PURPOSE: The antitumor activity and safety of tivozanib, which is a potent and 
selective vascular endothelial growth factor receptor-1, -2, and -3 inhibitor, 
was assessed in patients with advanced/metastatic renal cell carcinoma (RCC).
PATIENTS AND METHODS: In this phase II, randomized discontinuation trial, 272 
patients received open-label tivozanib 1.5 mg/d (one cycle equaled three 
treatment weeks followed by a 1-week break) orally for 16 weeks. Thereafter, 78 
patients who demonstrated ≥ 25% tumor shrinkage continued to take tivozanib, and 
118 patients with less than 25% tumor change were randomly assigned to receive 
tivozanib or a placebo in a double-blind manner; patients with ≥ 25% tumor 
growth were discontinued. Primary end points included safety, the objective 
response rate (ORR) at 16 weeks, and the percentage of randomly assigned 
patients who remained progression free after 12 weeks of double-blind treatment; 
secondary end points included progression-free survival (PFS).
RESULTS: Of 272 patients enrolled onto the study, 83% of patients had clear-cell 
histology, 73% of patients had undergone nephrectomy, and 54% of patients were 
treatment naive. The ORR after 16 weeks of tivozanib treatment was 18% (95% CI, 
14% to 23%). Of the 118 randomized patients, significantly more patients who 
were randomly assigned to receive double-blind tivozanib remained progression 
free after 12 weeks versus patients who received the placebo (49% v 21%; P = 
.001). Throughout the study, the ORR was 24% (95% CI, 19% to 30%), and the 
median PFS was 11.7 months (95% CI, 8.3 to 14.3 months) in the overall study 
population. The most common grade 3 and 4 treatment-related adverse event was 
hypertension (12%).
CONCLUSION: Tivozanib was active and well tolerated in patients with advanced 
RCC. These data support additional development of tivozanib in advanced RCC.