A drug interaction study evaluating the pharmacokinetics and toxicity of sorafenib in combination with capecitabine

Purpose To address tolerability and a possible pharmacologic interaction of capecitabine with sorafenib. Methods Patients with advanced solid tumors (ECOG PS 0-1) were included. Cohort A received capecitabine 750 mg/m(2) BID and Cohort B received capecitabine 1,000 mg/m(2) BID, both for 14 days of a 21-day cycle. Steady-state PK was obtained for capecitabine alone, sorafenib alone, and in combination. Cohort C explored an alternate schedule of 7-day on/7-day off flat dose capecitabine 1,000 mg BID with continuous dosing of sorafenib 400 mg BID. Results A total of 32 patients were enrolled between February 08 and April 09. Hand-foot skin reaction (HFSR) was the primary toxicity with 16 (50%) of the 32 patients experiencing grade 3 events (75% occurring during cycles 1-2). Grade 3 HFSR defined the maximum tolerated dose (MTD) of Cohort C at 1,000 mg BID flat dose of capecitabine. Other grade 3/4 toxicities were rare (diarrhea 6%, mucositis 3%, and fatigue 3%). Capecitabine did not change the C (max) or AUC((0-12)) of sorafenib. Co-administration of sorafenib with capecitabine 750 mg/m(2) (n = 6 patients) increased capecitabine AUC((0-12)) 15% and produced no change in the 5FU AUC((0-12)). At the capecitabine 1,000 mg/m(2) dose level (n = 12 pts), there was a 16% increase in capecitabine AUC((0-12)) and an 8% increase in 5FU AUC((0-12)). However, these trends were not statistically significant. Conclusions Co-administration of sorafenib resulted in a mild increase in capecitabine AUC, although not statistically significant. Capecitabine did not affect the exposure of sorafenib. The rate of grade 3 HFSR is concerning and limits the feasibility of prolonged dosing of sorafenib with capecitabine 1,000 mg/m(2) on the 21-day schedule.