Final results of a phase Ib study of tivozanib and FOLFOX6 in patients (pts) with advanced gastrointestinal (GI) tumors.

Abstract

4132 Background: Tivozanib is a potent, selective, oral small-molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2 and 3 with a long half-life. A Phase I study found tivozanib's maximum tolerated dose (MTD) to be 1.5 mg/d and responses were observed in pts with colorectal cancer (CRC) and other tumors. Tivozanib has shown additive anti-tumor activity with 5-fluorouracil in a preclinical breast tumor model. FOLFOX6 is a standard chemotherapy for GI cancers. This open-label, Phase Ib study (NCT00660153) sought to determine the MTD, dose-limiting toxicities (DLTs), pharmacokinetics (PK), and anti-tumor activity of escalating doses of tivozanib combined with a modified (m) FOLFOX6 regimen (85 mg/kg2 oxaliplatin) in pts with advanced GI tumors. Methods: Tivozanib was administered once daily in 4-week cycles (3 weeks on, 1 week off) with mFOLFOX6 administered on Days 1 and 15 of each cycle. Pts also received a single dose of tivozanib on day -5 for PK analysis. Pts were allowed to continue tivozanib following discontinuation of mFOLFOX6. Results: Twenty two pts (14:8 male:female; median age 58 years; 91% Caucasian) received tivozanib 0.5 mg (n=9), 1.0 mg (n=3), or 1.5 mg (n=10) and mFOLFOX6. Pts received a median of 5.2 (range 0.0 to 25.1) months of treatment. DLTs were observed in 2 pts on tivozanib 0.5 mg (reversible Grade [Gr] 3 diarrhea and Gr 3/4 transaminase elevations) and in 2 pts on tivozanib 1.5 mg (Gr 3 seizure and reversible Gr 3 vertigo). Other Gr 3/4 drug-related adverse events (AEs) included neutropenia, fatigue, and hypertension (n=2 each). Eight pts discontinued treatment due to AEs. The MTD for tivozanib with mFOLFOX6 was 1.5 mg. The disease control rate was 63% (<1% complete response, 27% partial response, 36% stable disease). Preliminary PK data showed no interaction between tivozanib and mFOLFOX6. Eight additional pts enrolled at the 1.5 mg dose level are currently being evaluated. Final results will be presented. Conclusions: Tivozanib can be combined at its recommended dose of 1.5 mg/day with mFOLFOX6 for pts with advanced GI tumors. The combination was tolerable and showed encouraging anti-tumor activity. A Phase II study of this combination for mCRC is ongoing.