Treatment of Metastatic Melanoma

Eligibility Details: Key inclusion criteria: - Histologically confirmed unresectable or metastatic stage IIIB/C/D or IV melanoma using AJCC edition 8 - Previously treated for unresectable or metastatic melanoma: - Subjects with V600BRAF wild-type disease must have received prior systemic therapy for unresectable or metastatic melanoma with anti-PD-1/PD-L1. Additionally, subjects may have received anti-CTLA-4 as a single agent or in combination with anti-PD-1/PD-L1, irrespective of the sequence. No additional systemic treatment is allowed for advanced or metastatic melanoma. A maximum of two prior lines of systemic therapies for unresectable or metastatic melanoma are allowed. The last dose of prior therapy (anti-PD-1, anti-PD-L1 or anti-CTLA-4) must have been received more than four weeks before randomization. - Subjects with V600BRAF mutant disease must have received prior systemic therapy for unresectable or metastatic melanoma with anti-PD-1/PD-L1, and V600BRAF inhibitor. Additionally, subjects may have received anti-CTLA-4 as a single agent or in combination with anti-PD-1/PD-L1, or MEK inhibitor (in combination with V600BRAF inhibitor or as a single agent), irrespective of the sequence. No additional systemic treatment is allowed for advanced or metastatic melanoma . A maximum of three prior lines of systemic therapies for unresectable or metastatic melanoma are allowed. The last dose of prior therapy must have been received more than 4 weeks (for anti-PD-1, anti-PD-L1 or anti-CTLA-4) or more than 2 weeks (for V600BRAF or MEK inhibitor) prior to randomization. - All subjects (with V600BRAF wild-type disease and with V600BRAF mutant disease) must have documented disease progression as per RECIST v1.1 while on/after the last therapy received prior to study entry and while on/after treatment with anti-PD1/PD-L1. The last progression must have occured within 12 weeks prior to randomization in the study. - ECOG performance status 0-2 - At least one measurable lesion per RECIST v1.1 - At least one lesion, suitable for sequential mandatory tumor biopsies (screening and on-treatment) in accordance with the biopsy guidelines specified in protocol. The same lesion must be biopsied sequentially. - Screening tumor biopsy must fulfill the tissue quality criteria outlined in the protocol, as assessed by a local pathologist Key exclusion criteria common to all combination arms: - Subjects with uveal or mucosal melanoma - Presence of clinically active or unstable brain metastasis at time of screening. Note: Subjects with previously unstable brain lesions who have been definitively treated with stereotactic radiation therapy, surgery or gamma knife therapy are eligible. - Subjects with brain lesions who are untreated (i.e. newly discovered brain lesions during screening) or received whole brain radiation must have documented stable disease as assessed by two consecutive assessments ≥ 4 weeks apart and have not required steroids for at least ≥ 4 weeks prior to randomization. - Use of any live vaccines against infectious diseases within 3 months before randomization. - Active infection requiring systemic antibiotic therapy at time of randomization. - Systemic chronic steroid therapy (˃ 10mg/day prednisone or equivalent) or any other immunosuppressive therapy administered within 7 days prior to randomization. Note: Local steroids such as topical, inhaled, nasal and ophthalmic steroids are allowed. - Active, known or suspected autoimmune disease or a documented history of autoimmune disease. Note: Subjects with vitiligo, controlled type I diabetes mellitus on stable insulin dose, residual autoimmune-related hypothyroidism only requiring hormone replacement or psoriasis not requiring systemic treatment or conditions not expected to recur in the absence of an external trigger are permitted. - Prior allogenic bone marrow or solid organ transplant - History of known hypersensitivity to any of the investigational drugs used in this study - Prior systemic therapy for unresectable or metastatic melanoma with any investigational agent, or with any other agent except anti-PD-1/PD-L1 and anti-CTLA-4 (and V600BRAF and MEK inhibitors if subject has V600BRAF mutant disease). Prior neoadjuvant and/or adjuvant therapy for melanoma completed less than 6 months before the start of the study treatment (e.g targeted therapy, immunotherapy (e.g interferon, checkpoint inhibitors or any other immunotherapy), chemotherapy and tumor vaccines). - Medical history or current diagnosis of myocarditis - Cardiac Troponin T (or Troponin I) level > 2 x ULN at screening