Purpose: To assess the maximum tolerated dose (MTD)/dose-limiting toxicities (DLTs), safety, pharmacokinetics, and pharmacodynamics of tivozanib, a potent and selective oral VEGFR tyrosine kinase inhibitor. Experimental Design: Dose levels of 1.0, 1.5, and 2.0 mg/day tivozanib for 28 days followed by 14 days off 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), one patient experienced DLT consisting of grade 3 hypertension. This dose was determined as the MTD. Of 10 additional patients treated at 1.5 mg, one patient each experienced grade 3 hypertension and grade 3 fatigue, and two 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 sVEGFR-2 showed dose-dependent increases and decreases, respectively. Dynamic contrast-enhanced magnetic resonance imaging indicated reduction in tumor perfusion. Clinical activity was observed in renal cell cancer, colorectal cancer, and other tumors. Conclusions: 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 2 week off dosing regimen is 1.5 mg.
- Received February 15, 2011.
- Revision received August 23, 2011.
- Accepted September 11, 2011.
- Copyright © 2011, American Association for Cancer Research.