This is an open-label three-arm phase 2 trial (including a Simon stage 2 design) consisting of 90 stage III melanoma patients randomized 1:1:1 to receive either 2 courses 3 mg/kg ipilimumab + 1 mg/kg nivolumab every 3 weeks (Arm A), 2 courses 1 mg/kg ipilimumab + 3 mg/kg nivolumab every 3 weeks (Arm B), or 2 courses ipilimumab 3 mg/kg, directly followed by 2 courses nivolumab 3 mg/kg every 2 weeks (Arm C). All three treatment arms are applied prior to surgery at week 6, 30 patients per arm. Patients will be stratified according to treatment center. An interim analysis will be performed after 13 patients have been included in each arm, thus in total 39 patients have been included.

PRADO extension cohort The trial will enroll in total about 100-110 melanoma patients with macroscopic stage III disease (RECIST measurable disease); inclusion will stop when 50 patients have achieved a pCR or pnCR. All patients will be treated (after marker placement into the largest lymph node metastasis) with the winner combination identified in the first part of the OpACIN-neo study which is 2 courses ipilimumab 1mg/kg + nivolumab 3mg/kg, q3wks. After 6 weeks of treatment, the patients will undergo only surgical resection of the marked index lymph node. Thereafter subsequent surgery and adjuvant therapy will be performed according to the achieved pathologic response.

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