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

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

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

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.

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.