<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/NCT02968303</url>
  </required_header>
  <id_info>
    <org_study_id>MOMEL27 - COWBOY</org_study_id>
    <nct_id>NCT02968303</nct_id>
  </id_info>
  <brief_title>Induction Therapy With Vemurafenib and Cobimetinib to Optimize Nivolumab and Ipilimumab Therapy</brief_title>
  <acronym>COWBOY</acronym>
  <official_title>Phase 2 Study With COmbination of Vemurafenib With Cobimetinib in B-RAF V600E/K Mutated Melanoma Patients to Normalize LDH and Optimize Nivolumab and Ipilimumab therapY</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Radboud University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>The Netherlands Cancer Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Isala</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Radboud University Medical Center</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>
      Rationale:&#xD;
&#xD;
      The combination of ipilimumab and nivolumab induces relatively high response rates and&#xD;
      promising response depth in late stage melanoma. Nevertheless, it takes time till responses&#xD;
      occur and still a significant number of patients do not benefit from treatment, due to rapid&#xD;
      progressive disease or resistance to therapy.&#xD;
&#xD;
      In contrast to immunotherapies targeted therapies (BRAF or MEK inhibitors), can induce faster&#xD;
      and higher response rates, but often of shorter duration, even when combined.&#xD;
&#xD;
      Initial attempts of combining vemurafenib or dabrafenib + trametinib with ipilimumab failed&#xD;
      due to toxicity.&#xD;
&#xD;
      Patients with elevated levels of serum LDH are less likely to respond to immunotherapy&#xD;
      compared to patients with normal LDH levels. This does not mean that such patients do not&#xD;
      benefit at all from immunotherapy.&#xD;
&#xD;
      This raises the question, whether response rates upon immunotherapy can be improved by&#xD;
      upfront reduction of tumor burden and normalization of LDH.&#xD;
&#xD;
      The investigators postulate that induction therapy with combined BRAF+MEK inhibition, and&#xD;
      subsequent LDH normalization, can improve response rates to the rates seen in LDH normal&#xD;
      patients.&#xD;
&#xD;
      To address this question the investigators have setup a randomized phase 2 trial in&#xD;
      metastatic melanoma patients with elevated serum LDH comparing the response rates upon&#xD;
      ipilimumab + nivolumab versus ipilimumab + nivolumab preceded by 6 weeks of vemurafenib +&#xD;
      cobimetinib induction.&#xD;
&#xD;
      Furthermore, less than half of the patients treated with the combination of ipilimumab and&#xD;
      nivolumab received maintenance nivolumab, and approximately 40% of all patients discontinued&#xD;
      treatment for toxicity. In 70% of patients responses were ongoing despite discontinuation of&#xD;
      treatment due to toxicity. This raises the question, to what extent does maintenance therapy&#xD;
      add clinical benefit to an ongoing immune response. Preclinical data indicate even that&#xD;
      continuous restimulation of T cells can result in activation induced non-responsiveness&#xD;
      (anergy).&#xD;
&#xD;
      Therefore, a secondary objective of this trial will be, to test a response-driven nivolumab&#xD;
      scheme&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      Primary Objective • To compare efficacy of induction vemurafenib + cobimetinib followed by&#xD;
      ipilimumab + nivolumab (Arm A) versus upfront ipilimumab + nivolumab treatment (Arm B).&#xD;
&#xD;
      Secondary Objectives&#xD;
&#xD;
        -  To describe duration of response and overall survival induced by vemurafenib +&#xD;
           cobimetinib followed by the combination of ipilimumab + nivolumab (Arm A) as compared to&#xD;
           ipilimumab + nivolumab (Arm B)&#xD;
&#xD;
        -  To describe the rate and quality of toxicity observed in the two study arms&#xD;
&#xD;
        -  To describe the rate of ongoing responses upon response-driven flat dose (240mg q2w or&#xD;
           480mg q4w) nivolumab maintenance&#xD;
&#xD;
        -  To determine the immune-activating capacity of induction therapy with vemurafenib +&#xD;
           cobimetinib followed by the combination of ipilimumab + nivolumab.&#xD;
&#xD;
        -  To evaluate the changes in systemic immune competence&#xD;
&#xD;
      Study design:&#xD;
&#xD;
      This is a two-arm phase 2 study consisting of 200 BRAFV600E/K mutation-positive late-stage&#xD;
      melanoma patients with an elevated baseline LDH level (&gt; ULN, &lt; 3xULN) randomized 1:1&#xD;
      (stratified according to LDH) to receive either vemurafenib + cobimetinib directly followed&#xD;
      by ipilimumab + nivolumab (Arm A) or standard first line ipilimumab + nivolumab (Arm B).&#xD;
      Subsequently, patients in both arms will receive flat dose (240mg q2w or 480mg q4w) nivolumab&#xD;
      maintenance in a response-driven manner.&#xD;
&#xD;
      Study population:&#xD;
&#xD;
      Stage IV, or unresectable stage III, BRAFV600E/K mutation positive melanoma patients, naïve&#xD;
      for BRAF/MEK, PD-1/PD-L1 or CTLA-4 targeting therapy, 18 years and older.&#xD;
&#xD;
      Intervention:&#xD;
&#xD;
      Patients will be randomized 1:1 to receive either 6 weeks vemurafenib 960 mg bid +&#xD;
      cobimetinib 60 mg QD 21-day on, 7-day off (21/7) schedule, directly followed by 4 courses of&#xD;
      ipilimumab 3mg/kg q3wk + nivolumab 1mg/kg q3wk (Arm A) or first line standard 4 courses of&#xD;
      ipilimumab 3mg/kg q3wk + nivolumab 1mg/kg q3wk (Arm B).&#xD;
&#xD;
      Subsequently, patients in both arms will receive nivolumab maintenance flat dose (240mg q2w&#xD;
      or 480mg q4w) in a response-driven manner according to their response at week 18.&#xD;
&#xD;
      Main study parameters/endpoints:&#xD;
&#xD;
      Primary Endpoints&#xD;
&#xD;
      • Compare the best overall response rate (BORR) according to RECIST 1.1 of both arms at week&#xD;
      18 from start of treatment.&#xD;
&#xD;
      Secondary Endpoints&#xD;
&#xD;
        -  Progression-free survival (PFS) according to RECIST 1.1&#xD;
&#xD;
        -  Overall survival (OS)&#xD;
&#xD;
        -  Percentage of grade 3/4 toxicities according to CTCv4.03&#xD;
&#xD;
        -  Percentage of ongoing response, percentage of patients requiring re-induction, response&#xD;
           percentage upon re-induction&#xD;
&#xD;
        -  Changes in tumor-specific T cell responses&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">January 27, 2017</start_date>
  <completion_date type="Anticipated">October 2023</completion_date>
  <primary_completion_date type="Anticipated">October 2022</primary_completion_date>
  <phase>Phase 2</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>Best overall response rate (BORR) according to RECIST 1.1</measure>
    <time_frame>Week 18 from start of treatment</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS) according to RECIST 1.1</measure>
    <time_frame>1 and 2 years from start of treatment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>1 and 2 years from start of treatment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Grade 3/4 toxicities according to CTCv4.03</measure>
    <time_frame>Week 18 from start of treatment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of ongoing response</measure>
    <time_frame>1 and 2 years from start of treatment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Response percentage upon re-induction</measure>
    <time_frame>Week 18 from start of treatment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in tumor-specific T cell responses</measure>
    <time_frame>Week 18 from start of treatment</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">200</enrollment>
  <condition>Melanoma, Malignant, of Soft Parts</condition>
  <arm_group>
    <arm_group_label>Induction treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Induction vemurafenib and cobimetinib (6 weeks) directly followed by ipilimumab and nivolumab</description>
  </arm_group>
  <arm_group>
    <arm_group_label>No induction treatment</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Upfront ipilimumab and nivolumab without induction by vemurafenib and cobimetinib</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vemurafenib and Cobimetinib</intervention_name>
    <description>Combination of Vemurafenib with Cobimetinib in BRAF V600E/K mutated melanoma patients to normalize LDH and optimize immunotherapy with Nivolumab and Ipilimumab</description>
    <arm_group_label>Induction treatment</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adults 18 years and older&#xD;
&#xD;
          -  World Health Organization (WHO) Performance Status 0-2&#xD;
&#xD;
          -  Histologically or cytologically confirmed Stage IV, or unresectable stage III, BRAF&#xD;
             V600E/K mutated melanoma&#xD;
&#xD;
          -  Measurable disease according to RECIST 1.1&#xD;
&#xD;
          -  Signed and dated informed consent form&#xD;
&#xD;
          -  No prior immunotherapy targeting CTLA-4, PD-1 or PD-L1&#xD;
&#xD;
          -  No prior BRAFi and/ or MEKi therapy&#xD;
&#xD;
          -  No immunosuppressive medications&#xD;
&#xD;
          -  Screening laboratory values must meet the following criteria and should be obtained&#xD;
             within 10 days prior to randomization:&#xD;
&#xD;
               -  WBC ≥ 2.0x109/L, Neutrophils ≥ 1.0x109/L, Platelets ≥ 100 x109/L, Hemoglobin ≥&#xD;
                  5.0 mmol/L&#xD;
&#xD;
               -  Creatinine ≤ 2x ULN or creatinine clearance (CrCl) ≥ 40 ml/min&#xD;
&#xD;
               -  AST, ALT ≤ 3.0 x ULN (≤5 x ULN for patients with liver metastases)&#xD;
&#xD;
               -  Bilirubin ≤ 2.0 x ULN (except subjects with Gilbert Syndrome, who can have total&#xD;
                  bilirubin &lt; 3.0 mg/dL )&#xD;
&#xD;
               -  LDH &gt; ULN, &lt; 5.0 x ULN&#xD;
&#xD;
          -  No symptomatic brain metastases (asysmptomatic brain metastases, accidentally found&#xD;
             during screening can be included)&#xD;
&#xD;
          -  No leptomeningeal metastases&#xD;
&#xD;
          -  No active autoimmune disease requiring systemic treatment in the past 3 months or a&#xD;
             documented history of autoimmune disease, or history of syndrome that required&#xD;
             systemic steroids, at daily dose of ≥10mg prednisone or equivalent, or&#xD;
             immunosuppressive medications. (Subjects with vitiligo or resolved childhood&#xD;
             asthma/atopy are excluded from this rule (and will not be excluded from this study).&#xD;
             Subjects that require intermittent use of bronchodilators or local steroid injections&#xD;
             would not be excluded from the study. Subjects with hypothyroidism stable on hormone&#xD;
             replacement or Sjorgen's syndrome will not be excluded from the study.)&#xD;
&#xD;
          -  No evidence of interstitial lung disease or active, non-infectious pneumonitis&#xD;
&#xD;
          -  No active infection requiring therapy&#xD;
&#xD;
          -  No known additional malignancy that is progressing or requires active treatment&#xD;
&#xD;
          -  Women of childbearing potential (WOCBP) must use appropriate method(s) of&#xD;
             contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30&#xD;
             days + the time required for nivolumab to undergo five half-lives) after the last dose&#xD;
             of study medication&#xD;
&#xD;
          -  WOBCP must have a negative serum or urine pregnancy test within 96 hours prior to the&#xD;
             start of study treatment and must not be breast feeding&#xD;
&#xD;
          -  Men must agree to the use of male contraception during the study treatment period and&#xD;
             for at least 31 weeks after the last dose of study drug.&#xD;
&#xD;
          -  Currently not participating in a study of an investigational agent or using an&#xD;
             investigational device within 4 weeks of the first dose of treatment.&#xD;
&#xD;
          -  No underlying medical conditions that, in the Investigator's opinion, will make the&#xD;
             administration of study drug hazardous or obscure the interpretation of toxicity&#xD;
             determination or adverse events&#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_contact>
    <last_name>Rutger HT Koornstra, MD</last_name>
    <phone>+31243610354</phone>
    <email>Rutger.Koornstra@radboudumc.nl</email>
  </overall_contact>
  <location>
    <facility>
      <name>The Netherlands Cancer Institute</name>
      <address>
        <city>Amsterdam</city>
        <zip>1066 CX</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Christian U Blank, Prof MD PhD</last_name>
      <phone>+31205129111</phone>
      <email>c.blank@nki.nl</email>
    </contact>
    <investigator>
      <last_name>Christian U Blank, Prof MD PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Vrije Universiteit Medisch Centrum</name>
      <address>
        <city>Amsterdam</city>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Fons van den Eertwegh, MD, PhD</last_name>
      <phone>020 4444336</phone>
      <email>vandeneertwegh@vumc.nl</email>
    </contact>
    <investigator>
      <last_name>Fons van den Eertwegh, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Amphia Ziekenhuis Breda</name>
      <address>
        <city>Breda</city>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>ten Tije, MD, PhD</last_name>
      <phone>076 595 5000</phone>
      <email>AtenTije@amphia.nl</email>
    </contact>
    <investigator>
      <last_name>ten Tije, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Maxima MC</name>
      <address>
        <city>Eindhoven</city>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Vreugdenhil, MD, PhD</last_name>
      <phone>040 888 6130</phone>
      <email>g.vreugdenhil@mmc.nl</email>
    </contact>
    <investigator>
      <last_name>Vreugdenhil, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Medisch Spectrum Twente</name>
      <address>
        <city>Enschede</city>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Djura Piersma, MD, PhD</last_name>
      <phone>0534872440</phone>
      <email>d.piersma@mst.nl</email>
    </contact>
    <investigator>
      <last_name>Djura Piersma, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Universitair Medisch Centrum Groningen</name>
      <address>
        <city>Groningen</city>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Hilde Jalving, MD, PhD</last_name>
      <phone>050 361 6161</phone>
      <email>m.jalving@umcg.nl</email>
    </contact>
    <investigator>
      <last_name>Hilde Jalving, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Zuyderland Medisch Centrum Heerlen</name>
      <address>
        <city>Heerlen</city>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Franchette van den Berkmortel, MD, PhD</last_name>
      <phone>045 576 6666</phone>
      <email>f.vandenberkmortel@zuyderland.nl</email>
    </contact>
    <investigator>
      <last_name>Franchette van den Berkmortel, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Leids Universitair Medisch Centrum</name>
      <address>
        <city>Leiden</city>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ellen Kapiteijn, MD, PhD</last_name>
      <phone>071 526 91 11</phone>
      <email>H.W.Kapiteijn@lumc.nl</email>
    </contact>
    <investigator>
      <last_name>Ellen Kapiteijn, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Maastricht UMC+</name>
      <address>
        <city>Maastricht</city>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Maureen Aarts, MD, PhD</last_name>
      <phone>043 387 65 43</phone>
      <email>mjb.essers.aarts@mumc.nl</email>
    </contact>
    <investigator>
      <last_name>Maureen Aarts, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Radboudumc</name>
      <address>
        <city>Nijmegen</city>
        <zip>6525GA</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Rutger HT Koornstra, MD</last_name>
      <phone>+31243610354</phone>
      <email>Rutger.Koornstra@radboudumc.nl</email>
    </contact>
    <contact_backup>
      <last_name>Hettie Maters, MSc</last_name>
      <phone>+31243655388</phone>
      <email>studies.onco@radboudumc.nl</email>
    </contact_backup>
    <investigator>
      <last_name>Rutger HT Koornstra, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Erasmus MC</name>
      <address>
        <city>Rotterdam</city>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Wim Kruijt, MD, PhD</last_name>
      <phone>010 704 07 04</phone>
      <email>w.kruit@erasmusmc.nl</email>
    </contact>
    <investigator>
      <last_name>Wim Kruijt, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>UMC Utrecht</name>
      <address>
        <city>Utrecht</city>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Karijn Suijkerbuijk, MD, PhD</last_name>
      <phone>088 7555555</phone>
      <email>K.Suijkerbuijk@umcutrecht.nl</email>
    </contact>
    <investigator>
      <last_name>K.Suijkerbuijk@umcutrecht.nl Suijkerbuijk, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Isala</name>
      <address>
        <city>Zwolle</city>
        <zip>8025 AB</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Johannes WB de Groot, MD PhD</last_name>
      <phone>+31384245000</phone>
      <email>j.w.b.de.groot@isala.nl</email>
    </contact>
    <investigator>
      <last_name>Johannes WB de Groot, MD PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>November 11, 2016</study_first_submitted>
  <study_first_submitted_qc>November 15, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 18, 2016</study_first_posted>
  <last_update_submitted>June 3, 2020</last_update_submitted>
  <last_update_submitted_qc>June 3, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">June 5, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Radboud University Medical Center</investigator_affiliation>
    <investigator_full_name>Rutger Koornstra</investigator_full_name>
    <investigator_title>Medical Oncologist</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Melanoma</mesh_term>
    <mesh_term>Sarcoma, Clear Cell</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vemurafenib</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT02968303
org study id: MOMEL27 - COWBOY
nct id: NCT02968303
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Rationale:

      The combination of ipilimumab and nivolumab induces relatively high response rates and
      promising response depth in late stage melanoma. Nevertheless, it takes time till responses
      occur and still a significant number of patients do not benefit from treatment, due to rapid
      progressive disease or resistance to therapy.

      In contrast to immunotherapies targeted therapies (BRAF or MEK inhibitors), can induce faster
      and higher response rates, but often of shorter duration, even when combined.

      Initial attempts of combining vemurafenib or dabrafenib + trametinib with ipilimumab failed
      due to toxicity.

      Patients with elevated levels of serum LDH are less likely to respond to immunotherapy
      compared to patients with normal LDH levels. This does not mean that such patients do not
      benefit at all from immunotherapy.

      This raises the question, whether response rates upon immunotherapy can be improved by
      upfront reduction of tumor burden and normalization of LDH.

      The investigators postulate that induction therapy with combined BRAF+MEK inhibition, and
      subsequent LDH normalization, can improve response rates to the rates seen in LDH normal
      patients.

      To address this question the investigators have setup a randomized phase 2 trial in
      metastatic melanoma patients with elevated serum LDH comparing the response rates upon
      ipilimumab + nivolumab versus ipilimumab + nivolumab preceded by 6 weeks of vemurafenib +
      cobimetinib induction.

      Furthermore, less than half of the patients treated with the combination of ipilimumab and
      nivolumab received maintenance nivolumab, and approximately 40% of all patients discontinued
      treatment for toxicity. In 70% of patients responses were ongoing despite discontinuation of
      treatment due to toxicity. This raises the question, to what extent does maintenance therapy
      add clinical benefit to an ongoing immune response. Preclinical data indicate even that
      continuous restimulation of T cells can result in activation induced non-responsiveness
      (anergy).

      Therefore, a secondary objective of this trial will be, to test a response-driven nivolumab
      scheme

      Objectives:

      Primary Objective • To compare efficacy of induction vemurafenib + cobimetinib followed by
      ipilimumab + nivolumab (Arm A) versus upfront ipilimumab + nivolumab treatment (Arm B).

      Secondary Objectives

        -  To describe duration of response and overall survival induced by vemurafenib +
           cobimetinib followed by the combination of ipilimumab + nivolumab (Arm A) as compared to
           ipilimumab + nivolumab (Arm B)

        -  To describe the rate and quality of toxicity observed in the two study arms

        -  To describe the rate of ongoing responses upon response-driven flat dose (240mg q2w or
           480mg q4w) nivolumab maintenance

        -  To determine the immune-activating capacity of induction therapy with vemurafenib +
           cobimetinib followed by the combination of ipilimumab + nivolumab.

        -  To evaluate the changes in systemic immune competence

      Study design:

      This is a two-arm phase 2 study consisting of 200 BRAFV600E/K mutation-positive late-stage
      melanoma patients with an elevated baseline LDH level (> ULN, < 3xULN) randomized 1:1
      (stratified according to LDH) to receive either vemurafenib + cobimetinib directly followed
      by ipilimumab + nivolumab (Arm A) or standard first line ipilimumab + nivolumab (Arm B).
      Subsequently, patients in both arms will receive flat dose (240mg q2w or 480mg q4w) nivolumab
      maintenance in a response-driven manner.

      Study population:

      Stage IV, or unresectable stage III, BRAFV600E/K mutation positive melanoma patients, naïve
      for BRAF/MEK, PD-1/PD-L1 or CTLA-4 targeting therapy, 18 years and older.

      Intervention:

      Patients will be randomized 1:1 to receive either 6 weeks vemurafenib 960 mg bid +
      cobimetinib 60 mg QD 21-day on, 7-day off (21/7) schedule, directly followed by 4 courses of
      ipilimumab 3mg/kg q3wk + nivolumab 1mg/kg q3wk (Arm A) or first line standard 4 courses of
      ipilimumab 3mg/kg q3wk + nivolumab 1mg/kg q3wk (Arm B).

      Subsequently, patients in both arms will receive nivolumab maintenance flat dose (240mg q2w
      or 480mg q4w) in a response-driven manner according to their response at week 18.

      Main study parameters/endpoints:

      Primary Endpoints

      • Compare the best overall response rate (BORR) according to RECIST 1.1 of both arms at week
      18 from start of treatment.

      Secondary Endpoints

        -  Progression-free survival (PFS) according to RECIST 1.1

        -  Overall survival (OS)

        -  Percentage of grade 3/4 toxicities according to CTCv4.03

        -  Percentage of ongoing response, percentage of patients requiring re-induction, response
           percentage upon re-induction

        -  Changes in tumor-specific T cell responses
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Best overall response rate (BORR) according to RECIST 1.1
time frame: Week 18 from start of treatment
measure: Progression-free survival (PFS) according to RECIST 1.1
time frame: 1 and 2 years from start of treatment
measure: Overall survival (OS)
time frame: 1 and 2 years from start of treatment
measure: Grade 3/4 toxicities according to CTCv4.03
time frame: Week 18 from start of treatment
measure: Percentage of ongoing response
time frame: 1 and 2 years from start of treatment
measure: Response percentage upon re-induction
time frame: Week 18 from start of treatment
measure: Changes in tumor-specific T cell responses
time frame: Week 18 from start of treatment
arm group label: Induction treatment
arm group type: Experimental
description: Induction vemurafenib and cobimetinib (6 weeks) directly followed by ipilimumab and nivolumab
arm group label: No induction treatment
arm group type: No Intervention
description: Upfront ipilimumab and nivolumab without induction by vemurafenib and cobimetinib
intervention type: Drug
intervention name: Vemurafenib and Cobimetinib
description: Combination of Vemurafenib with Cobimetinib in BRAF V600E/K mutated melanoma patients to normalize LDH and optimize immunotherapy with Nivolumab and Ipilimumab
arm group label: Induction treatment
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Rutger HT Koornstra, MD
phone: +31243610354
email: Rutger.Koornstra@radboudumc.nl
facility: 
status: Recruiting
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status: Not yet recruiting
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country: Netherlands
responsible party type: Principal Investigator
investigator affiliation: Radboud University Medical Center
investigator full name: Rutger Koornstra
investigator title: Medical Oncologist
mesh term: Melanoma
mesh term: Sarcoma, Clear Cell
mesh term: Vemurafenib
sharing ipd: Undecided