Safety and Pharmacokinetics of Sorafenib Combined With Capecitabine in Patients With Advanced Solid Tumors: Results of a Phase 1 Trial

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Abstract

Sorafenib (twice daily [bid]) plus capecitabine (2 weeks on schedule/1 week off schedule) safety and pharmacokinetics were investigated in patients with advanced solid tumors (N = 35). Cohort 1 (n = 13) included sorafenib 200 mg bid and capecitabine 1050 mg/m2bid; cohort 2 (n = 4), sorafenib 400 mg bid and capecitabine 1050 mg/m2bid; cohort 3 (n = 6), sorafenib 200 mg bid and capecitabine 1050 mg/m2bid (cycles 1 and 2), then 400 mg bid and capecitabine 1050 mg/m2bid (cycle 3 onwards); and cohort 4 (n = 12), sorafenib 400 mg bid and capecitabine 850 mg/m2bid. The combination of sorafenib and capecitabine was generally well tolerated. Most frequent drugrelated adverse events were hand-foot skin reaction (HFSR, 89%), diarrhea (71%), and fatigue (69%). The HFSR was dose-limiting toxicities in 6 patients. Sorafenib exposure (Cmax and AUC0-12) was unaffected by concomitant capecitabine. Concomitant sorafenib moderately increased capecitabine and 5-fluorouracil (metabolite) exposure when the capecitabine dose was 1050 mg/m2bid. Simultaneous administration of 400 mg bid sorafenib and 850 mg/m2bid capecitabine, however, had only minor effects on the exposure to capecitabine and 5-fluorouracil. Based on the overall toxicity profile and pharmacokinetic parameters, the recommended phase 2 doses were therefore sorafenib 400 mg bid and capecitabine 850 mg/m2bid, as scheduled above.

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