Phase 1 trial of S-1 in combination with sorafenib for patients with advanced hepatocellular carcinoma

Purpose Sorafenib is a multi-kinase inhibitor, which was approved as first-line treatment for patients with advanced hepatocellular carcinoma (HCC). We conducted a phase 1 study of sorafenib plus S-1 in patients with advanced HCC. Experimental design We designed to escalate S-1 at 4 different dose levels with fixed dose of sorafenib. Four dose levels were as follows: level 1, D1-14 S-1 50 mg/m²/day + D1-21 sorafenib 400 mg bid; level 2, D1-14 S-1 60 mg/m²/day + D1-21 sorafenib 400 mg bid; level 3,, D1-14 S-1 70 mg/m²/day + D1-21 sorafenib 400 mg bid; level 4, D1-14 S-1 80 mg/m²/day + D1-21 sorafenib 400 mg bid. The treatment was repeated every 3 weeks. Results From August 2009 to July 2010, 20 patients with advanced HCC were enrolled. The median age was 48 years (range, 29–74). Eighteen (90%) patients had hepatitis B viral infection and 19 (95%) patients were rated as Child-Pugh class A. The dose-limiting toxicities were grade 4 infection and thrombocytopenia. After a median follow-up duration of 8.6 months (range, 3.7–14.2 months), median PFS was 3.9 months (95% CI, 0.8–7.0 months) and median OS was 10.4 months (95% CI, 0–22.4 months). In pharmacokinetic analysis, there was no statistically significant drug interaction between sorafenib and S-1. Conclusions The combination of sorafenib and S-1 showed tolerable toxicity profile and modest clinical efficacy in patients with advanced HCC. The recommended dose of sorafenib and S-1 was 400 mg twice daily and 40 mg/m² twice daily, respectively.