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

Primary Purpose

Merkel Cell Carcinoma

Status
Active
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Nivolumab
Sponsored by
Prof. Dr. med. Dirk Schadendorf
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Merkel Cell Carcinoma focused on measuring Merkel cell carcinoma, Adjuvant, Nivolumab

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • University Hospital Essen, Dermatology
  • Charité Universitätsmedizin Berlin
  • Elbeklinikum Buxtehude
  • University Hospital Dresden, Dermatology
  • HELIOS Klinikum Erfurt
  • Universitätsklinikum Freiburg
  • SRH Wald-Klinikum Gera
  • Hannover Medical School
  • National Centre for Tumour Diseases (NCT)
  • University Hospital Schleswig-Holstein, Kiel
  • Universitätsklinikum Leipzig Klinik u. Poliklinik f. Dermatologie, Venerologie u. Allergologie
  • Universitätsklinikum Mainz Hautklinik und Poliklinik
  • Universitätsklinikum Mannheim Klinik f. Dermatologie, Venerologie u. Allergologie
  • University Hospital München (LMU)
  • Universitätsklinikum Münster Zentrale Studienkoordination für innovative Dermatologie (ZID)
  • Specialist clinic in Hornheide
  • Universitätsklinikum Regensburg
  • University Hospital Tübingen
  • Universitätsklinikum Würzburg Klinik u. Poliklinik f. Dermatologie, Venerologie u. Allergologie
  • The Netherlands Cancer Institute / Antoni van Leeuwenhoek Hospital (NKI/AVL)

Arms of the Study

Arm 1

Arm 2

Arm Type

No Intervention

Experimental

Arm Label

Observation

Nivolumab

Arm Description

After complete resection of Merkel cell carcinoma, patients randomized to the observational arm will be observed only

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).

Outcomes

Primary Outcome Measures

Disease-free survival (DFS) rate at 12 months
The number of patients alive and free of disease at 12 months after randomization in arm A compared to DFS in arm B.
Disease-free survival (DFS) rate at 24 months
The number of patients alive and free of disease at 24 months after randomization
Disease-free survival (DFS) rate at 48 months
The number of patients alive and free of disease at 48 months after randomization

Secondary Outcome Measures

Number of adverse events
Adverse events according to CTCAE, Version 4.0 criteria, that are related to the administration of Ipilimumab
Overall survival rate at 12 months
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.
Overall survival rate at 24 months
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.
Overall survival rate at 48 months
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.
Disease-free survival (DFS)
Time from randomization to recurrence of tumor
Overall survival (OS)
Time from randomization to death of patient

Full Information

First Posted
June 20, 2014
Last Updated
September 13, 2022
Sponsor
Prof. Dr. med. Dirk Schadendorf
Collaborators
Bristol-Myers Squibb
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1. Study Identification

Unique Protocol Identification Number
NCT02196961
Brief Title
Adjuvant Therapy of Completely Resected Merkel Cell Carcinoma With Immune Checkpoint Blocking Antibodies vs Observation
Acronym
ADMEC-O
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 Type
Interventional

2. Study Status

Record Verification Date
September 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
June 2014 (Actual)
Primary Completion Date
August 31, 2024 (Anticipated)
Study Completion Date
August 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Prof. Dr. med. Dirk Schadendorf
Collaborators
Bristol-Myers Squibb

4. Oversight

Data Monitoring Committee
No

5. 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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Merkel Cell Carcinoma
Keywords
Merkel cell carcinoma, Adjuvant, Nivolumab

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
180 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Observation
Arm Type
No Intervention
Arm Description
After complete resection of Merkel cell carcinoma, patients randomized to the observational arm will be observed only
Arm Title
Nivolumab
Arm Type
Experimental
Arm 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(s)
Nivolumab
Other Intervention Name(s)
Opdivo
Intervention Description
adjuvant treatment of completely resected Merkel cell carcinoma
Primary Outcome Measure Information:
Title
Disease-free survival (DFS) rate at 12 months
Description
The number of patients alive and free of disease at 12 months after randomization in arm A compared to DFS in arm B.
Time Frame
1 years post last patient first treatment/randomization
Title
Disease-free survival (DFS) rate at 24 months
Description
The number of patients alive and free of disease at 24 months after randomization
Time Frame
2 years post last patient first treatment/randomization
Title
Disease-free survival (DFS) rate at 48 months
Description
The number of patients alive and free of disease at 48 months after randomization
Time Frame
4 years post last patient first treatment/randomization
Secondary Outcome Measure Information:
Title
Number of adverse events
Description
Adverse events according to CTCAE, Version 4.0 criteria, that are related to the administration of Ipilimumab
Time Frame
1, 2 and 4 years post last patient first treatment/randomization
Title
Overall survival rate at 12 months
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.
Time Frame
1 year post last patient first treatment/randomization
Title
Overall survival rate at 24 months
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.
Time Frame
2 years post last patient first treatment/randomization
Title
Overall survival rate at 48 months
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.
Time Frame
4 years post last patient first treatment/randomization
Title
Disease-free survival (DFS)
Description
Time from randomization to recurrence of tumor
Time Frame
1, 2 and 4 years post last patient first treatment/randomization
Title
Overall survival (OS)
Description
Time from randomization to death of patient
Time Frame
1, 2 and 4 years post last patient first treatment/randomization
Other Pre-specified Outcome Measures:
Title
Distant-metastases-free survival (DMFS) at 12 months after randomization
Description
Number of patients free of distant metastases at 12 months after randomization
Time Frame
1 year post last patient first treatment/randomization
Title
Distant-metastases-free survival (DMFS) at 24 months after randomization
Description
Number of patients free of distant metastases at 24 months after randomization
Time Frame
2 years post last patient first treatment/randomization
Title
Distant-metastases-free survival (DMFS) at 48 months after randomization
Description
Number of patients free of distant metastases at 48 months after randomization
Time Frame
4 years post last patient first treatment/randomization
Title
Identification of prognostic/predictive biomarkers
Description
Identify and validate prognostic/predictive biomarkers such as immune status, kinetics of the absolute lymphocyte count (ALC), or tumor microenvironment characteristics
Time Frame
2 and 4 years post last patient first treatment/randomization
Title
Quality of life (EORTC QLQ-C30) until 24 months after 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
Time Frame
2 years post last patient first treatment/randomization

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: The patient is willing and able to give written informed consent. Central histological confirmation of diagnosis of Merkel cell carcinoma (MCC). All MCC manifestations have been completely resected by surgery within 12 weeks before enrolment. No currently present metastases (as confirmed by standard imaging studies (e.g. suggested by S2k guidelines)). No previous systemic therapy for MCC. 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) ECOG performance status 0 or 1. No active or chronic infection with HIV, Hepatitis B (HBV) or C (HCV). Men and women, ≥ 18 years of age. 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. 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: 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. Other serious illnesses, e.g., serious infections requiring i.v. antibiotics. 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. 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. Any non-oncology vaccine therapy for up to 1 month before or after any dose of nivolumab. 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). Chronic use of immunosuppressive agents or systemic corticosteroids. 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. The patient has psychiatric or addictive disorders that may compromise his/her ability to give informed consent or to comply with the trial procedures. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness. Men of reproductive potential unwilling to use an adequate method to avoid pregnancy for additional 7 months after the last dose of investigational product. Use of any investigational or non-registered product (drug or vaccine) other than the study treatment.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Dirk Schadendorf, Prof. Dr.
Organizational Affiliation
University Hospital, Essen
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Hospital Essen, Dermatology
City
Essen
State/Province
NRW
ZIP/Postal Code
45122
Country
Germany
Facility Name
Charité Universitätsmedizin Berlin
City
Berlin
ZIP/Postal Code
10117
Country
Germany
Facility Name
Elbeklinikum Buxtehude
City
Buxtehude
ZIP/Postal Code
21614
Country
Germany
Facility Name
University Hospital Dresden, Dermatology
City
Dresden
ZIP/Postal Code
01307
Country
Germany
Facility Name
HELIOS Klinikum Erfurt
City
Erfurt
ZIP/Postal Code
99089
Country
Germany
Facility Name
Universitätsklinikum Freiburg
City
Freiburg
ZIP/Postal Code
79104
Country
Germany
Facility Name
SRH Wald-Klinikum Gera
City
Gera
ZIP/Postal Code
07548
Country
Germany
Facility Name
Hannover Medical School
City
Hannover
ZIP/Postal Code
30625
Country
Germany
Facility Name
National Centre for Tumour Diseases (NCT)
City
Heidelberg
ZIP/Postal Code
69120
Country
Germany
Facility Name
University Hospital Schleswig-Holstein, Kiel
City
Kiel
ZIP/Postal Code
24105
Country
Germany
Facility Name
Universitätsklinikum Leipzig Klinik u. Poliklinik f. Dermatologie, Venerologie u. Allergologie
City
Leipzig
ZIP/Postal Code
04103
Country
Germany
Facility Name
Universitätsklinikum Mainz Hautklinik und Poliklinik
City
Mainz
ZIP/Postal Code
55131
Country
Germany
Facility Name
Universitätsklinikum Mannheim Klinik f. Dermatologie, Venerologie u. Allergologie
City
Mannheim
ZIP/Postal Code
68167
Country
Germany
Facility Name
University Hospital München (LMU)
City
Munich
ZIP/Postal Code
80337
Country
Germany
Facility Name
Universitätsklinikum Münster Zentrale Studienkoordination für innovative Dermatologie (ZID)
City
Münster
ZIP/Postal Code
48149
Country
Germany
Facility Name
Specialist clinic in Hornheide
City
Münster
ZIP/Postal Code
48157
Country
Germany
Facility Name
Universitätsklinikum Regensburg
City
Regensburg
ZIP/Postal Code
93053
Country
Germany
Facility Name
University Hospital Tübingen
City
Tübingen
ZIP/Postal Code
72076
Country
Germany
Facility Name
Universitätsklinikum Würzburg Klinik u. Poliklinik f. Dermatologie, Venerologie u. Allergologie
City
Würzburg
ZIP/Postal Code
97080
Country
Germany
Facility Name
The Netherlands Cancer Institute / Antoni van Leeuwenhoek Hospital (NKI/AVL)
City
Amsterdam
ZIP/Postal Code
1066 CX
Country
Netherlands

12. IPD Sharing Statement

Plan to Share IPD
No

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Adjuvant Therapy of Completely Resected Merkel Cell Carcinoma With Immune Checkpoint Blocking Antibodies vs Observation

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