Phase I, pharmacogenomic, drug-interaction study of sorafenib and bevacizumab in combination with paclitaxel in patients with advanced refractory solid tumors.

Vascular endothelial growth factor (VEGF) blockade does not uniformly result in clinical benefit. We evaluated safety, dose-limiting toxicities (DLTs), recommended phase II dose (RP2D), antitumor efficacy, and exploratory biomarkers including pharmacogenomics and pharmacokinetics with sorafenib, bevacizumab and paclitaxel in refractory cancer patients. The study had a "3+3" design, using paclitaxel 80 mg/m2 QW x 3 every 4 weeks, bevacizumab 5 mg/kg Q2W, and sorafenib 200 or 400 mg BID, 5 or 7 days/week (5/7, 7/7). The maximum tolerated dose (MTD) cohort was expanded. Twenty-seven patients enrolled in 3 cohorts: sorafenib 200 mg BID 5/7, 200 mg BID 7/7, 400 mg BID 5/7. DLTs were grade 3 neutropenia > 7 days (cohort 1, 1), grade 3 hypertension (cohort 2, 1), grade 3 hand-foot skin reaction (HFSR) (cohort 3, 2). MTD was sorafenib 200 mg BID 7/7. Six DLTs occurred in cohort 2 expansion: grade 3 HFSR (2), grade 2 HFSR with sorafenib delay > 7 days (2), grade 4 cerebrovascular accident (1), grade 3 neutropenia > 7 days (1). RP2D was sorafenib 200 mg BID 5/7. Most patients (62%) dose reduced sorafenib to 200 mg QD 5/7 after a median 3 (range 2-17) cycles. Response rates were 48% overall (27), and 64% for ovarian cancers (14). VEGF-A-1154AA and -7TT recessive homozygous genotypes conferred worse overall survival vs alternative genotypes (7 vs 22 months). Intermittent, low-dose sorafenib (200 mg BID 5/7) combined with bevacizumab and paclitaxel was tolerable and had high antitumor efficacy in refractory cancer patients (NCT00572078).