Phase I dose-finding study of sorafenib in combination with capecitabine and cisplatin as a first-line treatment in patients with advanced gastric cancer

Background To define maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and preliminary efficacy of sorafenib plus capecitabine/cisplatin in advanced gastric cancer (AGC) patients. Methods Four dose-level combinations were tested in a standard 3 + 3 dose escalation design. Level 1: sorafenib 400 mg/d, capecitabine 1,600 mg/m2/d, cisplatin 80 mg/m2. Level 2: sorafenib 800 mg/d, capecitabine 1,600 mg/m2/d, cisplatin 80 mg/m2. Level 3: sorafenib 800 mg/d, capecitabine 2,000 mg/m2/d, cisplatin 80 mg/m2. Level 1A: sorafenib 800 mg/d, capecitabine 1,600 mg/m2/d, cisplatin 60 mg/m2. Results There were 1 DLT at Level 2, and 2 DLTs at Level 3 (Level 3 was MTD). Since the relative dose intensity (RDI) of sorafenib and capecitabine could not be maintained at Level 2, Level 1A was newly investigated. As no DLT was observed and RDI remained above 80%, Level 1A is the recommended dose for the next clinical trial. Objective response rate was 62.5% (10 of 16 patients, 95% CI; 38.8–86.2%). Median progression-free survival and overall survival were 10.0 months (95% CI; 7.4–13.8) and 14.7 months (95% CI; 12.0–20.0), respectively. Conclusions Sorafenib 400 mg bid daily, capecitabine 800 mg/m2 bid (days 1–14), and cisplatin 60 mg/m2 (day 1) is recommended for further development in AGC.