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Adjuvant Therapy of Completely Resected Merkel Cell Carcinoma With Immune Checkpoint Blocking Antibodies Versus Observation (ADMEC-O)

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ClinicalTrials.gov Identifier: NCT02196961
Recruitment Status : Recruiting
First Posted : July 22, 2014
Last Update Posted : August 29, 2017
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Prof. Dr. med. Dirk Schadendorf, University Hospital, Essen

Brief Summary:

Primary Objective:

To estimate the efficacy of adjuvant nivolumab monotherapy in completely resected Merkel cell carcinoma (MCC) patients; i.e. the primary endpoint is disease-free survival (DFS) in arm A at 12 months, defined as the number of patients alive and free of disease at 12 months after randomization compared to DFS in arm B.

Secondary Objectives:

To assess safety and additional efficacy parameters of the ipilimumab or nivolumab treatment in MCC, as well as to characterize potential biomarkers; secondary endpoints are: (i) adverse events according to CTCAE (Common Terminology Criteria for Adverse Events), Version 4.0 criteria, that are definitely, probably, or possibly related to the administration of ipilimumab, (ii) Overall survival rate at 12 months, defined as the number of patients surviving at 12 months after randomization divided by the total number of patients randomized, (iii) DFS rate at 12 months, defined as the number of patients alive and free of disease at 12 months after randomization divided by the total number of patients randomized.


Condition or disease Intervention/treatment Phase
Merkel Cell Carcinoma Drug: Ipilimumab Drug: Nivolumab Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 177 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Study Start Date : June 2014
Estimated Primary Completion Date : March 2021
Estimated Study Completion Date : March 2021


Arm Intervention/treatment
No Intervention: Observation
After complete resection of Merkel cell carcinoma, patients randomized to the observational arm will be observed only
Experimental: Ipilimumab (closed treatment arm)
After complete resection of Merkel cell carcinoma, patients randomized to the treatment arm will receive ipilimumab as a single agent (3 mg/kg) administered intravenously over a 90 minute period every 3 weeks for a total of four doses, as tolerated, i.e. day 1 (week 1), day 22 (week 4), day 43 (week 7), day 64 (week 10).
Drug: Ipilimumab
adjuvant treatment of completely resected Merkel cell carcinoma
Other Name: Yervoy

Experimental: Nivolumab
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).
Drug: Nivolumab
adjuvant treatment of completely resected Merkel cell carcinoma
Other Name: Opdivo




Primary Outcome Measures :
  1. Disease-free survival (DFS) at 12 months [ Time Frame: 1 year post last patient first treatment/randomization ]
    The number of patients alive and free of disease at 12 months after randomization in arm A compared to DFS in arm B.


Secondary Outcome Measures :
  1. Number of adverse events [ Time Frame: 1 year post last patient first treatment/randomization ]
    Adverse events according to CTCAE, Version 4.0 criteria, that are related to the administration of Ipilimumab

  2. Overall survival rate at 12 months [ Time Frame: 1 year post last patient first treatment/randomization ]
    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.

  3. DFS rate at 12 months [ Time Frame: 1 year post last patient first treatment/randomization ]
    Number of patients alive and free of disease at 12 months after randomization divided by the total number of patients randomized.


Other Outcome Measures:
  1. Disease free survival [ Time Frame: 1 year post last patient first treatment/randomization ]
    Number of patients free of disease at the end of study

  2. Overall survival [ Time Frame: 1 year post last patient first treatment/randomization ]
    Number of patients still alive at the end of study

  3. Identification of prognostic/predictive biomarkers [ Time Frame: 1 year post last patient first treatment/randomization ]
    Identify and validate prognostic/predictive biomarkers such as immune status, kinetics of the absolute lymphocyte count (ALC), or tumor microenvironment characteristics



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. The patient is willing and able to give written informed consent.
  2. Central histological confirmation of diagnosis of Merkel cell carcinoma (MCC).
  3. All MCC manifestations have been completely resected by surgery within 12 weeks before enrolment.
  4. No currently present metastases (as confirmed by standard imaging studies (e.g. suggested by S2k guidelines)).
  5. No previous systemic therapy for MCC.
  6. Required values for initial laboratory tests:

    • WBC ≥ 2000/uL
    • ANC ≥ 1000/uL
    • Platelets ≥ 75 x 103/uL
    • Hemoglobin ≥ 8 g/dL (≥ 80 g/L)
    • Creatinine ≤ 2.0 x ULN
    • AST/ALT ≤ 2.5 x ULN
    • Total Bilirubin ≤ 2.0 x ULN, (except patients with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL)
  7. ECOG performance status 0 or 1.
  8. No active or chronic infection with HIV, Hepatitis B (HBV) or C (HCV).
  9. Men and women, ≥ 18 years of age.
  10. Women of childbearing potential (WOCBP) must be using an adequate method of contraception (Pearl-Index < 1) to avoid pregnancy for up to 12 weeks (for ipilimumab therapy) or for 5 months (for nivolumab therapy) after the last dose of investigational product, in such a manner that the risk of pregnancy is minimized. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not post-menopausal. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours before the start of ipilimumab or nivolumab.
  11. Men of fathering potential must be using an adequate method of contraception to avoid conception for up to 12 weeks (for ipilimumab therapy) or for 7 months (for nivolumab therapy) after the last dose of investigational product in such a manner that the risk of pregnancy is minimized.

Exclusion Criteria:

  1. Autoimmune disease: Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's Disease, are excluded from this study, as are patients with a history of symptomatic disease requiring systemic steroids (e.g., rheumatoid arthritis, systemic progressive sclerosis, systemic lupus erythematosus, autoimmune vasculitis); autoimmune motor neuropathy.
  2. Other serious illnesses, e.g., serious infections requiring i.v. antibiotics.
  3. The patient is known to be positive for Human Immunodeficiency Virus (HIV) or other chronic infections (HBV, HCV) or has another confirmed or suspected immunosuppressive or immune deficient condition.
  4. Any underlying medical or psychiatric condition, which in the opinion of the investigator will make the administration of ipilimumab or nivolumab hazardous or obscure the interpretation of adverse events (AEs), such as a condition associated with frequent diarrhea.
  5. Any non-oncology vaccine therapy for up to 1 month before or after any dose of ipilimumab or nivolumab.
  6. A history of prior or current treatment with a T cell potentiating agent (e.g. IL-2, interferon, anti-CTLA-4, anti-CD137, anti-PD1, anti-PD-L1, or anti-OX40 antibody).
  7. Chronic use of immunosuppressive agents or systemic corticosteroids.
  8. Women of childbearing potential (WOCBP), defined above in Section 5.1, who:

    • are unwilling or unable to use an acceptable method of contraception to avoid pregnancy for up to 12 weeks (for ipilimumab therapy) or for 5 months (for nivolumab therapy) after the last dose of investigational product
    • have a positive pregnancy test at baseline
    • are pregnant or breastfeeding.
  9. The patient has psychiatric or addictive disorders that may compromise his/her ability to give informed consent or to comply with the trial procedures.
  10. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness.
  11. Men of reproductive potential unwilling to use an adequate method to avoid pregnancy for up to 12 weeks (for ipilimumab therapy) or for 7 months (for nivolumab therapy) after the last dose of investigational product.
  12. Use of any investigational or non-registered product (drug or vaccine) other than the study treatment.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02196961


Contacts
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Contact: Dirk Schadendorf, Prof. Dr. +49 201-723 4342 ext 4342 Dirk.Schadendorf@uk-essen.de

Locations
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Germany
University Hospital Essen, Dermatology Recruiting
Essen, NRW, Germany, 45122
Contact: Dirk Schadendorf, Prof. Dr.    +49-201- 723 ext 4342    dirk.schadendorf@uk-essen.de   
Contact: Lisa Zimmer, Dr. med.       lisa.zimmer@uk-essen.de   
Principal Investigator: Dirk Schadendorf, Prof. Dr.         
Charité Universitätsmedizin Berlin Active, not recruiting
Berlin, Germany, 10117
Elbeklinikum Buxtehude Recruiting
Buxtehude, Germany, 21614
Contact: Peter Mohr, Dr. med.       peter.mohr@elbekliniken.de   
Contact: Leonie Bluhm, Dr. med.       leonie.bluhm@elbekliniken.de   
Principal Investigator: Peter Mohr, Dr. med.         
University Hospital Dresden, Dermatology Recruiting
Dresden, Germany, 01307
Contact: Friedegund Meier, Prof. Dr.       friedegund.meier@uniklinikum-dresden.de   
Contact: Marlene Garzarolli, Dr. med.       marlene.garzarolli@uniklinikum-dresden.de   
Principal Investigator: Friedegund Meier, Prof. Dr.         
SRH Wald-Klinikum Gera Active, not recruiting
Gera, Germany, 07548
Hannover Medical School Recruiting
Hannover, Germany, 30625
Contact: Ralf Gutzmer, Prof. Dr.       gutzmer.ralf@mh-hannover.de   
Principal Investigator: Ralf Guztmer, Prof. Dr.         
National Centre for Tumour Diseases (NCT) Recruiting
Heidelberg, Germany, 69120
Contact: Jessica Hassel, Dr. med.       jessica.hassel@med.uni-heidelberg.de   
Contact: Martin Hartmann, Dr. med.       martin.hartmann@med.uni-heidelberg.de   
Principal Investigator: Jessica Hassel, Dr. med.         
University Hospital Schleswig-Holstein, Kiel Recruiting
Kiel, Germany, 24105
Contact: Katharina Kähler, Dr. med.       kkaehler@dermatology.uni-kiel.de   
Contact: Axel Hauschild, Prof. Dr.       ahauschild@dermatology.uni-kiel.de   
Principal Investigator: Axel Hauschild, Prof. Dr.         
University Hospital München (LMU) Recruiting
Munich, Germany, 80337
Contact: Carola Berking, Prof. Dr.       carola.berking@med.uni-muenchen.de   
Contact: Tanja Maier, Dr. med.       tanja.maier@med.uni-muenchen.de   
Principal Investigator: Carola Berking, Prof. Dr.         
Specialist clinic in Hornheide Recruiting
Münster, Germany, 48157
Contact: Michael Fluck, Dr.       michael.fluck@fachklinik-hornheide.de   
Principal Investigator: Michael Fluck, Dr.         
University Hospital Tübingen Recruiting
Tübingen, Germany, 72076
Contact: Claus Garbe, Prof. Dr.       claus.garbe@med.uni-tuebingen.de   
Contact: Thomas Eigentler, Dr. med.       thomas.eigentler@med.uni-tuebingen.de   
Principal Investigator: Claus Garbe, Prof. Dr.         
Sponsors and Collaborators
Prof. Dr. med. Dirk Schadendorf
Bristol-Myers Squibb
Investigators
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Principal Investigator: Dirk Schadendorf, Prof. Dr. University Hospital, Essen

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Responsible Party: Prof. Dr. med. Dirk Schadendorf, University Hospital, Essen
ClinicalTrials.gov Identifier: NCT02196961     History of Changes
Other Study ID Numbers: CA184-205
First Posted: July 22, 2014    Key Record Dates
Last Update Posted: August 29, 2017
Last Verified: August 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Prof. Dr. med. Dirk Schadendorf, University Hospital, Essen:
Merkel cell carcinoma
Adjuvant
Nivolumab
Ipilimumab

Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Merkel Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Polyomavirus Infections
DNA Virus Infections
Virus Diseases
Tumor Virus Infections
Carcinoma, Neuroendocrine
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Adenocarcinoma
Neoplasms, Nerve Tissue
Antibodies
Antibodies, Blocking
Nivolumab
Ipilimumab
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Immunological
Antineoplastic Agents