Optimal Neo-adjuvant Combination Scheme of Ipilimumab and Nivolumab

Inclusion Criteria: * Adults at least 18 years of age * World Health Organization (WHO) Performance Status 0 or 1 * Cytologically or histologically confirmed resectable stage III melanoma with one or more macroscopic lymph node metastases (measurable according to RECIST 1.1), that can be biopsied, and no history of in-transit metastases within the last 6 months * No other malignancies, except adequately treated and a cancer-related life-expectancy of more than 5 years * Patient willing to undergo triple tumor biopsies and extra blood withdrawal during screening and in case of relapse * No prior immunotherapy targeting CTLA-4, PD-1 or PD-L1 * No immunosuppressive medications within 6 months prior study inclusion * Screening laboratory values must meet the following criteria: WBC ≥ 2.0x109/L, Neutrophils ≥1.5x109/L, Platelets ≥100 x109/L, Hemoglobin ≥5.5 mmol/L, Creatinine ≤1.5x ULN, AST ≤ 1.5 x ULN, ALT ≤ 1.5 x ULN, Bilirubin ≤1.5 X ULN * Normal LDH * Women of childbearing potential (WOCBP) must use appropriate method(s) of contra-ception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug * Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of ipilimumab + nivolumab * Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product * Women who are not of childbearing potential (i.e., who are postmenopausal), or surgically sterile as well as azoospermic men do not require contraception * Patient is capable of understanding and complying with the protocol requirements and has signed the Informed Consent document. Exclusion Criteria: * Distantly metastasized melanoma * History of in-transit metastases within the last 6 months * No measurable lesion according to RECIST 1.1 * Subjects with any active autoimmune disease or a documented history of autoimmune disease, or history of syndrome that required systemic steroids or immunosuppressive medications, except for subjects with vitiligo or resolved childhood asthma/atopy * Prior CTLA-4 or PD-1/PD-L1 targeting immunotherapy * Radiotherapy prior or post-surgery * Patients will be excluded if they test positive for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody), indicating acute or chronic infection * Patients will be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) * Allergies and Adverse Drug Reaction * History of allergy to study drug components * History of severe hypersensitivity reaction to any monoclonal antibody * Underlying medical conditions that, in the Investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity determination or adverse events; * Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids; * Use of other investigational drugs before study drug administration 30 days and 5 half-times before study inclusion * Pregnant or nursing