E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
completely resected Merkel cell carcinoma |
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E.1.1.1 | Medical condition in easily understood language |
Merkel cell carcinoma after surgical removal of the tumor |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064025 |
E.1.2 | Term | Merkel cell carcinoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To estimate the efficacy of adjuvant nivolumab monotherapy in completely resected MCC patients in terms of disease-free survival (DFS) rate at 12, 24 and 48 months after date of randomization. |
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E.2.2 | Secondary objectives of the trial |
To describe the safety profile and additional efficacy parameters of the nivolumab treatment in MCC in terms of - 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 rate at 12, 24 and 48 months after randomization
Explorative Objectives: - To assess distant-metastases-free survival (DMFS) and DMFS rate at 12, 24 and 48 months after randomization - To identify and validate prognostic/predictive biomarkers such as immune status, kinetics of the absolute lymphocyte count (ALC), or tumor microenvironment characteristics - To assess quality of life (EORTC QLQ-C30) until 24 months after randomization
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Translational Research Program. The biology and the immunology of MCC are only partially understood, thus it appears mandatory to implement a comprehensive translational research program in order to establish the means to identify the group of patients most likely to benefit from therapy. This translational research program will focus on the immune monitoring of the MCC patients treated in the phase II trial, as well as aim at the discovery of predictive and/or surrogate biomarkers for a successful immune therapy of MCC. The randomized design of the study allows distinguishing predictive from prognostic biomarkers. To reach this goal, sampling for translational research studies (tumor tissue, peripheral blood mononuclear cells (PBMC), plasma, serum) will be done as described in the study protocol. These studies include: - Prognostic/predictive value of the presence of tumor infiltrating lymphocytes in MCC lesions prior to therapy - Expression of immune modulatory molecules in the tumor - Presence of immune modulatory cells in the tumor - Association with MCPyV - Detection of circulating free MCC-specific DNS/microRNA in plasma and serum |
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E.3 | Principal 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 of 0 or 1. 8. No active or chronic infection with HIV, Hepatitis B or C. 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 during treatment phase and for additional 7 months after the last dose of nivolumab) in such a manner that the risk of pregnancy is minimized.
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E.4 | Principal 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. 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 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 during treatment phase and 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 during treatment phase and 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.
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E.5 End points |
E.5.1 | Primary end point(s) |
the primary endpoint is disease-free survival (DFS) rate at 12, 24 and 48 months after date of randomization. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
at 12,24 and 48 months after date of randomization |
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E.5.2 | Secondary end point(s) |
- 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 rate at 12, 24 and 48 months after randomization
Explorative Objectives: - Distant-metastasis-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 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
DFS and DFS rate: at 12, 24 and 48 months after randomization OS and OS rate: at 12, 24 and 48 months after randomization DMFS and DMFS rate: at 12, 24 and 48 months after randomization Quality of Life until 24 months after randomization |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 20 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 21 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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2 years post LPFV (last patient first visit). First visit of the patient is defined as date of first infusion (treatment arm) or date of randomization (observation arm) |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 10 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |