Background: Sitravatinib (MGCD516) is an oral, potent small molecule inhibitor of a closely related spectrum of receptor tyrosine kinases (RTKs) including the TAM family (AXL, MER), split RTKs (VEGFR2, PDGFR, KIT), RET and MET. Because of the importance of sitravatinib targets in the pathogenesis of ccRCC and putative roles for MET and AXL in intrinsic and acquired resistance to anti-angiogenic agents, sitravatinib was evaluated in patients (pts) with ccRCC after failure of AAT. Methods: Study 516-001 is a Phase 1/1b study of sitravatinib in pts with advanced solid tumors. After determination of the MTD in Phase 1, pts with ccRCC after failure of AAT and pts with qualifying genetic alterations in sitravatinib targets were enrolled into distinct Phase1b cohorts using respective multi-stage designs. Pts received 150mg sitravatinib once daily in continuous 21-day cycles and were evaluated for safety, PK and clinical activity. Here we report on the completion of Stage 2 enrollment of the Phase1b ccRCC cohort. Results: 89 pts (50 men/39 women; median age 67 years; range 36-84) with advanced solid tumors were enrolled in Phase1b cohorts, including 28 pts (20 men/8 women; median age 67.5 years; range 47-77) in the ccRCC cohort who received a median of 3 prior treatment regimens. Prior AAT included sunitinib (n=17), pazopanib (n=13) and axitinib (n=9); 12 pts received ≥2 prior angiogenesis inhibitors. One partial response (PR) among the first 10 evaluable ccRCC pts in Stage 1 met criteria for enrollment of a total of 20 evaluable pts for Stage 2, where 4 confirmed PRs were observed and an unconfirmed PR in a pt who had received 4 prior AATs. Prolonged stable disease for at least 24 weeks was observed in an additional 5 pts. Treatment-related AEs (>20% of pts; Grades 1-3) included diarrhea, hypertension, nausea, vomiting, fatigue and decreased appetite. Conclusions: Stage 2 enrollment of the Study 516-001 Phase1b cohort of ccRCC refractory to AAT was completed. Sitravatinib treatment resulted in 4 confirmed PRs in a heavily pre-treated patient population and demonstrated a manageable safety profile. Further evaluation of sitravatinib in ccRCC is warranted. Clinical trial information: NCT02219711