- Prior treatment with a BRAF or a MEK inhibitor - Prior systemic anti-cancer treatment for Stage IIIC (unresectable) or Stage IV (metastatic) melanoma. Prior systemic treatment in the adjuvant setting is allowed. (Note: Ipilimumab treatment must end at least 8 weeks prior to randomization.) - The subject has received major surgery or certain types of cancer therapy within 21 days of starting treatment - Current use of prohibited medication listed in the protocol - Left ventricular ejection fraction less than the lower limit of normal - Uncontrolled blood pressure - History or current evidence of retinal vein occlusion or central serous retinopathy - Brain metastases unless previously treated with surgery or stereotactic radiosurgery and the disease has been stable for at least 12 weeks - The subject is pregnant or nursing.