Background: Tivozanib is a biochemically potent and selective VEGF tyrosine kinase inhibitor in clinical development in RCC. Other agents used for treatment of RCC inhibit multiple tyrosine kinases in addition to the VEGF receptor tyrosine kinase, leading to off-target toxicities such as fatigue, hand-foot syndrome, stomatitis, and neutropenia. The adverse event (AE) profile of tivozanib demonstrates minimal off-target toxicities. TIVO-1 (AV-951-09-301) was an open-label, randomized, controlled, multi-national, multi-center, parallel-arm trial comparing tivozanib to sorafenib in patients with advanced RCC. The blinded independent radiological assessment showed the median progression free survival (mPFS) in the tivozanib arm to be 11.9 months (95% confidence interval (CI) [9.3, 14.7]), compared with 9.1 months (95% CI [7.3, 9.5]) in the sorafenib arm (p = 0.042, HR = 0.797). Overall survival had a negative trend, most likely due to a one-way crossover for patients randomized to sorafenib. This study is designed, in part, to demonstrate that the negative trend in OS was an artifact. Methods: Subjects with metastatic RCC who have failed 2 or 3 prior systemic regimens, one of which includes a VEGFR TKI other than sorafenib or tivozanib, will be randomized in a 1:1 ratio stratified by the IMDC risk category (favorable; intermediate; poor) and prior therapy (two VEGFR TKIs; a prior checkpoint inhibitor plus a prior VEGFR TKI; a prior VEGFR TKI plus any other systemic agent). The primary objective is to compare the progression-free survival (PFS) of subjects randomized to tivozanib with those randomized to sorafenib as assessed by blinded independent radiological review (IRR). Secondary endpoints are overall survival, objective response rate, and duration of response. Clinical trial information: NCT02627963