Background: Targeted agents have improved outcomes in advanced renal cell carcinoma (aRCC), but patients (pts) inevitably develop resistance. Programmed death-1 receptor ligand (PD-L1) is a key therapeutic target in the reactivation of the immune response against multiple cancers, including RCC. Avelumab* is a fully human IgG1 anti-PD-L1 antibody showing clinical activity in several tumor types. Axitinib is a receptor tyrosine kinase inhibitor (TKI) indicated for treatment of aRCC after failure of one prior systemic therapy; axitinib also shows clinical activity as a first-line (1L) therapy. In recent trials, anti-PD-1/TKI combinations have shown promising clinical efficacy in aRCC, and preliminary data suggest better tolerability for the combination with axitinib. This open-label, multicenter, dose-finding study (NCT02493751) evaluates the novel combination of avelumab + axitinib as 1L therapy in pts with aRCC. Methods: The primary objective for this global phase Ib study is to assess safety and tolerability of avelumab + axitinib, defined by dose-limiting toxicities, and determine the maximum tolerated dose (MTD). Eligibility criteria include: histologically confirmed aRCC with a clear cell component, archival or fresh tumor biopsy, ECOG PS 0-1, no prior immunotherapy, and no prior systemic therapy for aRCC. Up to 55 pts will receive avelumab (10 mg/kg or 5 mg/kg as a 1h IV infusion Q2W) + axitinib (5 mg or 3 mg orally BID) in dose-finding and dose-expansion parts and treatment will be given until confirmed disease progression, unacceptable toxicity, withdrawal, or study termination. Other objectives include assessment of objective tumor response (RECIST 1.1), disease control, progression-free survival, OS, duration of response, time to response, pharmacokinetics, pharmacodynamics, immunogenicity, tumor tissue biomarkers, and safety (NCI-CTCAE v4.03). Enrollment began in Oct 2015. A phase 3 trial of avelumab + axitinib vs sunitinib monotherapy as 1L treatment of aRCC is planned. *Proposed INN. Clinical trial information: NCT02493751