<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/NCT02196961</url>
  </required_header>
  <id_info>
    <org_study_id>CA184-205</org_study_id>
    <nct_id>NCT02196961</nct_id>
  </id_info>
  <brief_title>Adjuvant Therapy of Completely Resected Merkel Cell Carcinoma With Immune Checkpoint Blocking Antibodies vs Observation</brief_title>
  <acronym>ADMEC-O</acronym>
  <official_title>Prospective Randomized Trial of an Adjuvant Therapy of Completely Resected Merkel Cell Carcinoma (MCC) With Immune Checkpoint Blocking Antibodies (Nivolumab, Opdivo®; Ipilimumab (Yervoy®) Every 3 Weeks for 12 Weeks Versus Observation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Prof. Dr. med. Dirk Schadendorf</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University Hospital, Essen</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Primary objective: To estimate the efficacy of adjuvant nivolumab monotherapy in completely&#xD;
      resected MCC patients&#xD;
&#xD;
      Primary endpoint: Disease-free survival (DFS) rate evaluated at 12, 24 and 48 months after&#xD;
      date of randomization&#xD;
&#xD;
      Secondary Objectives: To describe the safety profile and additional efficacy parameters of&#xD;
      the nivolumab treatment in MCC&#xD;
&#xD;
      Secondary endpoints:&#xD;
&#xD;
        -  Adverse events according to CTCAE, Version 4.0 criteria, that are related to the&#xD;
           administration of nivolumab&#xD;
&#xD;
        -  Disease-free survival (DFS)&#xD;
&#xD;
        -  Overall survival (OS) and OS rates at 12, 24 and 48 months after randomization&#xD;
&#xD;
      Explorative Endpoints:&#xD;
&#xD;
        -  Distant-metastases-free survival (DMFS) and DMFS rate at 12, 24 and 48 months after&#xD;
           randomization&#xD;
&#xD;
        -  Identification and validation of prognostic/predictive biomarkers&#xD;
&#xD;
        -  Quality of life (EORTC QLQ-C30) until 24 months after randomization&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is an international, open-label, randomized, multicenter phase II study to assess the&#xD;
      efficacy of adjuvant nivolumab therapy in completely resected MCC patients. In the initial&#xD;
      trial design, the immune modulating treatment was based on CTLA-4 blockade by ipilimumab;&#xD;
      however, the advent of PD-1/PD-L1 blockade in the palliative treatment of MCC (presented at&#xD;
      AACR, ASCO and ESMO) dramatically changed the treatment environment to an extent that&#xD;
      applying treatments other than by PD-1/PD-L1 blockade had become very difficult. Moreover,&#xD;
      the side effects of PD-1/PD-L1 blocking are far less frequent than side effects of&#xD;
      ipilimumab. Consequently, randomization into the previous Ipilimumab treatment arm A was&#xD;
      stopped. New patients will be randomized to nivolumab treatment instead. Patients randomized&#xD;
      already into the Ipilimumab-arm will be evaluated descriptively for efficacy and safety.&#xD;
      Patients already randomized into the observation arm (arm B) will be evaluated together with&#xD;
      the newly randomized arm B-patients. A total of 177 patients with completely resected MCC&#xD;
      will be enrolled over a recruitment period of 36 months into this trial, and randomized 2:1&#xD;
      as mentioned above. Patients will be stratified by sex, age, and stage of disease.&#xD;
&#xD;
      Examinations and Follow-up Phase:&#xD;
&#xD;
      The disease will be assessed at baseline, and thereafter every 12 weeks according to the&#xD;
      current German guidelines for the management of MCC patients for 24 months after&#xD;
      randomization, or until withdrawal of informed consent, lost to follow-up, or death,&#xD;
      whichever occurs first. In addition, the patient's quality of life will be evaluated at&#xD;
      baseline (pretreatment visit) and every 3 months until 24 months after randomization using a&#xD;
      standard questionnaire (EORTC QLQC30).&#xD;
&#xD;
      After 24 months, additional FU visits (or phone calls) will be conducted 6-monthly recording&#xD;
      survival and tumor status including subsequent therapies until withdrawal of informed&#xD;
      consent, lost to follow-up, death or end of study, whichever occurs first.&#xD;
&#xD;
      End of study is defined as 48 months post LPFV (last patient first visit = date of&#xD;
      randomization).&#xD;
&#xD;
      Same methods of assessment (e.g. ultrasonography, CT or MRI scans) used at baseline will be&#xD;
      used during follow-up.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">June 2014</start_date>
  <completion_date type="Anticipated">August 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">August 31, 2024</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>Disease-free survival (DFS) rate at 12 months</measure>
    <time_frame>1 years post last patient first treatment/randomization</time_frame>
    <description>The number of patients alive and free of disease at 12 months after randomization in arm A compared to DFS in arm B.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Disease-free survival (DFS) rate at 24 months</measure>
    <time_frame>2 years post last patient first treatment/randomization</time_frame>
    <description>The number of patients alive and free of disease at 24 months after randomization</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Disease-free survival (DFS) rate at 48 months</measure>
    <time_frame>4 years post last patient first treatment/randomization</time_frame>
    <description>The number of patients alive and free of disease at 48 months after randomization</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of adverse events</measure>
    <time_frame>1, 2 and 4 years post last patient first treatment/randomization</time_frame>
    <description>Adverse events according to CTCAE, Version 4.0 criteria, that are related to the administration of Ipilimumab</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival rate at 12 months</measure>
    <time_frame>1 year post last patient first treatment/randomization</time_frame>
    <description>Overall survival rate at 12 months, defined as the number of patients alive at 12 months after randomization divided by the total number of patients randomized.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival rate at 24 months</measure>
    <time_frame>2 years post last patient first treatment/randomization</time_frame>
    <description>Overall survival rate at 24 months, defined as the number of patients alive at 24 months after randomization divided by the total number of patients randomized.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival rate at 48 months</measure>
    <time_frame>4 years post last patient first treatment/randomization</time_frame>
    <description>Overall survival rate at 48 months, defined as the number of patients alive at 48 months after randomization divided by the total number of patients randomized.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease-free survival (DFS)</measure>
    <time_frame>1, 2 and 4 years post last patient first treatment/randomization</time_frame>
    <description>Time from randomization to recurrence of tumor</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>1, 2 and 4 years post last patient first treatment/randomization</time_frame>
    <description>Time from randomization to death of patient</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Distant-metastases-free survival (DMFS) at 12 months after randomization</measure>
    <time_frame>1 year post last patient first treatment/randomization</time_frame>
    <description>Number of patients free of distant metastases at 12 months after randomization</description>
  </other_outcome>
  <other_outcome>
    <measure>Distant-metastases-free survival (DMFS) at 24 months after randomization</measure>
    <time_frame>2 years post last patient first treatment/randomization</time_frame>
    <description>Number of patients free of distant metastases at 24 months after randomization</description>
  </other_outcome>
  <other_outcome>
    <measure>Distant-metastases-free survival (DMFS) at 48 months after randomization</measure>
    <time_frame>4 years post last patient first treatment/randomization</time_frame>
    <description>Number of patients free of distant metastases at 48 months after randomization</description>
  </other_outcome>
  <other_outcome>
    <measure>Identification of prognostic/predictive biomarkers</measure>
    <time_frame>2 and 4 years post last patient first treatment/randomization</time_frame>
    <description>Identify and validate prognostic/predictive biomarkers such as immune status, kinetics of the absolute lymphocyte count (ALC), or tumor microenvironment characteristics</description>
  </other_outcome>
  <other_outcome>
    <measure>Quality of life (EORTC QLQ-C30) until 24 months after randomization</measure>
    <time_frame>2 years post last patient first treatment/randomization</time_frame>
    <description>The patient's quality of life will be evaluated at baseline (pretreatment visit) and every 3 months until 24 months after randomization using a standard questionnaire</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">180</enrollment>
  <condition>Merkel Cell Carcinoma</condition>
  <arm_group>
    <arm_group_label>Observation</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>After complete resection of Merkel cell carcinoma, patients randomized to the observational arm will be observed only</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Nivolumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>After complete resection of Merkel cell carcinoma, patients randomized to the treatment arm will receive nivolumab at a fixed dose of 480 mg by IV infusion every 4 weeks for up to one year (i.e.13 doses).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>adjuvant treatment of completely resected Merkel cell carcinoma</description>
    <arm_group_label>Nivolumab</arm_group_label>
    <other_name>Opdivo</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. The patient is willing and able to give written informed consent.&#xD;
&#xD;
          2. Central histological confirmation of diagnosis of Merkel cell carcinoma (MCC).&#xD;
&#xD;
          3. All MCC manifestations have been completely resected by surgery within 12 weeks before&#xD;
             enrolment.&#xD;
&#xD;
          4. No currently present metastases (as confirmed by standard imaging studies (e.g.&#xD;
             suggested by S2k guidelines)).&#xD;
&#xD;
          5. No previous systemic therapy for MCC.&#xD;
&#xD;
          6. Required values for initial laboratory tests:&#xD;
&#xD;
               -  WBC ≥ 2000/uL&#xD;
&#xD;
               -  ANC ≥ 1000/uL&#xD;
&#xD;
               -  Platelets ≥ 75 x 103/uL&#xD;
&#xD;
               -  Hemoglobin ≥ 8 g/dL (≥ 80 g/L)&#xD;
&#xD;
               -  Creatinine ≤ 2.0 x ULN&#xD;
&#xD;
               -  AST/ALT ≤ 2.5 x ULN&#xD;
&#xD;
               -  Total Bilirubin ≤ 2.0 x ULN, (except patients with Gilbert's Syndrome, who must&#xD;
                  have a total bilirubin less than 3.0 mg/dL)&#xD;
&#xD;
          7. ECOG performance status 0 or 1.&#xD;
&#xD;
          8. No active or chronic infection with HIV, Hepatitis B (HBV) or C (HCV).&#xD;
&#xD;
          9. Men and women, ≥ 18 years of age.&#xD;
&#xD;
         10. Women of childbearing potential (WOCBP) must be using an adequate method of&#xD;
             contraception (Pearl-Index &lt; 1) to avoid pregnancy during treatment phase and for&#xD;
             additional 5 months after the last dose of nivolumab, in such a manner that the risk&#xD;
             of pregnancy is minimized. WOCBP include any female who has experienced menarche and&#xD;
             who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal&#xD;
             ligation, or bilateral oophorectomy) or is not post-menopausal. WOCBP must have a&#xD;
             negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent&#xD;
             units of HCG) within 72 hours before the start of nivolumab.&#xD;
&#xD;
         11. Men of fathering potential must be using an adequate method of contraception to avoid&#xD;
             conception and for 7 months after the last dose of nivolumab in such a manner that the&#xD;
             risk of pregnancy is minimized.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Autoimmune disease: Patients with a history of inflammatory bowel disease, including&#xD;
             ulcerative colitis and Crohn's Disease, are excluded from this study, as are patients&#xD;
             with a history of symptomatic disease requiring systemic steroids (e.g., rheumatoid&#xD;
             arthritis, systemic progressive sclerosis, systemic lupus erythematosus, autoimmune&#xD;
             vasculitis); autoimmune motor neuropathy.&#xD;
&#xD;
          2. Other serious illnesses, e.g., serious infections requiring i.v. antibiotics.&#xD;
&#xD;
          3. The patient is known to be positive for Human Immunodeficiency Virus (HIV) or other&#xD;
             chronic infections (HBV, HCV) or has another confirmed or suspected immunosuppressive&#xD;
             or immune deficient condition.&#xD;
&#xD;
          4. Any underlying medical or psychiatric condition, which in the opinion of the&#xD;
             investigator will make the administration of nivolumab hazardous or obscure the&#xD;
             interpretation of adverse events (AEs), such as a condition associated with frequent&#xD;
             diarrhea.&#xD;
&#xD;
          5. Any non-oncology vaccine therapy for up to 1 month before or after any dose of&#xD;
             nivolumab.&#xD;
&#xD;
          6. A history of prior or current treatment with a T cell potentiating agent (e.g. IL-2,&#xD;
             interferon, anti-CTLA-4, anti-CD137, anti-PD1, anti-PD-L1, or anti-OX40 antibody).&#xD;
&#xD;
          7. Chronic use of immunosuppressive agents or systemic corticosteroids.&#xD;
&#xD;
          8. Women of childbearing potential (WOCBP), defined above in Section 5.1, who:&#xD;
&#xD;
               -  are unwilling or unable to use an acceptable method of contraception to avoid&#xD;
                  pregnancy for additional 5 months after the last dose of investigational product&#xD;
&#xD;
               -  have a positive pregnancy test at baseline&#xD;
&#xD;
               -  are pregnant or breastfeeding.&#xD;
&#xD;
          9. The patient has psychiatric or addictive disorders that may compromise his/her ability&#xD;
             to give informed consent or to comply with the trial procedures.&#xD;
&#xD;
         10. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for&#xD;
             treatment of either a psychiatric or physical (e.g., infectious) illness.&#xD;
&#xD;
         11. Men of reproductive potential unwilling to use an adequate method to avoid pregnancy&#xD;
             for additional 7 months after the last dose of investigational product.&#xD;
&#xD;
         12. Use of any investigational or non-registered product (drug or vaccine) other than the&#xD;
             study treatment.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Dirk Schadendorf, Prof. Dr.</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Hospital, Essen</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University Hospital Essen, Dermatology</name>
      <address>
        <city>Essen</city>
        <state>NRW</state>
        <zip>45122</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Charité Universitätsmedizin Berlin</name>
      <address>
        <city>Berlin</city>
        <zip>10117</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Elbeklinikum Buxtehude</name>
      <address>
        <city>Buxtehude</city>
        <zip>21614</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Dresden, Dermatology</name>
      <address>
        <city>Dresden</city>
        <zip>01307</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>HELIOS Klinikum Erfurt</name>
      <address>
        <city>Erfurt</city>
        <zip>99089</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Freiburg</name>
      <address>
        <city>Freiburg</city>
        <zip>79104</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>SRH Wald-Klinikum Gera</name>
      <address>
        <city>Gera</city>
        <zip>07548</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hannover Medical School</name>
      <address>
        <city>Hannover</city>
        <zip>30625</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>National Centre for Tumour Diseases (NCT)</name>
      <address>
        <city>Heidelberg</city>
        <zip>69120</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Schleswig-Holstein, Kiel</name>
      <address>
        <city>Kiel</city>
        <zip>24105</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Leipzig Klinik u. Poliklinik f. Dermatologie, Venerologie u. Allergologie</name>
      <address>
        <city>Leipzig</city>
        <zip>04103</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Mainz Hautklinik und Poliklinik</name>
      <address>
        <city>Mainz</city>
        <zip>55131</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Mannheim Klinik f. Dermatologie, Venerologie u. Allergologie</name>
      <address>
        <city>Mannheim</city>
        <zip>68167</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital München (LMU)</name>
      <address>
        <city>Munich</city>
        <zip>80337</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Münster Zentrale Studienkoordination für innovative Dermatologie (ZID)</name>
      <address>
        <city>Münster</city>
        <zip>48149</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Specialist clinic in Hornheide</name>
      <address>
        <city>Münster</city>
        <zip>48157</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Regensburg</name>
      <address>
        <city>Regensburg</city>
        <zip>93053</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Tübingen</name>
      <address>
        <city>Tübingen</city>
        <zip>72076</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsklinikum Würzburg Klinik u. Poliklinik f. Dermatologie, Venerologie u. Allergologie</name>
      <address>
        <city>Würzburg</city>
        <zip>97080</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Netherlands Cancer Institute / Antoni van Leeuwenhoek Hospital (NKI/AVL)</name>
      <address>
        <city>Amsterdam</city>
        <zip>1066 CX</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>September 2022</verification_date>
  <study_first_submitted>June 20, 2014</study_first_submitted>
  <study_first_submitted_qc>July 19, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 22, 2014</study_first_posted>
  <last_update_submitted>September 13, 2022</last_update_submitted>
  <last_update_submitted_qc>September 13, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">September 16, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University Hospital, Essen</investigator_affiliation>
    <investigator_full_name>Prof. Dr. med. Dirk Schadendorf</investigator_full_name>
    <investigator_title>Prof. Dr. med. Dirk Schadendorf</investigator_title>
  </responsible_party>
  <keyword>Merkel cell carcinoma</keyword>
  <keyword>Adjuvant</keyword>
  <keyword>Nivolumab</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma, Merkel Cell</mesh_term>
    <mesh_term>Carcinoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nivolumab</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/NCT02196961
org study id: CA184-205
nct id: NCT02196961
lead sponsor: 
collaborator: 
has dmc: No
Primary objective: To estimate the efficacy of adjuvant nivolumab monotherapy in completely
      resected MCC patients

      Primary endpoint: Disease-free survival (DFS) rate evaluated at 12, 24 and 48 months after
      date of randomization

      Secondary Objectives: To describe the safety profile and additional efficacy parameters of
      the nivolumab treatment in MCC

      Secondary endpoints:

        -  Adverse events according to CTCAE, Version 4.0 criteria, that are related to the
           administration of nivolumab

        -  Disease-free survival (DFS)

        -  Overall survival (OS) and OS rates at 12, 24 and 48 months after randomization

      Explorative Endpoints:

        -  Distant-metastases-free survival (DMFS) and DMFS rate at 12, 24 and 48 months after
           randomization

        -  Identification and validation of prognostic/predictive biomarkers

        -  Quality of life (EORTC QLQ-C30) until 24 months after randomization
This is an international, open-label, randomized, multicenter phase II study to assess the
      efficacy of adjuvant nivolumab therapy in completely resected MCC patients. In the initial
      trial design, the immune modulating treatment was based on CTLA-4 blockade by ipilimumab;
      however, the advent of PD-1/PD-L1 blockade in the palliative treatment of MCC (presented at
      AACR, ASCO and ESMO) dramatically changed the treatment environment to an extent that
      applying treatments other than by PD-1/PD-L1 blockade had become very difficult. Moreover,
      the side effects of PD-1/PD-L1 blocking are far less frequent than side effects of
      ipilimumab. Consequently, randomization into the previous Ipilimumab treatment arm A was
      stopped. New patients will be randomized to nivolumab treatment instead. Patients randomized
      already into the Ipilimumab-arm will be evaluated descriptively for efficacy and safety.
      Patients already randomized into the observation arm (arm B) will be evaluated together with
      the newly randomized arm B-patients. A total of 177 patients with completely resected MCC
      will be enrolled over a recruitment period of 36 months into this trial, and randomized 2:1
      as mentioned above. Patients will be stratified by sex, age, and stage of disease.

      Examinations and Follow-up Phase:

      The disease will be assessed at baseline, and thereafter every 12 weeks according to the
      current German guidelines for the management of MCC patients for 24 months after
      randomization, or until withdrawal of informed consent, lost to follow-up, or death,
      whichever occurs first. In addition, the patient's quality of life will be evaluated at
      baseline (pretreatment visit) and every 3 months until 24 months after randomization using a
      standard questionnaire (EORTC QLQC30).

      After 24 months, additional FU visits (or phone calls) will be conducted 6-monthly recording
      survival and tumor status including subsequent therapies until withdrawal of informed
      consent, lost to follow-up, death or end of study, whichever occurs first.

      End of study is defined as 48 months post LPFV (last patient first visit = date of
      randomization).

      Same methods of assessment (e.g. ultrasonography, CT or MRI scans) used at baseline will be
      used during follow-up.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Disease-free survival (DFS) rate at 12 months
time frame: 1 years post last patient first treatment/randomization
description: The number of patients alive and free of disease at 12 months after randomization in arm A compared to DFS in arm B.
measure: Disease-free survival (DFS) rate at 24 months
time frame: 2 years post last patient first treatment/randomization
description: The number of patients alive and free of disease at 24 months after randomization
measure: Disease-free survival (DFS) rate at 48 months
time frame: 4 years post last patient first treatment/randomization
description: The number of patients alive and free of disease at 48 months after randomization
measure: Number of adverse events
time frame: 1, 2 and 4 years post last patient first treatment/randomization
description: Adverse events according to CTCAE, Version 4.0 criteria, that are related to the administration of Ipilimumab
measure: Overall survival rate at 12 months
time frame: 1 year post last patient first treatment/randomization
description: Overall survival rate at 12 months, defined as the number of patients alive at 12 months after randomization divided by the total number of patients randomized.
measure: Overall survival rate at 24 months
time frame: 2 years post last patient first treatment/randomization
description: Overall survival rate at 24 months, defined as the number of patients alive at 24 months after randomization divided by the total number of patients randomized.
measure: Overall survival rate at 48 months
time frame: 4 years post last patient first treatment/randomization
description: Overall survival rate at 48 months, defined as the number of patients alive at 48 months after randomization divided by the total number of patients randomized.
measure: Disease-free survival (DFS)
time frame: 1, 2 and 4 years post last patient first treatment/randomization
description: Time from randomization to recurrence of tumor
measure: Overall survival (OS)
time frame: 1, 2 and 4 years post last patient first treatment/randomization
description: Time from randomization to death of patient
measure: Distant-metastases-free survival (DMFS) at 12 months after randomization
time frame: 1 year post last patient first treatment/randomization
description: Number of patients free of distant metastases at 12 months after randomization
measure: Distant-metastases-free survival (DMFS) at 24 months after randomization
time frame: 2 years post last patient first treatment/randomization
description: Number of patients free of distant metastases at 24 months after randomization
measure: Distant-metastases-free survival (DMFS) at 48 months after randomization
time frame: 4 years post last patient first treatment/randomization
description: Number of patients free of distant metastases at 48 months after randomization
measure: Identification of prognostic/predictive biomarkers
time frame: 2 and 4 years post last patient first treatment/randomization
description: Identify and validate prognostic/predictive biomarkers such as immune status, kinetics of the absolute lymphocyte count (ALC), or tumor microenvironment characteristics
measure: Quality of life (EORTC QLQ-C30) until 24 months after randomization
time frame: 2 years post last patient first treatment/randomization
description: The patient's quality of life will be evaluated at baseline (pretreatment visit) and every 3 months until 24 months after randomization using a standard questionnaire
arm group label: Observation
arm group type: No Intervention
description: After complete resection of Merkel cell carcinoma, patients randomized to the observational arm will be observed only
arm group label: Nivolumab
arm group type: Experimental
description: After complete resection of Merkel cell carcinoma, patients randomized to the treatment arm will receive nivolumab at a fixed dose of 480 mg by IV infusion every 4 weeks for up to one year (i.e.13 doses).
intervention type: Drug
intervention name: Nivolumab
description: adjuvant treatment of completely resected Merkel cell carcinoma
arm group label: Nivolumab
other name: Opdivo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Dirk Schadendorf, Prof. Dr.
role: Principal Investigator
affiliation: University Hospital, Essen
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Germany
country: Netherlands
responsible party type: Sponsor-Investigator
investigator affiliation: University Hospital, Essen
investigator full name: Prof. Dr. med. Dirk Schadendorf
investigator title: Prof. Dr. med. Dirk Schadendorf
mesh term: Carcinoma, Merkel Cell
mesh term: Carcinoma
mesh term: Nivolumab
sharing ipd: No