<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/NCT03762018</url>
  </required_header>
  <id_info>
    <org_study_id>ETOP 13-18</org_study_id>
    <secondary_id>2018-002180-25</secondary_id>
    <secondary_id>MO40388</secondary_id>
    <nct_id>NCT03762018</nct_id>
  </id_info>
  <brief_title>BEAT-meso: Bevacizumab and Atezolizumab in Malignant Pleural Mesothelioma</brief_title>
  <acronym>BEAT-meso</acronym>
  <official_title>A Multicentre Randomised Phase III Trial Comparing Atezolizumab Plus Bevacizumab and Standard Chemotherapy Versus Bevacizumab and Standard Chemotherapy as First-line Treatment for Advanced Malignant Pleural Mesothelioma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>ETOP IBCSG Partners Foundation</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Hoffmann-La Roche</agency>
      <agency_class>Industry</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>
      The aim of this clinical trial is to assess the effect of treatment with a monoclonal&#xD;
      antibody called atezolizumab in patients diagnosed with a type of lung cancer called&#xD;
      malignant pleural mesothelioma. The efficacy (whether the treatment works), safety and&#xD;
      tolerability (side effects of treatment) of atezolizumab plus bevacizumab in combination with&#xD;
      standard chemotherapy versus bevacizumab in combination with standard chemotherapy will be&#xD;
      investigated.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer arising from the&#xD;
      mesothelial surface of the pleura. In Europe, the incidence is about 20 per million and is&#xD;
      almost always caused by asbestos exposure, with a usual lag time of 30 years between exposure&#xD;
      and presentation. Patients diagnosed with advanced MPM have limited treatment options,&#xD;
      representing a strict unmet need. Despite decades of clinical research, cytotoxic&#xD;
      chemotherapy remains one of the few therapeutic options that has been proven to improve&#xD;
      survival in advanced MPM in a randomised controlled trial.&#xD;
&#xD;
      The combination of cisplatin and pemetrexed has become standard first-line therapy worldwide&#xD;
      for patients who are not suitable for aggressive surgery or in whom chemotherapy is&#xD;
      recommended as part of a multimodality regimen. Carboplatin is often substituted for&#xD;
      cisplatin, due to simpler and shorter administration and assumption of a more favourable&#xD;
      toxicity profile based on experience in other diseases. Patients with MPM have limited&#xD;
      treatment options, representing a strict unmet need.&#xD;
&#xD;
      An antibody is a common type of protein usually made in the body in response to a foreign&#xD;
      substance. Antibodies attack foreign substances and protect against infection. The two&#xD;
      monoclonal antibodies (atezolizumab and bevacizumab) used in this trial are&#xD;
      laboratory-produced antibodies. Atezolizumab is engineered to attach to immune cells to&#xD;
      stimulate their activity against cancer cells.&#xD;
&#xD;
      Atezolizumab and bevacizumab are both approved by the European Medicines Agency for the&#xD;
      treatment of lung and other cancers. The addition of atezolizumab to bevacizumab plus&#xD;
      standard chemotherapy for the treatment of MPM is being investigated in this trial.&#xD;
&#xD;
      All participants will receive 4-6 cycles of standard chemotherapy consisting of carboplatin&#xD;
      AUC 5 (area under the plasma concentration versus time curve) plus pemetrexed 500mg/m^2 given&#xD;
      intravenously, on day 1 of every 3 week cycle for about 12 to 18 weeks.&#xD;
&#xD;
      Participants will be randomly assigned to one of two treatment groups:&#xD;
&#xD;
      Treatment 1&#xD;
&#xD;
        -  Bevacizumab 15 mg/kg intravenously on day 1 of every 3-week cycle, plus&#xD;
&#xD;
        -  4-6 cycles of chemotherapy&#xD;
&#xD;
      OR&#xD;
&#xD;
      Treatment 2&#xD;
&#xD;
        -  Atezolizumab 1200 mg fixed dose intravenously on day 1 of every 3-week cycle, plus&#xD;
&#xD;
        -  Bevacizumab 15 mg/kg, intravenously on day 1 of every 3-week cycle, plus&#xD;
&#xD;
        -  4-6 cycles of chemotherapy&#xD;
&#xD;
      Participants will continue to receive treatment until disease progression, or until treatment&#xD;
      is stopped at the request of the participant or treating doctor, or the participant withdraws&#xD;
      consent.&#xD;
&#xD;
      A total of 400 participants from approximately 45 centres in Europe are expected to be&#xD;
      included in this trial which will take approximately 6 years to be completed after the first&#xD;
      participant is enrolled.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">April 30, 2019</start_date>
  <completion_date type="Anticipated">January 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">January 31, 2024</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>Overall Survival (OS)</measure>
    <time_frame>From date of randomisation until death from any cause, assessed up to 58 months</time_frame>
    <description>Overall survival is defined as the time from the date of randomisation until death from any cause. Data for patients who are not reported as having died at the date of analysis will be censored at the date when they were last known to be alive. Data for patients without post-baseline information will be censored at the date of randomization (plus 1 day).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression-free Survival (PFS) according to the mRECIST v1.1</measure>
    <time_frame>From date of randomisation until documented progression or death, if progression is not documented, assessed up to 58 months</time_frame>
    <description>PFS is defined as the time from the date of randomisation until documented progression (according to the mRECIST v1.1) or death, if progression is not documented. Censoring (for participants without a PFS/death event) will occur at the date of last tumour assessment. Patients without a post-baseline tumour assessment will be censored at the date of randomization (plus 1 day).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective Response Rate (ORR)</measure>
    <time_frame>From start of protocol treatment acorss all time-points until end of protocol treatment or, as an alternative approach, until the end of follow-up, assessed up to 58 months</time_frame>
    <description>Defined as the percentage of patients that achieve a best overall response [complete response (CR) or partial response (PR)] evaluated according to the mRECIST v1.1 across all post-randomization time-points until the end of protocol treatment or, as an alternative approach, until the end of follow-up. Confirmation of response will not be required.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease Control (DC) at 24 weeks</measure>
    <time_frame>24 weeks after protocol treatment start</time_frame>
    <description>Defined as complete or partial response, or disease stabilisation at 24 weeks.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Treatment Failure (TTF)</measure>
    <time_frame>From randomisation until discontinuation of protocol treatment for any reason, assessed up to 58 months</time_frame>
    <description>Defined as the time from the date of randomisation to discontinuation of protocol treatment for any reason (including progression of disease, death, discontinuation of at least one of the drugs consisting the treatment combination due to any reason, such as toxicity or refusal). Censoring will occur at the last follow-up date.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of Response (DoR)</measure>
    <time_frame>From date of first documentation of objective response until date of first documented progression/ relapse or death, assessed up to 58 months</time_frame>
    <description>Defined as the interval from the date of first documentation of objective response (complete response or partial response, according to the mRECIST v1.1) to the date of first documented progression/ relapse or death.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants with treatment related adverse events according to Common Toxicity Criteria for Adverse Events (CTCAE) v5.0</measure>
    <time_frame>Assessed from the date of informed consent until 90 days after protocol treatment discontinuation. Analysed at 58 months after randomisation of the first patient</time_frame>
    <description>Assessed through analysis of the worst grade of toxicity/adverse events and will include all participants who received at least one dose of protocol treatment. Adverse events leading to dose interruption, withdrawal of protocol treatment and deaths, laboratory parameters and abnormalities and vital signs over the whole treatment period will be assessed and graded according to CTCAE v5.0 criteria.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">401</enrollment>
  <condition>Pleural Mesothelioma Malignant Advanced</condition>
  <arm_group>
    <arm_group_label>Bevacizumab plus chemotherapy</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Bevacizumab 15mg/kg intravenously on day 1 every 3 weeks plus 4-6 cycles of carboplatin AUC 5 plus pemetrexed 500mg/m^2 intravenously on day 1 every 3 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Atezolizumab plus bevacizumab plus chemotherapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Atezolizumab 1200mg intravenously on day 1 every 3 weeks plus bevacizumab 15mg/kg intravenously on day 1 every 3 weeks plus 4-6 cycles of carboplatin AUC 5 plus pemetrexed 500mg/m^2 intravenously on day 1 every 3 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Carboplatin</intervention_name>
    <description>Carboplatin belongs to the group of medicines known as alkylating agents. Carboplatin interferes with the growth of cancer cells, which eventually are destroyed.</description>
    <arm_group_label>Atezolizumab plus bevacizumab plus chemotherapy</arm_group_label>
    <arm_group_label>Bevacizumab plus chemotherapy</arm_group_label>
    <other_name>Carboplatin Accord</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pemetrexed</intervention_name>
    <description>Pemetrexed is a type of drug known as an anti metabolite. It stops cells making and repairing DNA so they can't grow and multiply.</description>
    <arm_group_label>Atezolizumab plus bevacizumab plus chemotherapy</arm_group_label>
    <arm_group_label>Bevacizumab plus chemotherapy</arm_group_label>
    <other_name>Alimta</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bevacizumab</intervention_name>
    <description>Bevacizumab is an angiogenesis inhibitor. It works by targeting a protein called vascular endothelial growth factor (VEGF) that helps cancers form new blood vessels. By stopping this process, bevacizumab 'suffocates' the blood supply to the cancer, shrinking it and stopping it from growing.</description>
    <arm_group_label>Atezolizumab plus bevacizumab plus chemotherapy</arm_group_label>
    <arm_group_label>Bevacizumab plus chemotherapy</arm_group_label>
    <other_name>Avastin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Atezolizumab</intervention_name>
    <description>Atezolizumab is in a class of medications called monoclonal antibodies. It works by blocking the action of a certain protein in cancer cells. This helps the immune system to fight against the cancer cells, and helps to slow tumor growth.</description>
    <arm_group_label>Atezolizumab plus bevacizumab plus chemotherapy</arm_group_label>
    <other_name>Tecentriq</other_name>
    <other_name>RO5541267</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically confirmed advanced malignant pleural mesothelioma (all histological&#xD;
             subtypes are eligible)&#xD;
&#xD;
          -  Not amenable for radical surgery based on local standards&#xD;
&#xD;
          -  Evaluable disease or measurable disease as assessed according to the modified response&#xD;
             evaluation criteria for solid tumours for mesothelioma (mRECIST) v1.1&#xD;
&#xD;
          -  Availability of tumour tissue for translational research&#xD;
&#xD;
          -  Age &gt;18 years&#xD;
&#xD;
          -  Performance Status 0-1&#xD;
&#xD;
          -  Life expectancy &gt;3 months&#xD;
&#xD;
          -  Adequate haematological, renal and liver function&#xD;
&#xD;
          -  Completed baseline quality of life (QoL) questionnaire&#xD;
&#xD;
          -  Women of childbearing potential and sexually active men must agree to use highly&#xD;
             effective contraception&#xD;
&#xD;
          -  Able to understand and give written informed consent and comply with trial procedures&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior treatment for malignant pleural mesothelioma. Prior radiotherapy for symptom&#xD;
             control is allowed, but the irradiated lesion cannot be used as target lesion. If the&#xD;
             patient has another target lesion, the patient is eligible.&#xD;
&#xD;
          -  Treatment with systemic immune-stimulatory agents within 4 weeks or five half-lives of&#xD;
             the drug prior to randomisation and during protocol treatment.&#xD;
&#xD;
          -  Treatment with systemic immunosuppressive medications within 2 weeks prior to&#xD;
             randomisation and during protocol treatment.&#xD;
&#xD;
          -  Previous allogeneic tissue/solid organ transplant&#xD;
&#xD;
          -  Live vaccines within 4 weeks prior to first dose of protocol treatment&#xD;
&#xD;
          -  Inadequately controlled hypertension&#xD;
&#xD;
          -  Prior history of hypertensive crisis or hypertensive encephalopathy&#xD;
&#xD;
          -  Significant vascular disease within 6 months prior to randomisation&#xD;
&#xD;
          -  History of haemoptysis&#xD;
&#xD;
          -  Evidence of bleeding diathesis or coagulopathy&#xD;
&#xD;
          -  Active autoimmune disease that has required systemic treatment in past 2 years&#xD;
&#xD;
          -  History of active diverticulitis&#xD;
&#xD;
          -  Previous treatment with atezolizumab and/or bevacizumab or parallel participation in&#xD;
             other interventional clinical trial with atezolizumab and/or bevacizumab.&#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>Enriqueta Felip, MD-PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Vall d'Hebron University Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Sanjay Popat, PhD, MBBS</last_name>
    <role>Study Chair</role>
    <affiliation>Royal Marsden NHS Foundation Trust</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University Hospital Leuven</name>
      <address>
        <city>Leuven</city>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU Liege</name>
      <address>
        <city>Liege</city>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Unicancer - Institut Bergonie</name>
      <address>
        <city>Bordeaux</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Caen- CHU</name>
      <address>
        <city>Caen</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Le Mans - CHG</name>
      <address>
        <city>Le Mans</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lyon - Centre Léon Bérard</name>
      <address>
        <city>Lyon</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Nord</name>
      <address>
        <city>Marseille</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Curie Cancer Center Paris</name>
      <address>
        <city>Paris</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Toulouse - CHU</name>
      <address>
        <city>Toulouse</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Tours - CHU</name>
      <address>
        <city>Tours</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>SS Antonio e Biagio e Cesare Arrigo Hospital</name>
      <address>
        <city>Alessandria</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>IRCCS Instituto Tumori Giovanni Paolo II</name>
      <address>
        <city>Bari</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fondazione IRCCS Istituto Nazionale die Tumori</name>
      <address>
        <city>Milan</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Instituto Europeo di Oncologia (IEO)</name>
      <address>
        <city>Milan</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>AULSS2 Marca Trevigiana Treviso</name>
      <address>
        <city>Treviso</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital of Turin</name>
      <address>
        <city>Turin</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Alicante University Hospital ISABIAL</name>
      <address>
        <city>Alicante</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>ICO Hospitalet</name>
      <address>
        <city>Barcelona</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vall Hebron University Hospital/Vall Hebron Institue Oncology</name>
      <address>
        <city>Barcelona</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Puerta de Hierro Hospital</name>
      <address>
        <city>Majadahonda</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Parc Tauli Sabadell</name>
      <address>
        <city>Sabadell</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Virgen del Rocio</name>
      <address>
        <city>Seville</city>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Complexo Hospitalario Universitario de Vigo</name>
      <address>
        <city>Vigo</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>Istituto Oncologica della Svizzera Italiana</name>
      <address>
        <city>Bellinzona</city>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ferdinando Cerciello</name>
      <address>
        <city>Bern</city>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kantonsspital Graubünden</name>
      <address>
        <city>Chur</city>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHUV</name>
      <address>
        <city>Lausanne</city>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Luzerner Kantonsspital</name>
      <address>
        <city>Lucerne</city>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kantonsspital St. Gallen</name>
      <address>
        <city>Saint Gallen</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>UniversitätSpital Zürich</name>
      <address>
        <city>Zürich</city>
        <country>Switzerland</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>Guy's and St Thomas' Hospital</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Marsden Hospital (Fulham Road)</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Marsden Hospital (Sutton)</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kent Oncology Centre</name>
      <address>
        <city>Maidstone</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Wythenshawe Hospital</name>
      <address>
        <city>Manchester</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Plymouth Hospitals NHS Trust</name>
      <address>
        <city>Plymouth</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Weston Park Hospital</name>
      <address>
        <city>Sheffield</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal Cornwall Hospital</name>
      <address>
        <city>Truro</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Belgium</country>
    <country>France</country>
    <country>Italy</country>
    <country>Spain</country>
    <country>Switzerland</country>
    <country>United Kingdom</country>
  </location_countries>
  <removed_countries>
    <country>Portugal</country>
    <country>Slovenia</country>
  </removed_countries>
  <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>Zalcman G, Mazieres J, Margery J, Greillier L, Audigier-Valette C, Moro-Sibilot D, Molinier O, Corre R, Monnet I, Gounant V, Riviere F, Janicot H, Gervais R, Locher C, Milleron B, Tran Q, Lebitasy MP, Morin F, Creveuil C, Parienti JJ, Scherpereel A; French Cooperative Thoracic Intergroup (IFCT). Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet. 2016 Apr 2;387(10026):1405-1414. doi: 10.1016/S0140-6736(15)01238-6. Epub 2015 Dec 21. Erratum In: Lancet. 2016 Apr 2;387(10026):e24.</citation>
    <PMID>26719230</PMID>
  </reference>
  <reference>
    <citation>Ceresoli GL, Zucali PA, Mencoboni M, Botta M, Grossi F, Cortinovis D, Zilembo N, Ripa C, Tiseo M, Favaretto AG, Soto-Parra H, De Vincenzo F, Bruzzone A, Lorenzi E, Gianoncelli L, Ercoli B, Giordano L, Santoro A. Phase II study of pemetrexed and carboplatin plus bevacizumab as first-line therapy in malignant pleural mesothelioma. Br J Cancer. 2013 Aug 6;109(3):552-8. doi: 10.1038/bjc.2013.368. Epub 2013 Jul 16.</citation>
    <PMID>23860535</PMID>
  </reference>
  <reference>
    <citation>Melero I, Berman DM, Aznar MA, Korman AJ, Perez Gracia JL, Haanen J. Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat Rev Cancer. 2015 Aug;15(8):457-72. doi: 10.1038/nrc3973.</citation>
    <PMID>26205340</PMID>
  </reference>
  <reference>
    <citation>Soto-Ortiz L, Finley SD. A cancer treatment based on synergy between anti-angiogenic and immune cell therapies. J Theor Biol. 2016 Apr 7;394:197-211. doi: 10.1016/j.jtbi.2016.01.026. Epub 2016 Jan 27.</citation>
    <PMID>26826488</PMID>
  </reference>
  <reference>
    <citation>Wallin JJ, Bendell JC, Funke R, Sznol M, Korski K, Jones S, Hernandez G, Mier J, He X, Hodi FS, Denker M, Leveque V, Canamero M, Babitski G, Koeppen H, Ziai J, Sharma N, Gaire F, Chen DS, Waterkamp D, Hegde PS, McDermott DF. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat Commun. 2016 Aug 30;7:12624. doi: 10.1038/ncomms12624.</citation>
    <PMID>27571927</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>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>Nowak AK. Chemotherapy for malignant pleural mesothelioma: a review of current management and a look to the future. Ann Cardiothorac Surg. 2012 Nov;1(4):508-15. doi: 10.3978/j.issn.2225-319X.2012.10.05. No abstract available.</citation>
    <PMID>23977545</PMID>
  </reference>
  <reference>
    <citation>Armato SG 3rd, Nowak AK. Revised Modified Response Evaluation Criteria in Solid Tumors for Assessment of Response in Malignant Pleural Mesothelioma (Version 1.1). J Thorac Oncol. 2018 Jul;13(7):1012-1021. doi: 10.1016/j.jtho.2018.04.034. Epub 2018 May 9. Erratum In: J Thorac Oncol. 2019 Mar;14(3):560.</citation>
    <PMID>29753121</PMID>
  </reference>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>November 20, 2018</study_first_submitted>
  <study_first_submitted_qc>November 30, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 3, 2018</study_first_posted>
  <last_update_submitted>April 20, 2023</last_update_submitted>
  <last_update_submitted_qc>April 20, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 21, 2023</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>Bevacizumab</mesh_term>
    <mesh_term>Atezolizumab</mesh_term>
    <mesh_term>Carboplatin</mesh_term>
    <mesh_term>Pemetrexed</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT03762018
org study id: ETOP 13-18
secondary id: 2018-002180-25
secondary id: MO40388
nct id: NCT03762018
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The aim of this clinical trial is to assess the effect of treatment with a monoclonal
      antibody called atezolizumab in patients diagnosed with a type of lung cancer called
      malignant pleural mesothelioma. The efficacy (whether the treatment works), safety and
      tolerability (side effects of treatment) of atezolizumab plus bevacizumab in combination with
      standard chemotherapy versus bevacizumab in combination with standard chemotherapy will be
      investigated.
Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer arising from the
      mesothelial surface of the pleura. In Europe, the incidence is about 20 per million and is
      almost always caused by asbestos exposure, with a usual lag time of 30 years between exposure
      and presentation. Patients diagnosed with advanced MPM have limited treatment options,
      representing a strict unmet need. Despite decades of clinical research, cytotoxic
      chemotherapy remains one of the few therapeutic options that has been proven to improve
      survival in advanced MPM in a randomised controlled trial.

      The combination of cisplatin and pemetrexed has become standard first-line therapy worldwide
      for patients who are not suitable for aggressive surgery or in whom chemotherapy is
      recommended as part of a multimodality regimen. Carboplatin is often substituted for
      cisplatin, due to simpler and shorter administration and assumption of a more favourable
      toxicity profile based on experience in other diseases. Patients with MPM have limited
      treatment options, representing a strict unmet need.

      An antibody is a common type of protein usually made in the body in response to a foreign
      substance. Antibodies attack foreign substances and protect against infection. The two
      monoclonal antibodies (atezolizumab and bevacizumab) used in this trial are
      laboratory-produced antibodies. Atezolizumab is engineered to attach to immune cells to
      stimulate their activity against cancer cells.

      Atezolizumab and bevacizumab are both approved by the European Medicines Agency for the
      treatment of lung and other cancers. The addition of atezolizumab to bevacizumab plus
      standard chemotherapy for the treatment of MPM is being investigated in this trial.

      All participants will receive 4-6 cycles of standard chemotherapy consisting of carboplatin
      AUC 5 (area under the plasma concentration versus time curve) plus pemetrexed 500mg/m^2 given
      intravenously, on day 1 of every 3 week cycle for about 12 to 18 weeks.

      Participants will be randomly assigned to one of two treatment groups:

      Treatment 1

        -  Bevacizumab 15 mg/kg intravenously on day 1 of every 3-week cycle, plus

        -  4-6 cycles of chemotherapy

      OR

      Treatment 2

        -  Atezolizumab 1200 mg fixed dose intravenously on day 1 of every 3-week cycle, plus

        -  Bevacizumab 15 mg/kg, intravenously on day 1 of every 3-week cycle, plus

        -  4-6 cycles of chemotherapy

      Participants will continue to receive treatment until disease progression, or until treatment
      is stopped at the request of the participant or treating doctor, or the participant withdraws
      consent.

      A total of 400 participants from approximately 45 centres in Europe are expected to be
      included in this trial which will take approximately 6 years to be completed after the first
      participant is enrolled.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall Survival (OS)
time frame: From date of randomisation until death from any cause, assessed up to 58 months
description: Overall survival is defined as the time from the date of randomisation until death from any cause. Data for patients who are not reported as having died at the date of analysis will be censored at the date when they were last known to be alive. Data for patients without post-baseline information will be censored at the date of randomization (plus 1 day).
measure: Progression-free Survival (PFS) according to the mRECIST v1.1
time frame: From date of randomisation until documented progression or death, if progression is not documented, assessed up to 58 months
description: PFS is defined as the time from the date of randomisation until documented progression (according to the mRECIST v1.1) or death, if progression is not documented. Censoring (for participants without a PFS/death event) will occur at the date of last tumour assessment. Patients without a post-baseline tumour assessment will be censored at the date of randomization (plus 1 day).
measure: Objective Response Rate (ORR)
time frame: From start of protocol treatment acorss all time-points until end of protocol treatment or, as an alternative approach, until the end of follow-up, assessed up to 58 months
description: Defined as the percentage of patients that achieve a best overall response [complete response (CR) or partial response (PR)] evaluated according to the mRECIST v1.1 across all post-randomization time-points until the end of protocol treatment or, as an alternative approach, until the end of follow-up. Confirmation of response will not be required.
measure: Disease Control (DC) at 24 weeks
time frame: 24 weeks after protocol treatment start
description: Defined as complete or partial response, or disease stabilisation at 24 weeks.
measure: Time to Treatment Failure (TTF)
time frame: From randomisation until discontinuation of protocol treatment for any reason, assessed up to 58 months
description: Defined as the time from the date of randomisation to discontinuation of protocol treatment for any reason (including progression of disease, death, discontinuation of at least one of the drugs consisting the treatment combination due to any reason, such as toxicity or refusal). Censoring will occur at the last follow-up date.
measure: Duration of Response (DoR)
time frame: From date of first documentation of objective response until date of first documented progression/ relapse or death, assessed up to 58 months
description: Defined as the interval from the date of first documentation of objective response (complete response or partial response, according to the mRECIST v1.1) to the date of first documented progression/ relapse or death.
measure: Number of participants with treatment related adverse events according to Common Toxicity Criteria for Adverse Events (CTCAE) v5.0
time frame: Assessed from the date of informed consent until 90 days after protocol treatment discontinuation. Analysed at 58 months after randomisation of the first patient
description: Assessed through analysis of the worst grade of toxicity/adverse events and will include all participants who received at least one dose of protocol treatment. Adverse events leading to dose interruption, withdrawal of protocol treatment and deaths, laboratory parameters and abnormalities and vital signs over the whole treatment period will be assessed and graded according to CTCAE v5.0 criteria.
arm group label: Bevacizumab plus chemotherapy
arm group type: Active Comparator
description: Bevacizumab 15mg/kg intravenously on day 1 every 3 weeks plus 4-6 cycles of carboplatin AUC 5 plus pemetrexed 500mg/m^2 intravenously on day 1 every 3 weeks
arm group label: Atezolizumab plus bevacizumab plus chemotherapy
arm group type: Experimental
description: Atezolizumab 1200mg intravenously on day 1 every 3 weeks plus bevacizumab 15mg/kg intravenously on day 1 every 3 weeks plus 4-6 cycles of carboplatin AUC 5 plus pemetrexed 500mg/m^2 intravenously on day 1 every 3 weeks
intervention type: Drug
intervention name: Carboplatin
description: Carboplatin belongs to the group of medicines known as alkylating agents. Carboplatin interferes with the growth of cancer cells, which eventually are destroyed.
arm group label: Atezolizumab plus bevacizumab plus chemotherapy
arm group label: Bevacizumab plus chemotherapy
other name: Carboplatin Accord
intervention type: Drug
intervention name: Pemetrexed
description: Pemetrexed is a type of drug known as an anti metabolite. It stops cells making and repairing DNA so they can't grow and multiply.
arm group label: Atezolizumab plus bevacizumab plus chemotherapy
arm group label: Bevacizumab plus chemotherapy
other name: Alimta
intervention type: Drug
intervention name: Bevacizumab
description: Bevacizumab is an angiogenesis inhibitor. It works by targeting a protein called vascular endothelial growth factor (VEGF) that helps cancers form new blood vessels. By stopping this process, bevacizumab 'suffocates' the blood supply to the cancer, shrinking it and stopping it from growing.
arm group label: Atezolizumab plus bevacizumab plus chemotherapy
arm group label: Bevacizumab plus chemotherapy
other name: Avastin
intervention type: Drug
intervention name: Atezolizumab
description: Atezolizumab is in a class of medications called monoclonal antibodies. It works by blocking the action of a certain protein in cancer cells. This helps the immune system to fight against the cancer cells, and helps to slow tumor growth.
arm group label: Atezolizumab plus bevacizumab plus chemotherapy
other name: Tecentriq
other name: RO5541267
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Enriqueta Felip, MD-PhD
role: Study Chair
affiliation: Vall d'Hebron University Hospital
last name: Sanjay Popat, PhD, MBBS
role: Study Chair
affiliation: Royal Marsden NHS Foundation Trust
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Belgium
country: France
country: Italy
country: Spain
country: Switzerland
country: United Kingdom
country: Portugal
country: Slovenia
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: Zalcman G, Mazieres J, Margery J, Greillier L, Audigier-Valette C, Moro-Sibilot D, Molinier O, Corre R, Monnet I, Gounant V, Riviere F, Janicot H, Gervais R, Locher C, Milleron B, Tran Q, Lebitasy MP, Morin F, Creveuil C, Parienti JJ, Scherpereel A; French Cooperative Thoracic Intergroup (IFCT). Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet. 2016 Apr 2;387(10026):1405-1414. doi: 10.1016/S0140-6736(15)01238-6. Epub 2015 Dec 21. Erratum In: Lancet. 2016 Apr 2;387(10026):e24.
PMID: 26719230
citation: Ceresoli GL, Zucali PA, Mencoboni M, Botta M, Grossi F, Cortinovis D, Zilembo N, Ripa C, Tiseo M, Favaretto AG, Soto-Parra H, De Vincenzo F, Bruzzone A, Lorenzi E, Gianoncelli L, Ercoli B, Giordano L, Santoro A. Phase II study of pemetrexed and carboplatin plus bevacizumab as first-line therapy in malignant pleural mesothelioma. Br J Cancer. 2013 Aug 6;109(3):552-8. doi: 10.1038/bjc.2013.368. Epub 2013 Jul 16.
PMID: 23860535
citation: Melero I, Berman DM, Aznar MA, Korman AJ, Perez Gracia JL, Haanen J. Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat Rev Cancer. 2015 Aug;15(8):457-72. doi: 10.1038/nrc3973.
PMID: 26205340
citation: Soto-Ortiz L, Finley SD. A cancer treatment based on synergy between anti-angiogenic and immune cell therapies. J Theor Biol. 2016 Apr 7;394:197-211. doi: 10.1016/j.jtbi.2016.01.026. Epub 2016 Jan 27.
PMID: 26826488
citation: Wallin JJ, Bendell JC, Funke R, Sznol M, Korski K, Jones S, Hernandez G, Mier J, He X, Hodi FS, Denker M, Leveque V, Canamero M, Babitski G, Koeppen H, Ziai J, Sharma N, Gaire F, Chen DS, Waterkamp D, Hegde PS, McDermott DF. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat Commun. 2016 Aug 30;7:12624. doi: 10.1038/ncomms12624.
PMID: 27571927
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: 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: Nowak AK. Chemotherapy for malignant pleural mesothelioma: a review of current management and a look to the future. Ann Cardiothorac Surg. 2012 Nov;1(4):508-15. doi: 10.3978/j.issn.2225-319X.2012.10.05. No abstract available.
PMID: 23977545
citation: Armato SG 3rd, Nowak AK. Revised Modified Response Evaluation Criteria in Solid Tumors for Assessment of Response in Malignant Pleural Mesothelioma (Version 1.1). J Thorac Oncol. 2018 Jul;13(7):1012-1021. doi: 10.1016/j.jtho.2018.04.034. Epub 2018 May 9. Erratum In: J Thorac Oncol. 2019 Mar;14(3):560.
PMID: 29753121
responsible party type: Sponsor
mesh term: Mesothelioma
mesh term: Mesothelioma, Malignant
mesh term: Bevacizumab
mesh term: Atezolizumab
mesh term: Carboplatin
mesh term: Pemetrexed
sharing ipd: No