A Study to Evaluate the Safety and Activity of Belvarafenib as a Single Agent and in Combination With Either Cobimetinib or Cobimetinib Plus Nivolumab in Patients With NRAS-mutant Advanced Melanoma.

This study will evaluate the safety, pharmacokinetics, and activity of belvarafenib as a single agent and in combination with either cobimetinib or cobimetinib plus nivolumab in patients with NRAS-mutant advanced melanoma who have received anti-PD-1/PD-L1 therapy.

The study will evaluate three treatment regimens in three arms: a belvarafenib monotherapy arm (Belva arm); a belvarafenib plus cobimetinib arm (Belva + Cobi arm) in an initial dose-finding phase followed by an expansion phase and a belvarafenib plus cobimetinib plus nivolumab arm (Belva + Cobi + Nivo arm) in a run-in phase followed by an expansion phase.

Inclusion Criteria: * ECOG Performance Status of 0 or 1 * Histologically confirmed, metastatic (recurrent or de novo Stage IV) or unresectable locally advanced (Stage III) cutaneous melanoma, that has progressed on or after treatment with anti-PD-1 or anti-PD-L1 therapy. Patients may have received up to two lines of systemic cancer therapy. Treatment with anti-PD-1/PD-L1 in the adjuvant setting is acceptable. Patients must have progressed disease at study entry * Documentation of NRAS mutation-positive within 5 years prior to screening * Tumor specimen availability * Adequate hematologic and end-organ function * Measurable disease per RECIST v1.1 Exclusion Criteria: * Prior treatment with a pan-RAF inhibitor * Treatment with systemic immunotherapy agents (e.g., anti-CTLA4, anti-PD(L)1, cytokine therapy, investigational therapy, etc.) within 28 days prior to C1D1 * Symptomatic, untreated, or actively progressing CNS metastases * History or signs/symptoms of clinically significant cardiovascular disease * Known clinically significant liver disease * History of autoimmune disease or immune deficiency * Prior treatment with a MEK inhibitor (cobimetinib arm) * History of or evidence of retinal pathology on ophthalmologic examination (cobimetinib arm) * History of immune-related AE attributed to prior anti-PD(L)1 therapy that resulted in permanent discontinuation of anti-PD(L)1 therapy (nivolumab arm)