Tivozanib is a potent and selective inhibitor of vascular endothelial growth 
factor receptor (VEGFR) tyrosine kinases. A previous clinical trial in the EU 
and USA indicated that tivozanib at the maximum tolerated dose of 1.5 mg/day 
showed an antitumor activity in patients with renal cell carcinoma. This 
Japanese phase I study was designed to determine the recommended phase II dose 
of tivozanib for Japanese patients; secondary objectives included 
pharmacokinetic/pharmacodynamic profiles and preliminary efficacy. Daily 
treatment with tivozanib in a 3-weeks-on/1-week-off cycle was examined in nine 
Japanese patients with advanced solid tumors in the 3 + 3 design (Level 1, 1.0 
mg; Level 2, 1.5 mg). No dose-limiting toxicity was observed throughout the 
study, and the maximum tolerated dose was not reached. The most commonly 
observed drug-related adverse events were diarrhea, dysphonia, rash, thyroid 
stimulating hormone increase, and with severity grade ≥3, hand-foot skin 
reaction, hypertension, and proteinuria. Those adverse events were generally 
well-manageable and mostly resolved within the tolerability evaluation period. 
Serum exposure to tivozanib resulted in t1/2 of more than >60 h. Increase of 
plasma VEGF and decrease of plasma VEGFR-1 and VEGFR-2 were observed 1-3 weeks 
after tivozanib treatment. Although no complete or partial response was 
observed, long-term stable disease continuing more than 170 days was observed in 
three renal cell carcinoma patients who had failed prior VEGFR inhibitors. In 
conclusion, 1.5 mg/day of tivozanib in a 3-weeks-on/1-week-off setting was 
tolerable in Japanese patients, and was recommended for further clinical trials 
in the Japanese population. Clinical trial Registration No: JapicCTI-090854.