<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/NCT02977052</url>
  </required_header>
  <id_info>
    <org_study_id>M16OPN</org_study_id>
    <secondary_id>2016-001984-35</secondary_id>
    <secondary_id>CA209-701</secondary_id>
    <nct_id>NCT02977052</nct_id>
  </id_info>
  <brief_title>Optimal Neo-adjuvant Combination Scheme of Ipilimumab and Nivolumab</brief_title>
  <acronym>OpACIN-neo</acronym>
  <official_title>Multicenter Phase 2 Study to Identify of the Optimal Neo-Adjuvant Combination Scheme of Ipilimumab and Nivolumab (OpACIN-neo)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The Netherlands Cancer Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>The Netherlands Cancer Institute</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is an open-label three-arm phase 2 trial (including a Simon stage 2 design) consisting&#xD;
      of 90 stage III melanoma patients randomized 1:1:1 to receive either 2 courses 3 mg/kg&#xD;
      ipilimumab + 1 mg/kg nivolumab every 3 weeks (Arm A), 2 courses 1 mg/kg ipilimumab + 3 mg/kg&#xD;
      nivolumab every 3 weeks (Arm B), or 2 courses ipilimumab 3 mg/kg, directly followed by 2&#xD;
      courses nivolumab 3 mg/kg every 2 weeks (Arm C). All three treatment arms are applied prior&#xD;
      to surgery at week 6, 30 patients per arm. Patients will be stratified according to treatment&#xD;
      center. An interim analysis will be performed after 13 patients have been included in each&#xD;
      arm, thus in total 39 patients have been included.&#xD;
&#xD;
      PRADO extension cohort The trial will enroll in total about 100-110 melanoma patients with&#xD;
      macroscopic stage III disease (RECIST measurable disease); inclusion will stop when 50&#xD;
      patients have achieved a pCR or pnCR. All patients will be treated (after marker placement&#xD;
      into the largest lymph node metastasis) with the winner combination identified in the first&#xD;
      part of the OpACIN-neo study which is 2 courses ipilimumab 1mg/kg + nivolumab 3mg/kg, q3wks.&#xD;
      After 6 weeks of treatment, the patients will undergo only surgical resection of the marked&#xD;
      index lymph node. Thereafter subsequent surgery and adjuvant therapy will be performed&#xD;
      according to the achieved pathologic response.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">November 2016</start_date>
  <completion_date type="Anticipated">June 2025</completion_date>
  <primary_completion_date type="Actual">January 3, 2020</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safety as measured by the frequency of grade 3/4 immune-related adverse events, using CTCAE 4.03</measure>
    <time_frame>During the first 12 weeks.</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Response rate according to RECIST 1.1</measure>
    <time_frame>At 6 weeks</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Pathological response according to central pathological revision, according to pathological response criteria</measure>
    <time_frame>At 6 weeks</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Pathologic response rate according to central revision of the marked index lymph node</measure>
    <time_frame>At 6 weeks, prior surgery</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>RFS at 24 months in patients achieving pCR or pnCR in their marked index lymph node and did not undergo CLND. RFS will be calculated from date of resection of the marked lymph node.</measure>
    <time_frame>24 months</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>RFS at 24 months in patients with pNR and being subsequently treated with adjuvant nivolumab+optional radiotherapy (or dabrafenib/trametinib if BRAFV600E pos. and treatment is approved). RFS will be calculated from day of resection of marked lymph node.</measure>
    <time_frame>24 months</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Recurrence Free Survival</measure>
    <time_frame>3 years after treatment initiation</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Description of late adverse events using CTCAE 4.03</measure>
    <time_frame>Up to 3 years after treatment initiation until new treatment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Description of associations of mutational load, RNA tumor signatures, and tumor educated platelet signatures with tumor immune infiltrates and response</measure>
    <time_frame>At 6 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Response rate according to RECIST 1.1 at week 6</measure>
    <time_frame>At 6 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>RFS at 2, 3 and 5 years</measure>
    <time_frame>Up to 5 years after treatment</time_frame>
  </secondary_outcome>
  <other_outcome>
    <measure>EFS at 2, 3 and 5 years</measure>
    <time_frame>Up to 5 years after treatment</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>DMFS at 2, 3 and 5 years</measure>
    <time_frame>Up to 5 years after treatment</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>OS at 2, 3 and 5 years</measure>
    <time_frame>Up to 5 years after treatment</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Grade 3/4 immune-related adverse event rate according to CTCAE v4.03 within the first 12 weeks</measure>
    <time_frame>At 12 weeks</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>• Surgical complication rates according to Clavien-Dindo surgical classification of only marked index lymph node resection vs. CLND</measure>
    <time_frame>At 12 weeks</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>• Description of late adverse event (up to 3 years after treatment initiation) according to CTCAE v4.03</measure>
    <time_frame>Up to 3 years after treatment</time_frame>
  </other_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">186</enrollment>
  <condition>Malignant Melanoma Stage III</condition>
  <arm_group>
    <arm_group_label>Arm A: 2 courses ipi 3 + nivo 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive 2 courses standard combination of ipilimumab 3 mg/kg + nivolumab 1 mg/kg q3wk prior to surgery at week 6. Blood for PBMCs and biopsies will be taken for translation research.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm B: 2 courses ipi 1 + nivo 3</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive 2 courses ipilimumab 1 mg/kg + nivolumab 3 mg/kg q3wk prior to surgery at week 6. Blood for PBMCs and biopsies will be taken for translation research.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm C: 2 courses ipi 3 + 2 courses nivo 3</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive 2 courses of ipilimumab 3 mg/kg q3wks, directly followed (&gt; 2 hours and &lt; 24 hours) by 2 courses nivolumab 3 mg/kg every 2 weeks prior to surgery at week 6. Blood for PBMCs and biopsies will be taken for translation research.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>PRADO extension cohort</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will be treated with 2 courses ipilimumab and nivolumab at the dose level defined as the winner dosing scheme from OpACIN-neo, which is the dosing schedule of arm B.&#xD;
Surgery and adjuvant therapy&#xD;
Patients achieving a pCR or pnCR will not undergo CLND and will not receive any adjuvant treatment. Structural follow-up will be perfomed every 12 weeks by CT, ultrasound of regional lymph nodes.&#xD;
Patients achieving a pPR will undergo CLND and start structural follow-up (including CT and physical examination) every 12 weeks thereafter without any adjuvant treatment.&#xD;
Patients achieving no response (pNR) will undergo CLND and start at week 12 with adjuvant nivolumab 480mg q4wks for 52 weeks + radiotherapy (according to patient's and physicians' decision). In patients that are BRAF V600E/K mutation positive, adjuvant BRAF+MEK</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ipilimumab</intervention_name>
    <arm_group_label>Arm A: 2 courses ipi 3 + nivo 1</arm_group_label>
    <arm_group_label>Arm B: 2 courses ipi 1 + nivo 3</arm_group_label>
    <arm_group_label>Arm C: 2 courses ipi 3 + 2 courses nivo 3</arm_group_label>
    <arm_group_label>PRADO extension cohort</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <arm_group_label>Arm A: 2 courses ipi 3 + nivo 1</arm_group_label>
    <arm_group_label>Arm B: 2 courses ipi 1 + nivo 3</arm_group_label>
    <arm_group_label>Arm C: 2 courses ipi 3 + 2 courses nivo 3</arm_group_label>
    <arm_group_label>PRADO extension cohort</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Surgery</intervention_name>
    <description>Surgery will be done at 6 weeks</description>
    <arm_group_label>Arm A: 2 courses ipi 3 + nivo 1</arm_group_label>
    <arm_group_label>Arm B: 2 courses ipi 1 + nivo 3</arm_group_label>
    <arm_group_label>Arm C: 2 courses ipi 3 + 2 courses nivo 3</arm_group_label>
    <arm_group_label>PRADO extension cohort</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Blood for PBMCs</intervention_name>
    <description>Blood will be taken for translational research on PBMCs</description>
    <arm_group_label>Arm A: 2 courses ipi 3 + nivo 1</arm_group_label>
    <arm_group_label>Arm B: 2 courses ipi 1 + nivo 3</arm_group_label>
    <arm_group_label>Arm C: 2 courses ipi 3 + 2 courses nivo 3</arm_group_label>
    <arm_group_label>PRADO extension cohort</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Biopsies</intervention_name>
    <description>Biopsies will be taken during screening and at relapse.</description>
    <arm_group_label>Arm A: 2 courses ipi 3 + nivo 1</arm_group_label>
    <arm_group_label>Arm B: 2 courses ipi 1 + nivo 3</arm_group_label>
    <arm_group_label>Arm C: 2 courses ipi 3 + 2 courses nivo 3</arm_group_label>
    <arm_group_label>PRADO extension cohort</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adults at least 18 years of age&#xD;
&#xD;
          -  World Health Organization (WHO) Performance Status 0 or 1&#xD;
&#xD;
          -  Cytologically or histologically confirmed resectable stage III melanoma with one or&#xD;
             more macroscopic lymph node metastases (measurable according to RECIST 1.1), that can&#xD;
             be biopsied, and no history of in-transit metastases within the last 6 months&#xD;
&#xD;
          -  No other malignancies, except adequately treated and a cancer-related life-expectancy&#xD;
             of more than 5 years&#xD;
&#xD;
          -  Patient willing to undergo triple tumor biopsies and extra blood withdrawal during&#xD;
             screening and in case of relapse&#xD;
&#xD;
          -  No prior immunotherapy targeting CTLA-4, PD-1 or PD-L1&#xD;
&#xD;
          -  No immunosuppressive medications within 6 months prior study inclusion&#xD;
&#xD;
          -  Screening laboratory values must meet the following criteria: WBC ≥ 2.0x109/L,&#xD;
             Neutrophils ≥1.5x109/L, Platelets ≥100 x109/L, Hemoglobin ≥5.5 mmol/L, Creatinine&#xD;
             ≤1.5x ULN, AST ≤ 1.5 x ULN, ALT ≤ 1.5 x ULN, Bilirubin ≤1.5 X ULN&#xD;
&#xD;
          -  Normal LDH&#xD;
&#xD;
          -  Women of childbearing potential (WOCBP) must use appropriate method(s) of&#xD;
             contra-ception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks&#xD;
             (30 days plus the time required for nivolumab to undergo five half-lives) after the&#xD;
             last dose of investigational drug&#xD;
&#xD;
          -  Women of childbearing potential must have a negative serum or urine pregnancy test&#xD;
             (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the&#xD;
             start of ipilimumab + nivolumab&#xD;
&#xD;
          -  Men who are sexually active with WOCBP must use any contraceptive method with a&#xD;
             failure rate of less than 1% per year. Men receiving nivolumab and who are sexually&#xD;
             active with WOCBP will be instructed to adhere to contraception for a period of 31&#xD;
             weeks after the last dose of investigational product&#xD;
&#xD;
          -  Women who are not of childbearing potential (i.e., who are postmenopausal), or&#xD;
             surgically sterile as well as azoospermic men do not require contraception&#xD;
&#xD;
          -  Patient is capable of understanding and complying with the protocol requirements and&#xD;
             has signed the Informed Consent document.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Distantly metastasized melanoma&#xD;
&#xD;
          -  History of in-transit metastases within the last 6 months&#xD;
&#xD;
          -  No measurable lesion according to RECIST 1.1&#xD;
&#xD;
          -  Subjects with any active autoimmune disease or a documented history of autoimmune&#xD;
             disease, or history of syndrome that required systemic steroids or immunosuppressive&#xD;
             medications, except for subjects with vitiligo or resolved childhood asthma/atopy&#xD;
&#xD;
          -  Prior CTLA-4 or PD-1/PD-L1 targeting immunotherapy&#xD;
&#xD;
          -  Radiotherapy prior or post-surgery&#xD;
&#xD;
          -  Patients will be excluded if they test positive for hepatitis B virus surface antigen&#xD;
             (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody), indicating acute or&#xD;
             chronic infection&#xD;
&#xD;
          -  Patients will be excluded if they have known history of testing positive for human&#xD;
             immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)&#xD;
&#xD;
          -  Allergies and Adverse Drug Reaction&#xD;
&#xD;
               -  History of allergy to study drug components&#xD;
&#xD;
               -  History of severe hypersensitivity reaction to any monoclonal antibody&#xD;
&#xD;
          -  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;
&#xD;
          -  Concurrent medical condition requiring the use of immunosuppressive medications, or&#xD;
             immunosuppressive doses of systemic or absorbable topical corticosteroids;&#xD;
&#xD;
          -  Use of other investigational drugs before study drug administration 30 days and 5&#xD;
             half-times before study inclusion&#xD;
&#xD;
          -  Pregnant or nursing&#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>Christian Blank, Prof.</last_name>
    <role>Study Chair</role>
    <affiliation>Medical oncologist/researcher</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Melanoma Institute Australia</name>
      <address>
        <city>Sydney</city>
        <state>New South Wales</state>
        <zip>2060</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Medical University of Vienna</name>
      <address>
        <city>Vienna</city>
        <zip>1090</zip>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Netherlands Cancer Institute</name>
      <address>
        <city>Amsterdam</city>
        <state>NH</state>
        <zip>1066CX</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Karolinska Institutet</name>
      <address>
        <city>Stockholm</city>
        <zip>S-171 76</zip>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Australia</country>
    <country>Austria</country>
    <country>Netherlands</country>
    <country>Sweden</country>
  </location_countries>
  <verification_date>April 2022</verification_date>
  <study_first_submitted>November 21, 2016</study_first_submitted>
  <study_first_submitted_qc>November 29, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 30, 2016</study_first_posted>
  <last_update_submitted>April 14, 2022</last_update_submitted>
  <last_update_submitted_qc>April 14, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">April 15, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Melanoma</keyword>
  <keyword>Ipilimumab</keyword>
  <keyword>Nivolumab</keyword>
  <keyword>Neo-adjuvant</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Melanoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nivolumab</mesh_term>
    <mesh_term>Ipilimumab</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/NCT02977052
org study id: M16OPN
secondary id: 2016-001984-35
secondary id: CA209-701
nct id: NCT02977052
lead sponsor: 
collaborator: 
has dmc: Yes
This is an open-label three-arm phase 2 trial (including a Simon stage 2 design) consisting
      of 90 stage III melanoma patients randomized 1:1:1 to receive either 2 courses 3 mg/kg
      ipilimumab + 1 mg/kg nivolumab every 3 weeks (Arm A), 2 courses 1 mg/kg ipilimumab + 3 mg/kg
      nivolumab every 3 weeks (Arm B), or 2 courses ipilimumab 3 mg/kg, directly followed by 2
      courses nivolumab 3 mg/kg every 2 weeks (Arm C). All three treatment arms are applied prior
      to surgery at week 6, 30 patients per arm. Patients will be stratified according to treatment
      center. An interim analysis will be performed after 13 patients have been included in each
      arm, thus in total 39 patients have been included.

      PRADO extension cohort The trial will enroll in total about 100-110 melanoma patients with
      macroscopic stage III disease (RECIST measurable disease); inclusion will stop when 50
      patients have achieved a pCR or pnCR. All patients will be treated (after marker placement
      into the largest lymph node metastasis) with the winner combination identified in the first
      part of the OpACIN-neo study which is 2 courses ipilimumab 1mg/kg + nivolumab 3mg/kg, q3wks.
      After 6 weeks of treatment, the patients will undergo only surgical resection of the marked
      index lymph node. Thereafter subsequent surgery and adjuvant therapy will be performed
      according to the achieved pathologic response.
allocation: Non-Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Safety as measured by the frequency of grade 3/4 immune-related adverse events, using CTCAE 4.03
time frame: During the first 12 weeks.
measure: Response rate according to RECIST 1.1
time frame: At 6 weeks
measure: Pathological response according to central pathological revision, according to pathological response criteria
time frame: At 6 weeks
measure: Pathologic response rate according to central revision of the marked index lymph node
time frame: At 6 weeks, prior surgery
measure: RFS at 24 months in patients achieving pCR or pnCR in their marked index lymph node and did not undergo CLND. RFS will be calculated from date of resection of the marked lymph node.
time frame: 24 months
measure: RFS at 24 months in patients with pNR and being subsequently treated with adjuvant nivolumab+optional radiotherapy (or dabrafenib/trametinib if BRAFV600E pos. and treatment is approved). RFS will be calculated from day of resection of marked lymph node.
time frame: 24 months
measure: Recurrence Free Survival
time frame: 3 years after treatment initiation
measure: Description of late adverse events using CTCAE 4.03
time frame: Up to 3 years after treatment initiation until new treatment
measure: Description of associations of mutational load, RNA tumor signatures, and tumor educated platelet signatures with tumor immune infiltrates and response
time frame: At 6 weeks
measure: Response rate according to RECIST 1.1 at week 6
time frame: At 6 weeks
measure: RFS at 2, 3 and 5 years
time frame: Up to 5 years after treatment
measure: EFS at 2, 3 and 5 years
time frame: Up to 5 years after treatment
measure: DMFS at 2, 3 and 5 years
time frame: Up to 5 years after treatment
measure: OS at 2, 3 and 5 years
time frame: Up to 5 years after treatment
measure: Grade 3/4 immune-related adverse event rate according to CTCAE v4.03 within the first 12 weeks
time frame: At 12 weeks
measure: • Surgical complication rates according to Clavien-Dindo surgical classification of only marked index lymph node resection vs. CLND
time frame: At 12 weeks
measure: • Description of late adverse event (up to 3 years after treatment initiation) according to CTCAE v4.03
time frame: Up to 3 years after treatment
arm group label: Arm A: 2 courses ipi 3 + nivo 1
arm group type: Experimental
description: Patients receive 2 courses standard combination of ipilimumab 3 mg/kg + nivolumab 1 mg/kg q3wk prior to surgery at week 6. Blood for PBMCs and biopsies will be taken for translation research.
arm group label: Arm B: 2 courses ipi 1 + nivo 3
arm group type: Experimental
description: Patients receive 2 courses ipilimumab 1 mg/kg + nivolumab 3 mg/kg q3wk prior to surgery at week 6. Blood for PBMCs and biopsies will be taken for translation research.
arm group label: Arm C: 2 courses ipi 3 + 2 courses nivo 3
arm group type: Experimental
description: Patients receive 2 courses of ipilimumab 3 mg/kg q3wks, directly followed (> 2 hours and < 24 hours) by 2 courses nivolumab 3 mg/kg every 2 weeks prior to surgery at week 6. Blood for PBMCs and biopsies will be taken for translation research.
arm group label: PRADO extension cohort
arm group type: Experimental
description: Patients will be treated with 2 courses ipilimumab and nivolumab at the dose level defined as the winner dosing scheme from OpACIN-neo, which is the dosing schedule of arm B.
Surgery and adjuvant therapy
Patients achieving a pCR or pnCR will not undergo CLND and will not receive any adjuvant treatment. Structural follow-up will be perfomed every 12 weeks by CT, ultrasound of regional lymph nodes.
Patients achieving a pPR will undergo CLND and start structural follow-up (including CT and physical examination) every 12 weeks thereafter without any adjuvant treatment.
Patients achieving no response (pNR) will undergo CLND and start at week 12 with adjuvant nivolumab 480mg q4wks for 52 weeks + radiotherapy (according to patient's and physicians' decision). In patients that are BRAF V600E/K mutation positive, adjuvant BRAF+MEK
intervention type: Drug
intervention name: Ipilimumab
arm group label: Arm A: 2 courses ipi 3 + nivo 1
arm group label: Arm B: 2 courses ipi 1 + nivo 3
arm group label: Arm C: 2 courses ipi 3 + 2 courses nivo 3
arm group label: PRADO extension cohort
intervention type: Drug
intervention name: Nivolumab
arm group label: Arm A: 2 courses ipi 3 + nivo 1
arm group label: Arm B: 2 courses ipi 1 + nivo 3
arm group label: Arm C: 2 courses ipi 3 + 2 courses nivo 3
arm group label: PRADO extension cohort
intervention type: Procedure
intervention name: Surgery
description: Surgery will be done at 6 weeks
arm group label: Arm A: 2 courses ipi 3 + nivo 1
arm group label: Arm B: 2 courses ipi 1 + nivo 3
arm group label: Arm C: 2 courses ipi 3 + 2 courses nivo 3
arm group label: PRADO extension cohort
intervention type: Procedure
intervention name: Blood for PBMCs
description: Blood will be taken for translational research on PBMCs
arm group label: Arm A: 2 courses ipi 3 + nivo 1
arm group label: Arm B: 2 courses ipi 1 + nivo 3
arm group label: Arm C: 2 courses ipi 3 + 2 courses nivo 3
arm group label: PRADO extension cohort
intervention type: Procedure
intervention name: Biopsies
description: Biopsies will be taken during screening and at relapse.
arm group label: Arm A: 2 courses ipi 3 + nivo 1
arm group label: Arm B: 2 courses ipi 1 + nivo 3
arm group label: Arm C: 2 courses ipi 3 + 2 courses nivo 3
arm group label: PRADO extension cohort
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Christian Blank, Prof.
role: Study Chair
affiliation: Medical oncologist/researcher
facility: 
facility: 
facility: 
facility: 
country: Australia
country: Austria
country: Netherlands
country: Sweden
responsible party type: Sponsor
mesh term: Melanoma
mesh term: Nivolumab
mesh term: Ipilimumab
sharing ipd: No