<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/NCT02991482</url>
  </required_header>
  <id_info>
    <org_study_id>ETOP 9-15</org_study_id>
    <secondary_id>2016-002062-31</secondary_id>
    <secondary_id>3475-594</secondary_id>
    <nct_id>NCT02991482</nct_id>
  </id_info>
  <brief_title>PembROlizuMab Immunotherapy Versus Standard Chemotherapy for Advanced prE-treated Malignant Pleural Mesothelioma</brief_title>
  <acronym>PROMISE-meso</acronym>
  <official_title>A Multicentre Randomised Phase III Trial Comparing Pembrolizumab Versus Standard Chemotherapy for Advanced Pre-treated Malignant Pleural Mesothelioma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>ETOP IBCSG Partners Foundation</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Merck Sharp &amp; Dohme LLC</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
    <collaborator>
      <agency>Frontier Science Foundation, Hellas</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>ETOP IBCSG Partners Foundation</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Trial comparing standard treatment (chemotherapy) with pembrolizumab treatment in patients&#xD;
      with advanced pretreated malignant mesothelioma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Mesothelioma is an aggressive malignancy usually affecting the surfaces of body coelomic&#xD;
      cavities. It most commonly originates from the pleura with a propensity to the lower parietal&#xD;
      pleura and costo-diaphragmatic recess, and is almost always caused by asbestos exposure, with&#xD;
      a usual lag time of 30 years between exposure and presentation. Outcomes for most patients&#xD;
      are invariably fatal, with median survival from presentation around 9-12 months in most&#xD;
      series due to difficulties in achieving a complete microscopic surgical resection and tumour&#xD;
      relative chemo-refractoriness. Whilst initially considered rare, due to the demand of&#xD;
      asbestos of all varieties associated with industrialization following the Second World War,&#xD;
      the background incidence of mesothelioma of 1/million has risen to 40/million in some&#xD;
      countries. In the UK, where substantial asbestos exposure continued until the 1970s, the&#xD;
      death rate is the highest in the world with a current epidemic of new cases, predicted to&#xD;
      continue for another 5-10 years. Two main histological subtypes of mesothelioma are&#xD;
      identified. The epitheliod subtype is the commonest, accounting for around 40% of cases,&#xD;
      whilst the sarcomatoid subtype is observed in 20% of cases; the latter being typically&#xD;
      aggressive and chemorefractory. Around 35% cases have features of both epitheliod and&#xD;
      sarcomatoid subtypes and are termed biphasic subtype.&#xD;
&#xD;
      For patients with pleural mesothelioma, in whom surgery is not considered appropriate,&#xD;
      systemic chemotherapy (platinum combined with pemetrexed) remains the international standard&#xD;
      of care. Cisplatin/pemetrexed is associated with a response rate of 41% and confers an OS&#xD;
      advantage of 3 months over cisplatin alone, and is the only licensed systemic therapy for&#xD;
      mesothelioma in Europe. Despite this, the median survival is 9-12 months from most series in&#xD;
      unresectable cases. At relapse, after platinum-based chemotherapy, no anti-cancer systemic&#xD;
      therapies are licensed. Whilst several small phase II studies and retrospective series have&#xD;
      suggested potential efficacy for chemotherapy with agents including carboplatin/gemcitabine,&#xD;
      or vinorelbine, none thus far have demonstrated efficacy benefit in a randomised study, with&#xD;
      median PFS rates reported of about 3 months for both gemcitabine and vinorelbine. There is&#xD;
      therefore a huge unmet need for effective therapy for patients with relapsed pleural&#xD;
      mesothelioma. The largest trial ever performed of systemic therapy in relapsed pleural&#xD;
      mesothelioma in 661 patients documented the natural outcome of this group of relapsed&#xD;
      mesothelioma patients, reporting a median OS of 27.1 weeks (6 months) and median PFS for 6.1&#xD;
      weeks (1.5 months) for placebo.&#xD;
&#xD;
      Programmed cell death-1 (PD-1) is a co-inhibitory molecule at the immunological synapse that&#xD;
      acts as a major regulator of adaptive immunity, and is exploited by tumour cells to result in&#xD;
      adaptive immune resistance (tolerance). This occurs when PD-1 binds to the ligands PD-L1&#xD;
      (B7H1) or PD-L2, which are expressed on many tumour types. High PD-L1 expression on tumours&#xD;
      is associated with poorer outcomes. Mesothelioma has been shown to express PD-L1, with a&#xD;
      small study identifying PDL1 expression in up to 40% of mesotheliomas. Moreover,&#xD;
      immunologically-mediated inflammation is known to be a key driver for mesothelioma&#xD;
      development via the Nalp3 imflammasome.&#xD;
&#xD;
      Pembrolizumab (MK-3475) is a potent and highly selective humanized monoclonal antibody (mAb)&#xD;
      of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its&#xD;
      ligands, PD-L1 and PD-L2.&#xD;
&#xD;
      There is a need to identify new ways for the systemic therapy of malignant mesothelioma and&#xD;
      immune checkpoint inhibition is a promising way forward. Results from the proposed trial will&#xD;
      contribute to overcoming tumour-specific immune suppression with immune checkpoint&#xD;
      inhibition.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 12, 2017</start_date>
  <completion_date type="Actual">November 30, 2021</completion_date>
  <primary_completion_date type="Actual">February 20, 2019</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Progression Free Survival (PFS) as Assessed by Independent Radiological Review</measure>
    <time_frame>Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).</time_frame>
    <description>To investigate whether treatment with pembrolizumab improves PFS, compared to standard, institutional choice chemotherapy, assessed according to RECIST 1.1 criteria based on independent radiological review; using Kaplan-Meier method and compared between the two treatment arms by a stratified log rank test.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Objective Response Rate by Independent Radiological Review</measure>
    <time_frame>Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).</time_frame>
    <description>Defined as the best overall response (complete or partial response) across all assessment time-points from randomisation to end of trial treatment, determined by RECIST 1.1 criteria.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival.</measure>
    <time_frame>Time from randomization of the first patient until database cutoff date for the OS analysis (Sep 2017 - Aug 2019; approximately 2 years).</time_frame>
    <description>Defined as time from the date of randomisation until death from any cause. Censoring will occur at the last follow-up date.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Treatment Failure.</measure>
    <time_frame>Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).</time_frame>
    <description>Time from from randomisation to discontinuation of treatment for any reason, including progression of disease, treatment toxicity, refusal and death, by Kaplan Meier method. Censoring will occur at the last follow-up date.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Patients Experienced AEs/SAEs</measure>
    <time_frame>Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).</time_frame>
    <description>The safety and tolerability of pembrolizumab treatment will be assessed through analysis of the worst grade of toxicity/adverse events according to CTCAE v4.0 criteria observed over the whole treatment period. Adverse events are collected from study treatment initiation to 30 days after treatment is ceased for any reason. Serious adverse events and events of clinical interest are collected within 90 days after last dose of trial treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival (PFS) Assessed by Investigator</measure>
    <time_frame>Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).</time_frame>
    <description>Investigator assessed PFS, from the date of randomisation until documented progression or death, if progression is not documented. Censoring occurs at the last tumor assessment.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">144</enrollment>
  <condition>Pleural Mesothelioma Malignant Advanced</condition>
  <arm_group>
    <arm_group_label>Pembrolizumab arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Pembrolizumab is administrated at 200 mg fixed dose i.v. on day 1 of every 3 week cycle for a maximum or 2 years (expected maximum of 36 doses), or until progression of disease determined according to RECIST 1.1 criteria or lack of tolerability, or until the patient declines further treatment.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard chemotherapy arm</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Gemcitabine (i.v. 1000 mg/m2) or vinorelbine (i.v. 30 mg/m2, or p.o 60/80 mg/m2) chemotherapy will be chosen on a per patient basis and delivered according to local standards. Chemotherapy will be administered on days 1 and 8 of every 3-week cycle. A maximum number of treatment cycles is not mandated.&#xD;
Patients randomised to the control arm will be allowed to cross over to receive pembrolizumab at progression, if cross-over criteria are met. Pembrolizumab administration will follow the same schedule as for patients in the experimental arm, i.e. 200 mg fixed dose i.v. on day 1 of every 3-week cycle for a maximum of 2 years or until trial termination.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pembrolizumab</intervention_name>
    <description>Pembrolizumab (MK-3475) is a potent and highly selective humanised monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances functional activity of the target lymphocytes to facilitate tumour regression and ultimately immune rejection.</description>
    <arm_group_label>Pembrolizumab arm</arm_group_label>
    <other_name>KEYTRUDA</other_name>
    <other_name>MK-3475</other_name>
    <other_name>SCH 900475</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Gemcitabine</intervention_name>
    <description>Gemcitabine replaces one of the building blocks of nucleic acids, in this case cytidine, during DNA replication. The process arrests tumour growth, as new nucleosides cannot be attached to the &quot;faulty&quot; nucleoside, resulting in apoptosis (cellular &quot;suicide&quot;).</description>
    <arm_group_label>Standard chemotherapy arm</arm_group_label>
    <other_name>Gemzar</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vinorelbine</intervention_name>
    <description>Vinorelbine is a vinca alkaloid cytotoxic chemotherapy that is available in intravenous and oral preparations with EMA licenses in lung cancer and breast cancer. Vinorelbine blocks mitosis in phase G2-M, causing cell death in interphase or at the following mitosis.</description>
    <arm_group_label>Standard chemotherapy arm</arm_group_label>
    <other_name>Navelbine</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically confirmed malignant pleural mesothelioma (all subtypes are eligible)&#xD;
&#xD;
          -  Progressing after or on previous platinum based chemotherapy.&#xD;
&#xD;
          -  Availability of tumour tissue for translational research.&#xD;
&#xD;
          -  Female and male patients aged 18 years or over.&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-1.&#xD;
&#xD;
          -  Life expectancy of at least 3 months.&#xD;
&#xD;
          -  Measurable or evaluable disease according to RECIST 1.1 criteria.&#xD;
&#xD;
          -  Adequate renal function&#xD;
&#xD;
          -  Creatinine 1.5 × Upper Limit of Normal (ULN) OR Calculated creatinine clearance 40&#xD;
             mL/min (using the Cockroft-Gault formula).&#xD;
&#xD;
          -  Adequate haematological function&#xD;
&#xD;
          -  Haemoglobin 90 g/L or 5.6 mmol/L&#xD;
&#xD;
          -  White Blood Cell (WBC) 1.0 × 109/L&#xD;
&#xD;
          -  Lymphocytes 0.5 g/L&#xD;
&#xD;
          -  Absolute neutrophils count (ANC) 1.5 × 109/L&#xD;
&#xD;
          -  Platelet count 100 × 109/L.&#xD;
&#xD;
          -  Adequate liver function&#xD;
&#xD;
          -  ALT and AST 2.5 × ULN. If the patient has liver metastases, ALT and AST must be ≤5 ×&#xD;
             ULN.&#xD;
&#xD;
          -  Women of childbearing potential, including women who had their last menstrual period&#xD;
             in the last 2 years, must have a negative serum or urine pregnancy test within 35 days&#xD;
             before randomisation (the test has to be repeated 72 hours before pembrolizumab&#xD;
             treatment start).&#xD;
&#xD;
          -  Written informed consent must be signed and dated by the patient and the investigator&#xD;
             prior to any trial-related intervention including the submission of mandatory&#xD;
             biomaterial.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior therapy with an anti-programmed cell death protein 1 (anti-PD-1),&#xD;
             anti-programmed cell death ligand 1 (anti-PD-L1), anti-programmed cell death ligand 2&#xD;
             (anti-PD-L2), anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4)&#xD;
             antibody (including ipilimumab or any other antibody or drug specifically targeting&#xD;
             T-cell co-stimulation or checkpoint pathways).&#xD;
&#xD;
          -  Prior therapy with gemcitabine or vinorelbine.&#xD;
&#xD;
          -  Known active central nervous system metastases and/or carcinomatous meningitis.&#xD;
             Patients with previously treated brain metastases may participate provided they are&#xD;
             stable (without evidence of progression by imaging for at least 4 weeks prior to&#xD;
             randomisation and any neurologic symptoms have returned to baseline), have no evidence&#xD;
             of new or enlarging brain metastases, and are not using steroids for at least 7 days&#xD;
             prior to randomisation. This exception does not include carcinomatous meningitis,&#xD;
             which is excluded regardless of clinical stability.&#xD;
&#xD;
          -  Known or suspected hypersensitivity to pembrolizumab or any of its excipients.&#xD;
&#xD;
          -  Known unstable or unresolved surgical or chemotherapy-related toxicity that would&#xD;
             compromise the patient's capacity to participate in the trial.&#xD;
&#xD;
          -  Previous allogeneic tissue/solid organ transplant.&#xD;
&#xD;
          -  Live vaccines within 30 days prior to first dose of pembrolizumab.&#xD;
&#xD;
          -  Regular intake of immune-modulating drugs (such as interferon, methotrexate).&#xD;
&#xD;
          -  History of (non-infectious) pneumonitis that required steroids, evidence of&#xD;
             interstitial lung disease or active, non-infectious pneumonitis.&#xD;
&#xD;
          -  Active autoimmune disease that has required systemic treatment in the past 2 years&#xD;
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive&#xD;
             drugs). Replacement therapy (i.e. thyroxine, insulin, or physiologic corticosteroid&#xD;
             replacement therapy for adrenal or pituitary insufficiency, etc.) or topical therapy&#xD;
             (e.g., steroids) for psoriasis or eczema is not considered a form of systemic&#xD;
             treatment.&#xD;
&#xD;
          -  Ongoing clinically serious infections requiring systemic antibiotic or antiviral,&#xD;
             antimicrobial, or antifungal therapy.&#xD;
&#xD;
          -  Human immunodeficiency virus (HIV) infection.&#xD;
&#xD;
          -  Known active hepatitis B or hepatitis C.&#xD;
&#xD;
          -  Known history of active tuberculosis.&#xD;
&#xD;
          -  Patients with diagnosed immunodeficiency or receiving systemic steroid therapy or any&#xD;
             other form of immunosuppressive therapy within 7 days prior to randomisation.&#xD;
&#xD;
          -  Patients with other serious diseases or clinical conditions, including but not limited&#xD;
             to uncontrolled active infection and any other serious underlying medical condition&#xD;
             that could affect the patient's capacity to participate in the trial.&#xD;
&#xD;
          -  Substance abuse, medical, psychological or social conditions that may interfere with&#xD;
             the patient's participation in the trial or evaluation of the trial results.&#xD;
&#xD;
          -  Women who are pregnant or in the period of lactation.&#xD;
&#xD;
          -  Sexually active men and women of childbearing potential who are not willing to use an&#xD;
             effective contraceptive method during the trial and up to 120 days following cessation&#xD;
             of trial treatment.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Sanjay Popat, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Royal Marsden NHS Foundation Trust</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Alessandra Curioni-Fontecedro, MD</last_name>
    <role>Study Chair</role>
    <affiliation>University Hospital, Zürich</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>ICO Hospitalet</name>
      <address>
        <city>Barcelona</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Teresa Herrera</name>
      <address>
        <city>La Coruña</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Clínico Universitario de Valladolid</name>
      <address>
        <city>Valladolid</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kantonsspital Aarau</name>
      <address>
        <city>Aarau</city>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Hospitalier Universitaire Vaudois</name>
      <address>
        <city>Lausanne</city>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kantonsspital Luzern</name>
      <address>
        <city>Luzern</city>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kantonsspital Winterthur</name>
      <address>
        <city>Winterthur</city>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Zürich</name>
      <address>
        <city>Zurich</city>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Maidstone and Tunbridge Wells NHS Trust, Kent Oncology Centre</name>
      <address>
        <city>Maidstone</city>
        <state>Kent</state>
        <zip>ME16 9QQ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Addenbrooke's Hospital</name>
      <address>
        <city>Cambridge</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clatterbridge Cancer Centre</name>
      <address>
        <city>Liverpool</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Marsden Hospital</name>
      <address>
        <city>London</city>
        <zip>SW3 6JJ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Guy's and St Thomas' Hospital</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Plymouth Hospitals NHS Trust</name>
      <address>
        <city>Plymouth</city>
        <zip>PL6 8DH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Weston Park Hospital</name>
      <address>
        <city>Sheffield</city>
        <zip>UK S10 2SJ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Spain</country>
    <country>Switzerland</country>
    <country>United Kingdom</country>
  </location_countries>
  <reference>
    <citation>Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro G Jr, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016 Apr 9;387(10027):1540-1550. doi: 10.1016/S0140-6736(15)01281-7. Epub 2015 Dec 19.</citation>
    <PMID>26712084</PMID>
  </reference>
  <reference>
    <citation>Robinson BW, Musk AW, Lake RA. Malignant mesothelioma. Lancet. 2005 Jul 30-Aug 5;366(9483):397-408. doi: 10.1016/S0140-6736(05)67025-0.</citation>
    <PMID>16054941</PMID>
  </reference>
  <reference>
    <citation>Fennell DA, Gaudino G, O'Byrne KJ, Mutti L, van Meerbeeck J. Advances in the systemic therapy of malignant pleural mesothelioma. Nat Clin Pract Oncol. 2008 Mar;5(3):136-47. doi: 10.1038/ncponc1039.</citation>
    <PMID>18227828</PMID>
  </reference>
  <reference>
    <citation>Rake C, Gilham C, Hatch J, Darnton A, Hodgson J, Peto J. Occupational, domestic and environmental mesothelioma risks in the British population: a case-control study. Br J Cancer. 2009 Apr 7;100(7):1175-83. doi: 10.1038/sj.bjc.6604879. Epub 2009 Mar 3.</citation>
    <PMID>19259084</PMID>
  </reference>
  <reference>
    <citation>Tsiouris A, Walesby RK. Malignant pleural mesothelioma: current concepts in treatment. Nat Clin Pract Oncol. 2007 Jun;4(6):344-52. doi: 10.1038/ncponc0839.</citation>
    <PMID>17534390</PMID>
  </reference>
  <reference>
    <citation>Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, Niyikiza C, Paoletti P. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003 Jul 15;21(14):2636-44. doi: 10.1200/JCO.2003.11.136.</citation>
    <PMID>12860938</PMID>
  </reference>
  <reference>
    <citation>Krug LM, Kindler HL, Calvert H, Manegold C, Tsao AS, Fennell D, Ohman R, Plummer R, Eberhardt WE, Fukuoka K, Gaafar RM, Lafitte JJ, Hillerdal G, Chu Q, Buikhuisen WA, Lubiniecki GM, Sun X, Smith M, Baas P. Vorinostat in patients with advanced malignant pleural mesothelioma who have progressed on previous chemotherapy (VANTAGE-014): a phase 3, double-blind, randomised, placebo-controlled trial. Lancet Oncol. 2015 Apr;16(4):447-56. doi: 10.1016/S1470-2045(15)70056-2. Epub 2015 Mar 20. Erratum In: Lancet Oncol. 2015 May;16(5):e199.</citation>
    <PMID>25800891</PMID>
  </reference>
  <verification_date>August 2022</verification_date>
  <study_first_submitted>December 9, 2016</study_first_submitted>
  <study_first_submitted_qc>December 9, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 13, 2016</study_first_posted>
  <results_first_submitted>September 8, 2021</results_first_submitted>
  <results_first_submitted_qc>December 31, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">February 7, 2022</results_first_posted>
  <last_update_submitted>August 23, 2022</last_update_submitted>
  <last_update_submitted_qc>August 23, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">August 24, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>MPM</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Mesothelioma</mesh_term>
    <mesh_term>Mesothelioma, Malignant</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>
    <mesh_term>Vinorelbine</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>October 31, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/82/NCT02991482/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>January 15, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/82/NCT02991482/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Pembrolizumab Arm</title>
          <description>Pembrolizumab is administrated at 200 mg fixed dose i.v. on day 1 of every 3 week cycle for a maximum or 2 years (expected maximum of 36 doses), or until progression of disease determined according to RECIST 1.1 criteria or lack of tolerability, or until the patient declines further treatment.&#xD;
Pembrolizumab: Pembrolizumab (MK-3475) is a potent and highly selective humanised monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances functional activity of the target lymphocytes to facilitate tumour regression and ultimately immune rejection.</description>
        </group>
        <group group_id="P2">
          <title>Standard Chemotherapy Arm</title>
          <description>Gemcitabine (i.v. 1000 mg/m2) or vinorelbine (i.v. 30 mg/m2, or p.o 60/80 mg/m2) chemotherapy will be chosen on a per patient basis and delivered according to local standards. Chemotherapy will be administered on days 1 and 8 of every 3-week cycle. A maximum number of treatment cycles is not mandated.&#xD;
Patients randomised to the control arm will be allowed to cross over to receive pembrolizumab at progression, if cross-over criteria are met. Pembrolizumab administration will follow the same schedule as for patients in the experimental arm, i.e. 200 mg fixed dose i.v. on day 1 of every 3-week cycle for a maximum of 2 years or until trial termination.&#xD;
Gemcitabine: Gemcitabine replaces one of the building blocks of nucleic acids, in this case cytidine, during DNA replication. The process arrests tumour growth, as new nucleosides cannot be attached to the &quot;faulty&quot; nucleoside, resulting in apoptosis (cellular &quot;suicide&quot;).&#xD;
Vinorelbine: Vinorelbine is a vinca alkaloid cytotoxic chemotherapy that is available in intravenous and oral preparations with EMA licenses in lung cancer and breast cancer. Vinorelbine blocks mitosis in phase G2-M, causing cell death in interphase or at the following mitosis.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="73"/>
                <participants group_id="P2" count="71"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Crossed-over to Pembrolizumab at Progression</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="45"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="5"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="65"/>
                <participants group_id="P2" count="66"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Disease progression</title>
              <participants_list>
                <participants group_id="P1" count="56"/>
                <participants group_id="P2" count="47"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="6"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Patient decision</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <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="6"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Clinical deterioration</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Patient feeling too unwell</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Worsening of performance status</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Death prior to study drug initiation</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Consent withdrawal prior to study drug initiation</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Pembrolizumab Arm</title>
          <description>Pembrolizumab is administrated at 200 mg fixed dose i.v. on day 1 of every 3 week cycle for a maximum or 2 years (expected maximum of 36 doses), or until progression of disease determined according to RECIST 1.1 criteria or lack of tolerability, or until the patient declines further treatment.&#xD;
Pembrolizumab: Pembrolizumab (MK-3475) is a potent and highly selective humanised monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances functional activity of the target lymphocytes to facilitate tumour regression and ultimately immune rejection.</description>
        </group>
        <group group_id="B2">
          <title>Standard Chemotherapy Arm</title>
          <description>Gemcitabine (i.v. 1000 mg/m2) or vinorelbine (i.v. 30 mg/m2, or p.o 60/80 mg/m2) chemotherapy will be chosen on a per patient basis and delivered according to local standards. Chemotherapy will be administered on days 1 and 8 of every 3-week cycle. A maximum number of treatment cycles is not mandated.&#xD;
Patients randomised to the control arm will be allowed to cross over to receive pembrolizumab at progression, if cross-over criteria are met. Pembrolizumab administration will follow the same schedule as for patients in the experimental arm, i.e. 200 mg fixed dose i.v. on day 1 of every 3-week cycle for a maximum of 2 years or until trial termination.&#xD;
Gemcitabine: Gemcitabine replaces one of the building blocks of nucleic acids, in this case cytidine, during DNA replication. The process arrests tumour growth, as new nucleosides cannot be attached to the &quot;faulty&quot; nucleoside, resulting in apoptosis (cellular &quot;suicide&quot;).&#xD;
Vinorelbine: Vinorelbine is a vinca alkaloid cytotoxic chemotherapy that is available in intravenous and oral preparations with EMA licenses in lung cancer and breast cancer. Vinorelbine blocks mitosis in phase G2-M, causing cell death in interphase or at the following mitosis.</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="73"/>
            <count group_id="B2" value="71"/>
            <count group_id="B3" value="144"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="73"/>
                    <count group_id="B2" value="71"/>
                    <count group_id="B3" value="144"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="69.0" lower_limit="52.0" upper_limit="83.0"/>
                    <measurement group_id="B2" value="71.0" lower_limit="53.0" upper_limit="83.0"/>
                    <measurement group_id="B3" value="70.0" lower_limit="52.0" upper_limit="83.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Age category</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="73"/>
                    <count group_id="B2" value="71"/>
                    <count group_id="B3" value="144"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>&lt;70 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="42"/>
                    <measurement group_id="B2" value="29"/>
                    <measurement group_id="B3" value="71"/>
                  </measurement_list>
                </category>
                <category>
                  <title>≥70 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="31"/>
                    <measurement group_id="B2" value="42"/>
                    <measurement group_id="B3" value="73"/>
                  </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>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="73"/>
                    <count group_id="B2" value="71"/>
                    <count group_id="B3" value="144"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="26"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="58"/>
                    <measurement group_id="B2" value="60"/>
                    <measurement group_id="B3" value="118"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race and Ethnicity Not Collected</title>
          <population>Race and Ethnicity were not collected from any participant.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="0"/>
                    <count group_id="B2" value="0"/>
                    <count group_id="B3" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <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>Count of Participants</param>
          <class_list>
            <class>
              <title>United Kingdom</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="73"/>
                    <count group_id="B2" value="71"/>
                    <count group_id="B3" value="144"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="54"/>
                    <measurement group_id="B2" value="53"/>
                    <measurement group_id="B3" value="107"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Switzerland</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="73"/>
                    <count group_id="B2" value="71"/>
                    <count group_id="B3" value="144"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="14"/>
                    <measurement group_id="B3" value="27"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Spain</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="73"/>
                    <count group_id="B2" value="71"/>
                    <count group_id="B3" value="144"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Histologic subtype</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="73"/>
                    <count group_id="B2" value="71"/>
                    <count group_id="B3" value="144"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Epithelioid</title>
                  <measurement_list>
                    <measurement group_id="B1" value="66"/>
                    <measurement group_id="B2" value="62"/>
                    <measurement group_id="B3" value="128"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Non-epithelioid</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Smoking history</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="73"/>
                    <count group_id="B2" value="71"/>
                    <count group_id="B3" value="144"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Current</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Former (≥100 cigarettes in the past during the whole life)</title>
                  <measurement_list>
                    <measurement group_id="B1" value="34"/>
                    <measurement group_id="B2" value="28"/>
                    <measurement group_id="B3" value="62"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Never (0-99 cigarettes during the whole life)</title>
                  <measurement_list>
                    <measurement group_id="B1" value="33"/>
                    <measurement group_id="B2" value="39"/>
                    <measurement group_id="B3" value="72"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown/Missing</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>ECOG performance status</title>
          <description>0: Fully active, able to carry on all pre-disease performance without restriction; 1: Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; 2: Ambulatory and capable of all selfcare but unable to carry out any work activities, up and about more than 50% of waking hours.&#xD;
Of note, although an ECOG performance status (PS) of 0 or 1 was mandatory to be included in the study, one patient was allowed to enter the study with ECOG PS of 2 due to leg braces.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="73"/>
                    <count group_id="B2" value="71"/>
                    <count group_id="B3" value="144"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>0</title>
                  <measurement_list>
                    <measurement group_id="B1" value="21"/>
                    <measurement group_id="B2" value="14"/>
                    <measurement group_id="B3" value="35"/>
                  </measurement_list>
                </category>
                <category>
                  <title>1</title>
                  <measurement_list>
                    <measurement group_id="B1" value="51"/>
                    <measurement group_id="B2" value="57"/>
                    <measurement group_id="B3" value="108"/>
                  </measurement_list>
                </category>
                <category>
                  <title>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>EORTC score</title>
          <description>EORTC prognostic score (EPS) was calculated based on Fennell et al.(2005) prognostic model. This model takes into account WBC count, ECOG PS, histologic subtype and gender. A value of smaller or equal to 1.27 signifies a &quot;good prognosis&quot; while a value of more than 1.27 a &quot;poor prognosis&quot;.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="73"/>
                    <count group_id="B2" value="71"/>
                    <count group_id="B3" value="144"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Good prognosis</title>
                  <measurement_list>
                    <measurement group_id="B1" value="45"/>
                    <measurement group_id="B2" value="54"/>
                    <measurement group_id="B3" value="99"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Poor prognosis</title>
                  <measurement_list>
                    <measurement group_id="B1" value="28"/>
                    <measurement group_id="B2" value="17"/>
                    <measurement group_id="B3" value="45"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Prior treatment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="73"/>
                    <count group_id="B2" value="71"/>
                    <count group_id="B3" value="144"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Carboplatin/Pemetrexed</title>
                  <measurement_list>
                    <measurement group_id="B1" value="27"/>
                    <measurement group_id="B2" value="27"/>
                    <measurement group_id="B3" value="54"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Cisplatin/Pemetrexed</title>
                  <measurement_list>
                    <measurement group_id="B1" value="24"/>
                    <measurement group_id="B2" value="22"/>
                    <measurement group_id="B3" value="46"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Platinum+/-Pemetrexed+/-Other</title>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="17"/>
                    <measurement group_id="B3" value="30"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Cisplatin/Pemetrexed and Carboplatin/Pemetrexed</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Missing</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>PD-L1 Tumour proportion score</title>
          <description>PD-L1 expression (PD-L1 tumor proportion score) was evaluated by immunohistochemistry (IHC) assay using clone SP263. PD-L1 was quantified as number of positive cells and scored as percentage of PD-L1 positive cells within tumor region. The following classification of PD-L1 scoring was used: 0 to &lt;1% positive tumor cells; 1 to &lt;20% positive tumor cells; &gt;=20% positive tumor cells; Not Evaluable; Not scored.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="73"/>
                    <count group_id="B2" value="71"/>
                    <count group_id="B3" value="144"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>&lt;1%</title>
                  <measurement_list>
                    <measurement group_id="B1" value="36"/>
                    <measurement group_id="B2" value="30"/>
                    <measurement group_id="B3" value="66"/>
                  </measurement_list>
                </category>
                <category>
                  <title>1-20%</title>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                    <measurement group_id="B2" value="18"/>
                    <measurement group_id="B3" value="38"/>
                  </measurement_list>
                </category>
                <category>
                  <title>≥20%</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="14"/>
                    <measurement group_id="B3" value="25"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not evaluable</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not scored</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Progression Free Survival (PFS) as Assessed by Independent Radiological Review</title>
        <description>To investigate whether treatment with pembrolizumab improves PFS, compared to standard, institutional choice chemotherapy, assessed according to RECIST 1.1 criteria based on independent radiological review; using Kaplan-Meier method and compared between the two treatment arms by a stratified log rank test.</description>
        <time_frame>Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).</time_frame>
        <population>All efficacy evaluations were conducted in the intent-to-treat (ITT) population.</population>
        <group_list>
          <group group_id="O1">
            <title>Pembrolizumab Arm</title>
            <description>Pembrolizumab is administrated at 200 mg fixed dose i.v. on day 1 of every 3 week cycle for a maximum or 2 years (expected maximum of 36 doses), or until progression of disease determined according to RECIST 1.1 criteria or lack of tolerability, or until the patient declines further treatment.&#xD;
Pembrolizumab: Pembrolizumab (MK-3475) is a potent and highly selective humanised monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances functional activity of the target lymphocytes to facilitate tumour regression and ultimately immune rejection.</description>
          </group>
          <group group_id="O2">
            <title>Standard Chemotherapy Arm</title>
            <description>Gemcitabine (i.v. 1000 mg/m2) or vinorelbine (i.v. 30 mg/m2, or p.o 60/80 mg/m2) chemotherapy will be chosen on a per patient basis and delivered according to local standards. Chemotherapy will be administered on days 1 and 8 of every 3-week cycle. A maximum number of treatment cycles is not mandated.&#xD;
Patients randomised to the control arm will be allowed to cross over to receive pembrolizumab at progression, if cross-over criteria are met. Pembrolizumab administration will follow the same schedule as for patients in the experimental arm, i.e. 200 mg fixed dose i.v. on day 1 of every 3-week cycle for a maximum of 2 years or until trial termination.&#xD;
Gemcitabine: Gemcitabine replaces one of the building blocks of nucleic acids, in this case cytidine, during DNA replication. The process arrests tumour growth, as new nucleosides cannot be attached to the &quot;faulty&quot; nucleoside, resulting in apoptosis (cellular &quot;suicide&quot;).&#xD;
Vinorelbine: Vinorelbine is a vinca alkaloid cytotoxic chemotherapy that is available in intravenous and oral preparations with EMA licenses in lung cancer and breast cancer. Vinorelbine blocks mitosis in phase G2-M, causing cell death in interphase or at the following mitosis.</description>
          </group>
        </group_list>
        <measure>
          <title>Progression Free Survival (PFS) as Assessed by Independent Radiological Review</title>
          <description>To investigate whether treatment with pembrolizumab improves PFS, compared to standard, institutional choice chemotherapy, assessed according to RECIST 1.1 criteria based on independent radiological review; using Kaplan-Meier method and compared between the two treatment arms by a stratified log rank test.</description>
          <population>All efficacy evaluations were conducted in the intent-to-treat (ITT) 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="73"/>
                <count group_id="O2" value="71"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.5" lower_limit="2.1" upper_limit="4.2"/>
                    <measurement group_id="O2" value="3.4" lower_limit="2.2" upper_limit="4.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.76</p_value>
            <method>Log Rank</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Objective Response Rate by Independent Radiological Review</title>
        <description>Defined as the best overall response (complete or partial response) across all assessment time-points from randomisation to end of trial treatment, determined by RECIST 1.1 criteria.</description>
        <time_frame>Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Pembrolizumab Arm</title>
            <description>Pembrolizumab is administrated at 200 mg fixed dose i.v. on day 1 of every 3 week cycle for a maximum or 2 years (expected maximum of 36 doses), or until progression of disease determined according to RECIST 1.1 criteria or lack of tolerability, or until the patient declines further treatment.&#xD;
Pembrolizumab: Pembrolizumab (MK-3475) is a potent and highly selective humanised monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances functional activity of the target lymphocytes to facilitate tumour regression and ultimately immune rejection.</description>
          </group>
          <group group_id="O2">
            <title>Standard Chemotherapy Arm</title>
            <description>Gemcitabine (i.v. 1000 mg/m2) or vinorelbine (i.v. 30 mg/m2, or p.o 60/80 mg/m2) chemotherapy will be chosen on a per patient basis and delivered according to local standards. Chemotherapy will be administered on days 1 and 8 of every 3-week cycle. A maximum number of treatment cycles is not mandated.&#xD;
Patients randomised to the control arm will be allowed to cross over to receive pembrolizumab at progression, if cross-over criteria are met. Pembrolizumab administration will follow the same schedule as for patients in the experimental arm, i.e. 200 mg fixed dose i.v. on day 1 of every 3-week cycle for a maximum of 2 years or until trial termination.&#xD;
Gemcitabine: Gemcitabine replaces one of the building blocks of nucleic acids, in this case cytidine, during DNA replication. The process arrests tumour growth, as new nucleosides cannot be attached to the &quot;faulty&quot; nucleoside, resulting in apoptosis (cellular &quot;suicide&quot;).&#xD;
Vinorelbine: Vinorelbine is a vinca alkaloid cytotoxic chemotherapy that is available in intravenous and oral preparations with EMA licenses in lung cancer and breast cancer. Vinorelbine blocks mitosis in phase G2-M, causing cell death in interphase or at the following mitosis.</description>
          </group>
        </group_list>
        <measure>
          <title>Objective Response Rate by Independent Radiological Review</title>
          <description>Defined as the best overall response (complete or partial response) across all assessment time-points from randomisation to end of trial treatment, determined by RECIST 1.1 criteria.</description>
          <units>percentage of participants</units>
          <param>Number</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="73"/>
                <count group_id="O2" value="71"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="21.9" lower_limit="13.1" upper_limit="33.1"/>
                    <measurement group_id="O2" value="5.6" lower_limit="1.6" upper_limit="13.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival.</title>
        <description>Defined as time from the date of randomisation until death from any cause. Censoring will occur at the last follow-up date.</description>
        <time_frame>Time from randomization of the first patient until database cutoff date for the OS analysis (Sep 2017 - Aug 2019; approximately 2 years).</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Pembrolizumab Arm</title>
            <description>Pembrolizumab is administrated at 200 mg fixed dose i.v. on day 1 of every 3 week cycle for a maximum or 2 years (expected maximum of 36 doses), or until progression of disease determined according to RECIST 1.1 criteria or lack of tolerability, or until the patient declines further treatment.&#xD;
Pembrolizumab: Pembrolizumab (MK-3475) is a potent and highly selective humanised monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances functional activity of the target lymphocytes to facilitate tumour regression and ultimately immune rejection.</description>
          </group>
          <group group_id="O2">
            <title>Standard Chemotherapy Arm</title>
            <description>Gemcitabine (i.v. 1000 mg/m2) or vinorelbine (i.v. 30 mg/m2, or p.o 60/80 mg/m2) chemotherapy will be chosen on a per patient basis and delivered according to local standards. Chemotherapy will be administered on days 1 and 8 of every 3-week cycle. A maximum number of treatment cycles is not mandated.&#xD;
Patients randomised to the control arm will be allowed to cross over to receive pembrolizumab at progression, if cross-over criteria are met. Pembrolizumab administration will follow the same schedule as for patients in the experimental arm, i.e. 200 mg fixed dose i.v. on day 1 of every 3-week cycle for a maximum of 2 years or until trial termination.&#xD;
Gemcitabine: Gemcitabine replaces one of the building blocks of nucleic acids, in this case cytidine, during DNA replication. The process arrests tumour growth, as new nucleosides cannot be attached to the &quot;faulty&quot; nucleoside, resulting in apoptosis (cellular &quot;suicide&quot;).&#xD;
Vinorelbine: Vinorelbine is a vinca alkaloid cytotoxic chemotherapy that is available in intravenous and oral preparations with EMA licenses in lung cancer and breast cancer. Vinorelbine blocks mitosis in phase G2-M, causing cell death in interphase or at the following mitosis.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival.</title>
          <description>Defined as time from the date of randomisation until death from any cause. Censoring will occur at the last follow-up date.</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="73"/>
                <count group_id="O2" value="71"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="10.7" lower_limit="7.6" upper_limit="15.0"/>
                    <measurement group_id="O2" value="12.4" lower_limit="7.4" upper_limit="16.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Time to Treatment Failure.</title>
        <description>Time from from randomisation to discontinuation of treatment for any reason, including progression of disease, treatment toxicity, refusal and death, by Kaplan Meier method. Censoring will occur at the last follow-up date.</description>
        <time_frame>Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Pembrolizumab Arm</title>
            <description>Pembrolizumab is administrated at 200 mg fixed dose i.v. on day 1 of every 3 week cycle for a maximum or 2 years (expected maximum of 36 doses), or until progression of disease determined according to RECIST 1.1 criteria or lack of tolerability, or until the patient declines further treatment.&#xD;
Pembrolizumab: Pembrolizumab (MK-3475) is a potent and highly selective humanised monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances functional activity of the target lymphocytes to facilitate tumour regression and ultimately immune rejection.</description>
          </group>
          <group group_id="O2">
            <title>Standard Chemotherapy Arm</title>
            <description>Gemcitabine (i.v. 1000 mg/m2) or vinorelbine (i.v. 30 mg/m2, or p.o 60/80 mg/m2) chemotherapy will be chosen on a per patient basis and delivered according to local standards. Chemotherapy will be administered on days 1 and 8 of every 3-week cycle. A maximum number of treatment cycles is not mandated.&#xD;
Patients randomised to the control arm will be allowed to cross over to receive pembrolizumab at progression, if cross-over criteria are met. Pembrolizumab administration will follow the same schedule as for patients in the experimental arm, i.e. 200 mg fixed dose i.v. on day 1 of every 3-week cycle for a maximum of 2 years or until trial termination.&#xD;
Gemcitabine: Gemcitabine replaces one of the building blocks of nucleic acids, in this case cytidine, during DNA replication. The process arrests tumour growth, as new nucleosides cannot be attached to the &quot;faulty&quot; nucleoside, resulting in apoptosis (cellular &quot;suicide&quot;).&#xD;
Vinorelbine: Vinorelbine is a vinca alkaloid cytotoxic chemotherapy that is available in intravenous and oral preparations with EMA licenses in lung cancer and breast cancer. Vinorelbine blocks mitosis in phase G2-M, causing cell death in interphase or at the following mitosis.</description>
          </group>
        </group_list>
        <measure>
          <title>Time to Treatment Failure.</title>
          <description>Time from from randomisation to discontinuation of treatment for any reason, including progression of disease, treatment toxicity, refusal and death, by Kaplan Meier method. Censoring will occur at the last follow-up date.</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="73"/>
                <count group_id="O2" value="71"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.8" lower_limit="2.1" upper_limit="4.2"/>
                    <measurement group_id="O2" value="2.3" lower_limit="2.1" upper_limit="3.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Patients Experienced AEs/SAEs</title>
        <description>The safety and tolerability of pembrolizumab treatment will be assessed through analysis of the worst grade of toxicity/adverse events according to CTCAE v4.0 criteria observed over the whole treatment period. Adverse events are collected from study treatment initiation to 30 days after treatment is ceased for any reason. Serious adverse events and events of clinical interest are collected within 90 days after last dose of trial treatment.</description>
        <time_frame>Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).</time_frame>
        <population>Safety evaluation was conducted in the as-treated (AT) population: all randomised patients that received at least one dose of trial treatment, with treatment assignments designed according to actual study treatment received.</population>
        <group_list>
          <group group_id="O1">
            <title>Pembrolizumab Arm</title>
            <description>Pembrolizumab is administrated at 200 mg fixed dose i.v. on day 1 of every 3 week cycle for a maximum or 2 years (expected maximum of 36 doses), or until progression of disease determined according to RECIST 1.1 criteria or lack of tolerability, or until the patient declines further treatment.&#xD;
Pembrolizumab: Pembrolizumab (MK-3475) is a potent and highly selective humanised monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances functional activity of the target lymphocytes to facilitate tumour regression and ultimately immune rejection.</description>
          </group>
          <group group_id="O2">
            <title>Standard Chemotherapy Arm</title>
            <description>Gemcitabine (i.v. 1000 mg/m2) or vinorelbine (i.v. 30 mg/m2, or p.o 60/80 mg/m2) chemotherapy will be chosen on a per patient basis and delivered according to local standards. Chemotherapy will be administered on days 1 and 8 of every 3-week cycle. A maximum number of treatment cycles is not mandated.&#xD;
Patients randomised to the control arm will be allowed to cross over to receive pembrolizumab at progression, if cross-over criteria are met. Pembrolizumab administration will follow the same schedule as for patients in the experimental arm, i.e. 200 mg fixed dose i.v. on day 1 of every 3-week cycle for a maximum of 2 years or until trial termination.&#xD;
Gemcitabine: Gemcitabine replaces one of the building blocks of nucleic acids, in this case cytidine, during DNA replication. The process arrests tumour growth, as new nucleosides cannot be attached to the &quot;faulty&quot; nucleoside, resulting in apoptosis (cellular &quot;suicide&quot;).&#xD;
Vinorelbine: Vinorelbine is a vinca alkaloid cytotoxic chemotherapy that is available in intravenous and oral preparations with EMA licenses in lung cancer and breast cancer. Vinorelbine blocks mitosis in phase G2-M, causing cell death in interphase or at the following mitosis.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Patients Experienced AEs/SAEs</title>
          <description>The safety and tolerability of pembrolizumab treatment will be assessed through analysis of the worst grade of toxicity/adverse events according to CTCAE v4.0 criteria observed over the whole treatment period. Adverse events are collected from study treatment initiation to 30 days after treatment is ceased for any reason. Serious adverse events and events of clinical interest are collected within 90 days after last dose of trial treatment.</description>
          <population>Safety evaluation was conducted in the as-treated (AT) population: all randomised patients that received at least one dose of trial treatment, with treatment assignments designed according to actual study treatment received.</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="72"/>
                <count group_id="O2" value="70"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Experienced any adverse event</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="70"/>
                    <measurement group_id="O2" value="65"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Experienced treatment related adverse event</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="50"/>
                    <measurement group_id="O2" value="52"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Experienced treatment related adverse event of grade 3-5</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14"/>
                    <measurement group_id="O2" value="18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Experienced treatment related adverse event leading to death</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Experienced treatment related adverse event leading to treatment discontinuation</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                    <measurement group_id="O2" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression Free Survival (PFS) Assessed by Investigator</title>
        <description>Investigator assessed PFS, from the date of randomisation until documented progression or death, if progression is not documented. Censoring occurs at the last tumor assessment.</description>
        <time_frame>Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Pembrolizumab Arm</title>
            <description>Pembrolizumab is administrated at 200 mg fixed dose i.v. on day 1 of every 3 week cycle for a maximum or 2 years (expected maximum of 36 doses), or until progression of disease determined according to RECIST 1.1 criteria or lack of tolerability, or until the patient declines further treatment.&#xD;
Pembrolizumab: Pembrolizumab (MK-3475) is a potent and highly selective humanised monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances functional activity of the target lymphocytes to facilitate tumour regression and ultimately immune rejection.</description>
          </group>
          <group group_id="O2">
            <title>Standard Chemotherapy Arm</title>
            <description>Gemcitabine (i.v. 1000 mg/m2) or vinorelbine (i.v. 30 mg/m2, or p.o 60/80 mg/m2) chemotherapy will be chosen on a per patient basis and delivered according to local standards. Chemotherapy will be administered on days 1 and 8 of every 3-week cycle. A maximum number of treatment cycles is not mandated.&#xD;
Patients randomised to the control arm will be allowed to cross over to receive pembrolizumab at progression, if cross-over criteria are met. Pembrolizumab administration will follow the same schedule as for patients in the experimental arm, i.e. 200 mg fixed dose i.v. on day 1 of every 3-week cycle for a maximum of 2 years or until trial termination.&#xD;
Gemcitabine: Gemcitabine replaces one of the building blocks of nucleic acids, in this case cytidine, during DNA replication. The process arrests tumour growth, as new nucleosides cannot be attached to the &quot;faulty&quot; nucleoside, resulting in apoptosis (cellular &quot;suicide&quot;).&#xD;
Vinorelbine: Vinorelbine is a vinca alkaloid cytotoxic chemotherapy that is available in intravenous and oral preparations with EMA licenses in lung cancer and breast cancer. Vinorelbine blocks mitosis in phase G2-M, causing cell death in interphase or at the following mitosis.</description>
          </group>
        </group_list>
        <measure>
          <title>Progression Free Survival (PFS) Assessed by Investigator</title>
          <description>Investigator assessed PFS, from the date of randomisation until documented progression or death, if progression is not documented. Censoring occurs at the last tumor assessment.</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="73"/>
                <count group_id="O2" value="71"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.5" lower_limit="2.1" upper_limit="4.2"/>
                    <measurement group_id="O2" value="3.7" lower_limit="2.2" upper_limit="4.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse events were assessed from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years). All-Cause Mortality was assessed from the date of randomization up to 2 years. All-Cause Mortality was assessed from the date of randomization until database cutoff date for the OS analysis (Sep 2017 - Aug 2019; approximately 2 years).</time_frame>
      <desc>In the 'All Cause Mortality' section, number of at risk patients includes all randomized patients, while in the 'Serious Adverse Events' and 'Other (Not Including Serious) Adverse Events' sections, at risk patients refer to the population who received at least one dose of trial treatment (safety cohort).</desc>
      <group_list>
        <group group_id="E1">
          <title>Pembrolizumab Arm</title>
          <description>Pembrolizumab is administrated at 200 mg fixed dose i.v. on day 1 of every 3 week cycle for a maximum or 2 years (expected maximum of 36 doses), or until progression of disease determined according to RECIST 1.1 criteria or lack of tolerability, or until the patient declines further treatment.&#xD;
Pembrolizumab: Pembrolizumab (MK-3475) is a potent and highly selective humanised monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances functional activity of the target lymphocytes to facilitate tumour regression and ultimately immune rejection.</description>
        </group>
        <group group_id="E2">
          <title>Standard Chemotherapy Arm</title>
          <description>Gemcitabine (i.v. 1000 mg/m2) or vinorelbine (i.v. 30 mg/m2, or p.o 60/80 mg/m2) chemotherapy will be chosen on a per patient basis and delivered according to local standards. Chemotherapy will be administered on days 1 and 8 of every 3-week cycle. A maximum number of treatment cycles is not mandated.&#xD;
Patients randomised to the control arm will be allowed to cross over to receive pembrolizumab at progression, if cross-over criteria are met. Pembrolizumab administration will follow the same schedule as for patients in the experimental arm, i.e. 200 mg fixed dose i.v. on day 1 of every 3-week cycle for a maximum of 2 years or until trial termination.&#xD;
Gemcitabine: Gemcitabine replaces one of the building blocks of nucleic acids, in this case cytidine, during DNA replication. The process arrests tumour growth, as new nucleosides cannot be attached to the &quot;faulty&quot; nucleoside, resulting in apoptosis (cellular &quot;suicide&quot;).&#xD;
Vinorelbine: Vinorelbine is a vinca alkaloid cytotoxic chemotherapy that is available in intravenous and oral preparations with EMA licenses in lung cancer and breast cancer. Vinorelbine blocks mitosis in phase G2-M, causing cell death in interphase or at the following mitosis.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="48" subjects_at_risk="73"/>
                <counts group_id="E2" subjects_affected="44" subjects_at_risk="71"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="25" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="20" subjects_at_risk="70"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="70"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Cardiac arrest</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Atrial flutter</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Heart failure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Myocardial infarction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="70"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Adrenal insufficiency</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="70"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Colitis</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="70"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Malaise</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="70"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Cytokine release syndrome</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Hypophysitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="70"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Bronchial infection</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Catheter related infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Otitis media</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Infection NOS</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Lower respiratory infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Non-neutropaenic infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="70"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="70"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hypercalcemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Hyperkalemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="70"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Syncope</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="70"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Confusion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="70"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Acute kidney injury</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="70"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Pneumonitis</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="70"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="70"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="70"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="70" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="65" subjects_at_risk="70"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="11" subjects_at_risk="70"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="17" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="23" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="24" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="26" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="9" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Oral thrush</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="70"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="28" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="32" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="19" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="19" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Edema limbs</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Flu like symptoms</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="70"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Bronchial infection</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="70"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>GGT increased</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="70"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" subjects_affected="12" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="21" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="70"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Chest wall pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="70"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Peripheral sensory neuropathy</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Paresthesia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="70"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="70"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="20" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="16" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="70"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="70"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="72"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="70"/>
              </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>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Heidi Roschitzki</name_or_title>
      <organization>European Thoracic Oncology Platform (ETOP)</organization>
      <phone>+41 31 511 94 00</phone>
      <email>Heidi.Roschitzki@etop-eu.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/NCT02991482
org study id: ETOP 9-15
secondary id: 2016-002062-31
secondary id: 3475-594
nct id: NCT02991482
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Trial comparing standard treatment (chemotherapy) with pembrolizumab treatment in patients
      with advanced pretreated malignant mesothelioma.
Mesothelioma is an aggressive malignancy usually affecting the surfaces of body coelomic
      cavities. It most commonly originates from the pleura with a propensity to the lower parietal
      pleura and costo-diaphragmatic recess, and is almost always caused by asbestos exposure, with
      a usual lag time of 30 years between exposure and presentation. Outcomes for most patients
      are invariably fatal, with median survival from presentation around 9-12 months in most
      series due to difficulties in achieving a complete microscopic surgical resection and tumour
      relative chemo-refractoriness. Whilst initially considered rare, due to the demand of
      asbestos of all varieties associated with industrialization following the Second World War,
      the background incidence of mesothelioma of 1/million has risen to 40/million in some
      countries. In the UK, where substantial asbestos exposure continued until the 1970s, the
      death rate is the highest in the world with a current epidemic of new cases, predicted to
      continue for another 5-10 years. Two main histological subtypes of mesothelioma are
      identified. The epitheliod subtype is the commonest, accounting for around 40% of cases,
      whilst the sarcomatoid subtype is observed in 20% of cases; the latter being typically
      aggressive and chemorefractory. Around 35% cases have features of both epitheliod and
      sarcomatoid subtypes and are termed biphasic subtype.

      For patients with pleural mesothelioma, in whom surgery is not considered appropriate,
      systemic chemotherapy (platinum combined with pemetrexed) remains the international standard
      of care. Cisplatin/pemetrexed is associated with a response rate of 41% and confers an OS
      advantage of 3 months over cisplatin alone, and is the only licensed systemic therapy for
      mesothelioma in Europe. Despite this, the median survival is 9-12 months from most series in
      unresectable cases. At relapse, after platinum-based chemotherapy, no anti-cancer systemic
      therapies are licensed. Whilst several small phase II studies and retrospective series have
      suggested potential efficacy for chemotherapy with agents including carboplatin/gemcitabine,
      or vinorelbine, none thus far have demonstrated efficacy benefit in a randomised study, with
      median PFS rates reported of about 3 months for both gemcitabine and vinorelbine. There is
      therefore a huge unmet need for effective therapy for patients with relapsed pleural
      mesothelioma. The largest trial ever performed of systemic therapy in relapsed pleural
      mesothelioma in 661 patients documented the natural outcome of this group of relapsed
      mesothelioma patients, reporting a median OS of 27.1 weeks (6 months) and median PFS for 6.1
      weeks (1.5 months) for placebo.

      Programmed cell death-1 (PD-1) is a co-inhibitory molecule at the immunological synapse that
      acts as a major regulator of adaptive immunity, and is exploited by tumour cells to result in
      adaptive immune resistance (tolerance). This occurs when PD-1 binds to the ligands PD-L1
      (B7H1) or PD-L2, which are expressed on many tumour types. High PD-L1 expression on tumours
      is associated with poorer outcomes. Mesothelioma has been shown to express PD-L1, with a
      small study identifying PDL1 expression in up to 40% of mesotheliomas. Moreover,
      immunologically-mediated inflammation is known to be a key driver for mesothelioma
      development via the Nalp3 imflammasome.

      Pembrolizumab (MK-3475) is a potent and highly selective humanized monoclonal antibody (mAb)
      of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its
      ligands, PD-L1 and PD-L2.

      There is a need to identify new ways for the systemic therapy of malignant mesothelioma and
      immune checkpoint inhibition is a promising way forward. Results from the proposed trial will
      contribute to overcoming tumour-specific immune suppression with immune checkpoint
      inhibition.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Progression Free Survival (PFS) as Assessed by Independent Radiological Review
time frame: Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).
description: To investigate whether treatment with pembrolizumab improves PFS, compared to standard, institutional choice chemotherapy, assessed according to RECIST 1.1 criteria based on independent radiological review; using Kaplan-Meier method and compared between the two treatment arms by a stratified log rank test.
measure: Objective Response Rate by Independent Radiological Review
time frame: Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).
description: Defined as the best overall response (complete or partial response) across all assessment time-points from randomisation to end of trial treatment, determined by RECIST 1.1 criteria.
measure: Overall Survival.
time frame: Time from randomization of the first patient until database cutoff date for the OS analysis (Sep 2017 - Aug 2019; approximately 2 years).
description: Defined as time from the date of randomisation until death from any cause. Censoring will occur at the last follow-up date.
measure: Time to Treatment Failure.
time frame: Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).
description: Time from from randomisation to discontinuation of treatment for any reason, including progression of disease, treatment toxicity, refusal and death, by Kaplan Meier method. Censoring will occur at the last follow-up date.
measure: Percentage of Patients Experienced AEs/SAEs
time frame: Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).
description: The safety and tolerability of pembrolizumab treatment will be assessed through analysis of the worst grade of toxicity/adverse events according to CTCAE v4.0 criteria observed over the whole treatment period. Adverse events are collected from study treatment initiation to 30 days after treatment is ceased for any reason. Serious adverse events and events of clinical interest are collected within 90 days after last dose of trial treatment.
measure: Progression Free Survival (PFS) Assessed by Investigator
time frame: Time from randomization of the first patient until database cutoff date for the primary PFS analysis (Sep 2017 - Feb 2019; approximately 1.5 years).
description: Investigator assessed PFS, from the date of randomisation until documented progression or death, if progression is not documented. Censoring occurs at the last tumor assessment.
arm group label: Pembrolizumab arm
arm group type: Experimental
description: Pembrolizumab is administrated at 200 mg fixed dose i.v. on day 1 of every 3 week cycle for a maximum or 2 years (expected maximum of 36 doses), or until progression of disease determined according to RECIST 1.1 criteria or lack of tolerability, or until the patient declines further treatment.
arm group label: Standard chemotherapy arm
arm group type: Active Comparator
description: Gemcitabine (i.v. 1000 mg/m2) or vinorelbine (i.v. 30 mg/m2, or p.o 60/80 mg/m2) chemotherapy will be chosen on a per patient basis and delivered according to local standards. Chemotherapy will be administered on days 1 and 8 of every 3-week cycle. A maximum number of treatment cycles is not mandated.
Patients randomised to the control arm will be allowed to cross over to receive pembrolizumab at progression, if cross-over criteria are met. Pembrolizumab administration will follow the same schedule as for patients in the experimental arm, i.e. 200 mg fixed dose i.v. on day 1 of every 3-week cycle for a maximum of 2 years or until trial termination.
intervention type: Drug
intervention name: Pembrolizumab
description: Pembrolizumab (MK-3475) is a potent and highly selective humanised monoclonal antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2. This blockade enhances functional activity of the target lymphocytes to facilitate tumour regression and ultimately immune rejection.
arm group label: Pembrolizumab arm
other name: KEYTRUDA
other name: MK-3475
other name: SCH 900475
intervention type: Drug
intervention name: Gemcitabine
description: Gemcitabine replaces one of the building blocks of nucleic acids, in this case cytidine, during DNA replication. The process arrests tumour growth, as new nucleosides cannot be attached to the "faulty" nucleoside, resulting in apoptosis (cellular "suicide").
arm group label: Standard chemotherapy arm
other name: Gemzar
intervention type: Drug
intervention name: Vinorelbine
description: Vinorelbine is a vinca alkaloid cytotoxic chemotherapy that is available in intravenous and oral preparations with EMA licenses in lung cancer and breast cancer. Vinorelbine blocks mitosis in phase G2-M, causing cell death in interphase or at the following mitosis.
arm group label: Standard chemotherapy arm
other name: Navelbine
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Sanjay Popat, MD
role: Study Chair
affiliation: Royal Marsden NHS Foundation Trust
last name: Alessandra Curioni-Fontecedro, MD
role: Study Chair
affiliation: University Hospital, Zürich
facility: 
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country: Spain
country: Switzerland
country: United Kingdom
citation: Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro G Jr, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016 Apr 9;387(10027):1540-1550. doi: 10.1016/S0140-6736(15)01281-7. Epub 2015 Dec 19.
PMID: 26712084
citation: Robinson BW, Musk AW, Lake RA. Malignant mesothelioma. Lancet. 2005 Jul 30-Aug 5;366(9483):397-408. doi: 10.1016/S0140-6736(05)67025-0.
PMID: 16054941
citation: Fennell DA, Gaudino G, O'Byrne KJ, Mutti L, van Meerbeeck J. Advances in the systemic therapy of malignant pleural mesothelioma. Nat Clin Pract Oncol. 2008 Mar;5(3):136-47. doi: 10.1038/ncponc1039.
PMID: 18227828
citation: Rake C, Gilham C, Hatch J, Darnton A, Hodgson J, Peto J. Occupational, domestic and environmental mesothelioma risks in the British population: a case-control study. Br J Cancer. 2009 Apr 7;100(7):1175-83. doi: 10.1038/sj.bjc.6604879. Epub 2009 Mar 3.
PMID: 19259084
citation: Tsiouris A, Walesby RK. Malignant pleural mesothelioma: current concepts in treatment. Nat Clin Pract Oncol. 2007 Jun;4(6):344-52. doi: 10.1038/ncponc0839.
PMID: 17534390
citation: Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, Niyikiza C, Paoletti P. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003 Jul 15;21(14):2636-44. doi: 10.1200/JCO.2003.11.136.
PMID: 12860938
citation: Krug LM, Kindler HL, Calvert H, Manegold C, Tsao AS, Fennell D, Ohman R, Plummer R, Eberhardt WE, Fukuoka K, Gaafar RM, Lafitte JJ, Hillerdal G, Chu Q, Buikhuisen WA, Lubiniecki GM, Sun X, Smith M, Baas P. Vorinostat in patients with advanced malignant pleural mesothelioma who have progressed on previous chemotherapy (VANTAGE-014): a phase 3, double-blind, randomised, placebo-controlled trial. Lancet Oncol. 2015 Apr;16(4):447-56. doi: 10.1016/S1470-2045(15)70056-2. Epub 2015 Mar 20. Erratum In: Lancet Oncol. 2015 May;16(5):e199.
PMID: 25800891
responsible party type: Sponsor
mesh term: Mesothelioma
mesh term: Mesothelioma, Malignant
mesh term: Gemcitabine
mesh term: Pembrolizumab
mesh term: Vinorelbine
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 