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

• ClinicalTrials.gov Identifier: NCT02196961
• Recruitment Status: Active, not recruiting
• First Posted: July 22, 2014
• Last Update Posted: September 16, 2022
• Sponsor: Prof. Dr. med. Dirk Schadendorf
• Collaborator: Bristol-Myers Squibb
• Information provided by (Responsible Party): Prof. Dr. med. Dirk Schadendorf, University Hospital, Essen

Study Description

Brief Summary:

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

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

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 180 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
• Actual Study Start Date: June 2014
• Estimated Primary Completion Date: August 31, 2024
• Estimated Study Completion Date: August 31, 2024

Arms and Interventions

Arm	Intervention/treatment
No Intervention: Observation; After complete resection of Merkel cell carcinoma, patients randomized to the observational arm will be observed only
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

Outcome Measures

Primary Outcome Measures :

1. Disease-free survival (DFS) rate at 12 months [ Time Frame: 1 years 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.
2. Disease-free survival (DFS) rate at 24 months [ Time Frame: 2 years post last patient first treatment/randomization ]
   The number of patients alive and free of disease at 24 months after randomization
3. Disease-free survival (DFS) rate at 48 months [ Time Frame: 4 years post last patient first treatment/randomization ]
   The number of patients alive and free of disease at 48 months after randomization

Secondary Outcome Measures :

1. Number of adverse events [ Time Frame: 1, 2 and 4 years 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. Overall survival rate at 24 months [ Time Frame: 2 years post last patient first treatment/randomization ]
   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.
4. Overall survival rate at 48 months [ Time Frame: 4 years post last patient first treatment/randomization ]
   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.
5. Disease-free survival (DFS) [ Time Frame: 1, 2 and 4 years post last patient first treatment/randomization ]
   Time from randomization to recurrence of tumor
6. Overall survival (OS) [ Time Frame: 1, 2 and 4 years post last patient first treatment/randomization ]
   Time from randomization to death of patient

Other Outcome Measures:

1. Distant-metastases-free survival (DMFS) at 12 months after randomization [ Time Frame: 1 year post last patient first treatment/randomization ]
   Number of patients free of distant metastases at 12 months after randomization
2. Distant-metastases-free survival (DMFS) at 24 months after randomization [ Time Frame: 2 years post last patient first treatment/randomization ]
   Number of patients free of distant metastases at 24 months after randomization
3. Distant-metastases-free survival (DMFS) at 48 months after randomization [ Time Frame: 4 years post last patient first treatment/randomization ]
   Number of patients free of distant metastases at 48 months after randomization
4. Identification of prognostic/predictive biomarkers [ Time Frame: 2 and 4 years 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
5. Quality of life (EORTC QLQ-C30) until 24 months after randomization [ Time Frame: 2 years post last patient first treatment/randomization ]
   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

Eligibility Criteria

• 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 during treatment phase and for additional 5 months after the last dose of nivolumab, 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 nivolumab.
11. Men of fathering potential must be using an adequate method of contraception to avoid conception and for 7 months after the last dose of nivolumab 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 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 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 additional 5 months 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 additional 7 months after the last dose of investigational product.
12. Use of any investigational or non-registered product (drug or vaccine) other than the study treatment.

Contacts and Locations

Locations

Germany

University Hospital Essen, Dermatology

Essen, NRW, Germany, 45122

Charité Universitätsmedizin Berlin

Berlin, Germany, 10117

Elbeklinikum Buxtehude

Buxtehude, Germany, 21614

University Hospital Dresden, Dermatology

Dresden, Germany, 01307

HELIOS Klinikum Erfurt

Erfurt, Germany, 99089

Universitätsklinikum Freiburg

Freiburg, Germany, 79104

SRH Wald-Klinikum Gera

Gera, Germany, 07548

Hannover Medical School

Hannover, Germany, 30625

National Centre for Tumour Diseases (NCT)

Heidelberg, Germany, 69120

University Hospital Schleswig-Holstein, Kiel

Kiel, Germany, 24105

Universitätsklinikum Leipzig Klinik u. Poliklinik f. Dermatologie, Venerologie u. Allergologie

Leipzig, Germany, 04103

Universitätsklinikum Mainz Hautklinik und Poliklinik

Mainz, Germany, 55131

Universitätsklinikum Mannheim Klinik f. Dermatologie, Venerologie u. Allergologie

Mannheim, Germany, 68167

University Hospital München (LMU)

Munich, Germany, 80337

Universitätsklinikum Münster Zentrale Studienkoordination für innovative Dermatologie (ZID)

Münster, Germany, 48149

Specialist clinic in Hornheide

Münster, Germany, 48157

Universitätsklinikum Regensburg

Regensburg, Germany, 93053

University Hospital Tübingen

Tübingen, Germany, 72076

Universitätsklinikum Würzburg Klinik u. Poliklinik f. Dermatologie, Venerologie u. Allergologie

Würzburg, Germany, 97080

Netherlands

The Netherlands Cancer Institute / Antoni van Leeuwenhoek Hospital (NKI/AVL)

Amsterdam, Netherlands, 1066 CX

Sponsors and Collaborators

Prof. Dr. med. Dirk Schadendorf

Bristol-Myers Squibb

Investigators

• Principal Investigator: Dirk Schadendorf, Prof. Dr.; University Hospital, Essen

More Information

• Responsible Party: Prof. Dr. med. Dirk Schadendorf, University Hospital, Essen
• ClinicalTrials.gov Identifier: NCT02196961
• Other Study ID Numbers: CA184-205
• First Posted: July 22, 2014
• Last Update Posted: September 16, 2022
• Last Verified: September 2022

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

Additional relevant MeSH terms:

Carcinoma, Merkel Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Polyomavirus Infections; DNA Virus Infections; Virus Diseases; Infections; Tumor Virus Infections; Carcinoma, Neuroendocrine; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Adenocarcinoma; Neoplasms, Nerve Tissue; Nivolumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action