Clinical Trial Finder

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

Arms

Experimental: Arm A: 2 courses ipi 3 + nivo 1

Patients receive 2 courses standard combination of ipilimumab 3 mg/kg + nivolumab 1 mg/kg q3wk prior to surgery at week 6. Blood for PBMCs and biopsies will be taken for translation research.

Experimental: Arm B: 2 courses ipi 1 + nivo 3

Patients receive 2 courses ipilimumab 1 mg/kg + nivolumab 3 mg/kg q3wk prior to surgery at week 6. Blood for PBMCs and biopsies will be taken for translation research.

Experimental: Arm C: 2 courses ipi 3 + 2 courses nivo 3

Patients receive 2 courses of ipilimumab 3 mg/kg q3wks, directly followed (> 2 hours and < 24 hours) by 2 courses nivolumab 3 mg/kg every 2 weeks prior to surgery at week 6. Blood for PBMCs and biopsies will be taken for translation research.

Experimental: PRADO extension cohort

Patients will be treated with 2 courses ipilimumab and nivolumab at the dose level defined as the winner dosing scheme from OpACIN-neo, which is the dosing schedule of arm B. Surgery and adjuvant therapy - Patients achieving a pCR or pnCR will not undergo CLND and will not receive any adjuvant treatment. Structural follow-up will be perfomed every 12 weeks by CT, ultrasound of regional lymph nodes. - Patients achieving a pPR will undergo CLND and start structural follow-up (including CT and physical examination) every 12 weeks thereafter without any adjuvant treatment. - Patients achieving no response (pNR) will undergo CLND and start at week 12 with adjuvant nivolumab 480mg q4wks for 52 weeks + radiotherapy (according to patient's and physicians' decision). In patients that are BRAF V600E/K mutation positive, adjuvant BRAF+MEK

Interventions

Drug: - Ipilimumab

Drug: - Nivolumab

Procedure: - Surgery

Surgery will be done at 6 weeks

Procedure: - Blood for PBMCs

Blood will be taken for translational research on PBMCs

Procedure: - Biopsies

Biopsies will be taken during screening and at relapse.