Background: Pazopanib is an angiogenesis inhibitor targeting VEGFR-1, -2, and -3; PDGFR-α and -β; and the receptor c-Kit, and is indicated for the treatment of subjects with advanced RCC and advanced soft tissue sarcoma. MK-3475 (Merck) is a potent and highly-selective humanized mAb of the IgG4/kappa isotype designed to block directly the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Proangiogenic factors suppress various immune functions whereas antiangiogenic agents have potential to modulate the tumor microenvironment and improve immunotherapy. High expression of PD-L1 on tumor cells, and to a lesser extent of PD-L2, has been found to correlate with poor prognosis and survival in various cancer types including RCC [Thompson 2007]. An analysis of patients with RCC treated with paz demonstrated that elevated expression of PD-L1 correlates with shorter PFS [Figueroa 2013]. Additionally an objective response rate of 27% in RCC patients was reported in an early phase study with another antibody to PD-1 forall doses tested[Topalian 2012]. These findings suggest that MK-3475 may potentiate the activity of paz in patients with RCC. This Phase I/II trial has been undertaken to test the safety and tolerability of paz in combination with MK-3475 in advanced RCC, and assess the efficacy of the combination as compared with paz or MK-3475 alone. Methods: This is an open-label, 2-part multi-center study of paz and/or MK-3475 in treatment-naïve subjects with advanced predominantly clear cell RCC. Part 1 is Phase I dose escalation using a modified 3+ 3 design, with combination dosing starting at 800mg/day paz + 2mg/kgQ2W MK-3475, followed by an expansion cohort to confirm the maximum tolerated regimen and the recommended Phase 2 dose. Part 2 is a randomized 3-arm (1:1:1) Phase II study to evaluate the clinical efficacy and safety of paz + MK-3475 as compared to paz or MK-3475 alone. The primary endpoint in Part 2 is PFS by RECIST v1.1. Secondary endpoints are PFS rate at 18 months, PFS by modified RECIST criteria, overall response, stable disease ≥6 months, time to response, duration of response, overall survival, safety and tolerability. Part 1 has opened to enrollment. Clinical trial information: NCT02014636.