PURPOSE: To assess the maximum tolerated dose (MTD)/dose-limiting toxicities 
(DLT), safety, pharmacokinetics, and pharmacodynamics of tivozanib, a potent and 
selective oral VEGF receptor (VEGFR) tyrosine kinase inhibitor.
EXPERIMENTAL DESIGN: Dose levels of 1.0, 1.5, and 2.0 mg/d tivozanib for 28 days 
followed by 14 days of medication were explored in patients with advanced solid 
tumors.
RESULTS: Forty-one patients were enrolled. Animal data incorrectly predicted 
toxicity, resulting in DLTs at the starting dose (2.0 mg) consisting of grade 3 
proteinuria and hypertension and grade 3 ataxia. At 1.0 mg, no DLT was observed. 
At an intermediate dose (1.5 mg), 1 patient experienced DLT consisting of grade 
3 hypertension. This dose was determined as the MTD. Of 10 additional patients 
treated at 1.5 mg, 1 patient each experienced grade 3 hypertension and grade 3 
fatigue, and 2 patients experienced grade 3 and 4 transaminase elevation. In 12 
additional patients treated at 1.0 mg, no DLT was observed. Pharmacokinetics 
displayed long absorption time, dose proportional exposure, and a half-life of 
4.7 days. Plasma levels of VEGF-A and soluble VEGFR-2 showed dose-dependent 
increases and decreases, respectively. Dynamic contrast-enhanced MRI indicated 
reduction in tumor perfusion. Clinical activity was observed in renal cell 
cancer, colorectal cancer, and other tumors.
CONCLUSION: Tivozanib was well tolerated with manageable side effects. The 
pharmacokinetics profile revealed that tivozanib was suitable for once-daily 
dosing. Encouraging and durable clinical activity was observed. The recommended 
daily dose of tivozanib in a 4-week-on and 2-week-off dosing regimen is 1.5 mg.