Combination therapy: Intermittent sorafenib with bevacizumab yields activity and decreased toxicity

Abstract

Background:We previously reported preliminary results of our phase I study of continuous daily sorafenib with bevacizumab every other week for solid tumours. Toxicity was moderate, leading to additional dose levels (DL) testing intermittent sorafenib dosing.Methods:Seventeen patients with advanced solid tumours were treated on three additional DLs testing sorafenib days 1-5 per week. Dose level 4 was sorafenib 200 mg twice daily (b.i.d.) and bevacizumab 5 mg kg 1. DL5 alternated between bevacizumab 10 mg kg 1-sorafenib 200 mg b.i.d. (A) and sorafenib 400 mg b.i.d. with bevacizumab 5 mg kg 1 (B). Outcome and toxicity data from 19 epithelial ovarian cancer (EOC) patients from DL 1-5 were analysed.Results:Fewer patients required sorafenib dose reduction with the intermittent schedule (41 vs 74% daily, P0.01). Hand-foot skin reaction (HFSR) remained the primary cause of dose reduction (n5). Partial responses (12%) or disease stabilisation 4 months (53%; median 6 (4-26)) occurred in most patients on the intermittent schedule. Partial response occurred in 47% EOC patients treated in pooled analysis of duration 4-37 months.Conclusion:Intermittent sorafenib dosing with bevacizumab has promising clinical activity and less sorafenib dose reduction and side effects, but does not ameliorate HFSR. We are conducting a phase II clinical trial with intermittent sorafenib and bevacizumab in patients with EOC. © 2010 Cancer Research UK.