study: Vital signs assessments (blood pressure, pulse and body temperature), Laboratory assessments (hemoglobin, platelet count, White Blood Cell (WBC), Absolute Neutrophil Count (ANC) and Absolute Lymphocyte Count (ALC), albumin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, serum creatinine, creatinine clearance (for patients with creatinine levels > 1.5 x ULN), glucose and urea, International Normalized Ratio (INR)/ Prothrombin time (PT) and activated partial thromboplastin time (aPTT), total or free triiodothyronine (T3 or FT3), free thyroxine (FT4) and Thyroid-stimulating hormone (TSH)) and Urinalysis. A baseline standard 12-lead electrocardiogram (ECG) was mandatory. AEs were graded according to NCI-CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 4.03.
measure: Immune-related Objective Response Rate (irORR)
time frame: Through study treatment, and average of 3 months
description: Tumor response was assessed using Immune-Related Response Evaluation Criteria In Solid Tumors Criteria (irRECIST v 1.0). irORR is defined as the percentage of patients with a Immune-Related Complete Response (irCR) or Immune-Related Partial Response (irPR) out of the patients from the efficacy population. Per irRECIST, irCR is defined as the disappearance of all measurable and non-measurable lesions, and lymph nodes must decrease to < 10 mm in short axis; irPR is defined as an >=30% decrease in total measured tumor burden relative to baseline; Immune-Related Overall Response (irOR) = irCR + irPR.
measure: Immune-related Progression-Free Survival (irPFS)
time frame: Through study treatment, and average of 3 months
description: Tumor response was assessed using Immune-Related Response Evaluation Criteria In Solid Tumors Criteria (irRECIST v 1.0). irPFS was defined as the time from enrollment to the first documented progressive disease (PD), or death from any cause, whichever occurs first. PD is defined by irRECIST, as a 20% increase and minimum 5 mm absolute increase in total measured tumor burden compared with nadir, or a measurable increase in a non-target lesion, or the appearance of new lesions.
measure: Immune Related Clinical Benefit Rate (irCBR)
time frame: Through study treatment, and average of 3 months
description: Tumor response was assessed using Immune-Related Response Evaluation Criteria In Solid Tumors Criteria (irRECIST v 1.0). irCBR was defined as the percentage of patients with a Immune Related Complete Response (irCR) or Immune Related Partial Response (irPR) plus Immune Related Stable Disease (irSD) out of the efficacy population. Per irRECIST, irCR is defined as the disappearance of all measurable and non-measurable lesions, and lymph nodes must decrease to < 10 mm in short axis; irPR is defined as an >=30% decrease in total measured tumor burden relative to baseline; irSD is defined as a failure to meet criteria for irCR or irPR in the absence of progressive disease.
measure: Immune Related Clinical Benefit Rate (irCBR) at Least 24 Weeks
time frame: Through study treatment, and average of 3 months
description: Tumor response was assessed using Immune-Related Response Evaluation Criteria In Solid Tumors Criteria (irRECIST v 1.0). irCBR was defined as the percentage of patients with a Immune Related Complete Response (irCR) or Immune Related Partial Response (irPR) plus Immune Related stable disease (irSD) lasting at least 24 months out of the efficacy population. Per irRECIST, irCR is defined as the disappearance of all measurable and non-measurable lesions, and lymph nodes must decrease to < 10 mm in short axis; irPR is defined as an >=30% decrease in total measured tumor burden relative to baseline; irSD is defined as a failure to meet criteria for irCR or irPR in the absence of progressive disease at least 24 weeks.
measure: Immune Related Response Duration (irRD)
time frame: Through study treatment, and average of 3 months
description: Tumor response was assessed using Immune-Related Response Evaluation Criteria In Solid Tumors Criteria (irRECIST v 1.0). irRD was defined as the time from the first documentation of objective tumor response (immune related complete response (irCR) or immune related partial response (irPR)) to the first documented immune related progressive disease (irPD), or to death due to any cause, whichever occurs first. Per RECIST, irCR is defined as the disappearance of all measurable and non-measurable lesions, and lymph nodes must decrease to < 10 mm in short axis; irPR is defined as an >=30% decrease in total measured tumor burden relative to baseline; irPD is defined as a 20% increase and minimum 5 mm absolute increase in total measured tumor burden compared with nadir, or a measurable increase in a non-target lesion, or the appearance of new lesions.
arm group label: Single arm
arm group type: Experimental
description: Eligible patients will be enrolled and treated with Pembrolizumab (P) at a dose of 200mg as an intravenous (IV) infusion on day 1 of each 21-day cycle in combination with Gemcitabine (G) at a dose of 1,250mg/m2 or 1,000mg/m2 (this dose will be explored in combination with P in the initial exploratory run-in-phase if necessary) as a IV infusion on day 1 and 8 of each 21-day cycle.
Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first. An initial exploratory run-in-phase will be performed to test the safety of the combination and determine the Recommended Phase II Dose (RP2D) of G in combination with fixed doses of P.
intervention type: Drug
intervention name: Pembrolizumab
description: Pembrolizumab at a dose of 200mg as an intravenous (IV) 30 minutes infusion on day 1 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first. Patients completing 24 months of uninterrupted treatment with pembrolizumab or 35 administrations of study medication will stop pembrolizumab treatment (though may continue with gemcitabine). Subjects who stop pembrolizumab after 24 months may be eligible for up to one year of additional pembrolizumab treatment if they progress after stopping it.
arm group label: Single arm
other name: Keytruda
intervention type: Drug
intervention name: Gemcitabine
description: Gemcitabine at a dose of 1,250mg/m2 as an intravenous (IV) 60 minutes infusion on day 1 and 8 of each 21-day cycle. Treatment will be repeated on day 1 of each 21-day cycle until objective disease progression, clinical progression (under investigator criteria), unacceptable toxicity, death or withdrawal of consent, whichever occurs first.
arm group label: Single arm
other name: Gemzar
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Study Director
role: Study Director
affiliation: Hospital Universitario Virgen Macarena
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Spain
url: http://www.geicam.org/
description: GEICAM is a Spanish Breast Cancer Research Group
citation: de la Cruz-Merino L, Gion M, Cruz J, Alonso-Romero JL, Quiroga V, Moreno F, Andres R, Santisteban M, Ramos M, Holgado E, Cortes J, Lopez-Miranda E, Cortes A, Henao F, Palazon-Carrion N, Rodriguez LM, Ceballos I, Soto A, Puertes A, Casas M, Benito S, Chiesa M, Bezares S, Caballero R, Jimenez-Cortegana C, Sanchez-Margalet V, Rojo F. Pembrolizumab in combination with gemcitabine for patients with HER2-negative advanced breast cancer: GEICAM/2015-04 (PANGEA-Breast) study. BMC Cancer. 2022 Dec 3;22(1):1258. doi: 10.1186/s12885-022-10363-3.
PMID: 36463104
citation: de la Cruz-Merino L, Gion M, Cruz-Jurado J, Quiroga V, Andres R, Moreno F, Alonso-Romero JL, Ramos M, Holgado E, Cortes J, Lopez-Miranda E, Henao-Carrasco F, Palazon-Carrion N, Rodriguez LM, Ceballos I, Casas M, Benito S, Chiesa M, Bezares S, Caballero R, Jimenez-Cortegana C, Sanchez-Margalet V, Rojo F. Pembrolizumab Plus Gemcitabine in the Subset of Triple-Negative Advanced Breast Cancer Patients in the GEICAM/2015-04 (PANGEA-Breast) Study. Cancers (Basel). 2021 Oct 29;13(21):5432. doi: 10.3390/cancers13215432.
PMID: 34771596
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Gemcitabine
mesh term: Pembrolizumab
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 