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

Merkel Cell Carcinoma Clinical Trial

— 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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02196961
• Other study ID #: CA184-205
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: June 2014
• Est. completion date: August 31, 2024

Study information

• Verified date: November 2023
• Source: University Hospital, Essen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 180
• Est. completion date: August 31, 2024
• Est. primary completion date: August 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Merkel Cell
• Merkel Cell Carcinoma

Intervention

Drug:
• Nivolumab
adjuvant treatment of completely resected Merkel cell carcinoma

Locations

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

Sponsors (2)

Lead Sponsor	Collaborator
Prof. Dr. med. Dirk Schadendorf	Bristol-Myers Squibb

Countries where clinical trial is conducted

Germany,  Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Distant-metastases-free survival (DMFS) at 12 months after randomization	Number of patients free of distant metastases at 12 months after randomization	1 year post last patient first treatment/randomization
Other	Distant-metastases-free survival (DMFS) at 24 months after randomization	Number of patients free of distant metastases at 24 months after randomization	2 years post last patient first treatment/randomization
Other	Distant-metastases-free survival (DMFS) at 48 months after randomization	Number of patients free of distant metastases at 48 months after randomization	4 years post last patient first treatment/randomization
Other	Identification of prognostic/predictive biomarkers	Identify and validate prognostic/predictive biomarkers such as immune status, kinetics of the absolute lymphocyte count (ALC), or tumor microenvironment characteristics	2 and 4 years post last patient first treatment/randomization
Other	Quality of life (EORTC QLQ-C30) until 24 months after 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	2 years post last patient first treatment/randomization
Primary	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.	1 years post last patient first treatment/randomization
Primary	Disease-free survival (DFS) rate at 24 months	The number of patients alive and free of disease at 24 months after randomization	2 years post last patient first treatment/randomization
Primary	Disease-free survival (DFS) rate at 48 months	The number of patients alive and free of disease at 48 months after randomization	4 years post last patient first treatment/randomization
Secondary	Number of adverse events	Adverse events according to CTCAE, Version 4.0 criteria, that are related to the administration of Ipilimumab	1, 2 and 4 years post last patient first treatment/randomization
Secondary	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.	1 year post last patient first treatment/randomization
Secondary	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.	2 years post last patient first treatment/randomization
Secondary	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.	4 years post last patient first treatment/randomization
Secondary	Disease-free survival (DFS)	Time from randomization to recurrence of tumor	1, 2 and 4 years post last patient first treatment/randomization
Secondary	Overall survival (OS)	Time from randomization to death of patient	1, 2 and 4 years post last patient first treatment/randomization