Phase I pharmacokinetic study of S-1 plus cisplatin in patients with advanced gastric carcinoma

Purpose: The conversion rate of tegafur (a component of S-1) to fluorouracil (FU) differs in Asians and whites because of polymorphic differences in the CYP2A6 gene. S-1 with cisplatin is considered highly active in Japanese gastric cancer patients. Therefore, we initiated a phase I pharmacokinetic study of this combination in our gastric cancer patients. Patients and Methods: Patients received cisplatin intravenously on day 1 and S-1 orally, twice daily, on days 1 to 21 every 28 days. At level 1, the S-1 dose was 25 mg/m²/dose (50 mg/m²/d), but it was increased by 5 mg/m²/dose for the next level. Cisplatin was administered at 75 mg/m² (for levels 1 and 2) but was then reduced to 60 mg/m ² (level 1A). At every level, a cohort of three patients, which could be expanded to six patients, was studied. Maximum-tolerated dose (MTD) was determined based on the dose-limiting toxicity (DLT) in the first cycle. Patients with histologic proof of gastric adenocarcinoma and near-normal organ function were studied. Results: Sixteen patients were enrolled. No DLTs occurred at level 1. However, DLTs occurred at levels 2 and 1 A. The area under the curve for FU correlated significantly with DLT (P = .006) and grade 3 to 4 diarrhea (P = .004). Six partial responses were confirmed, including three at the MTD. Conclusion: At the established MTD of S-1 plus cisplatin, the S-1 dose (50 mg/m²/d for 21 days) is lower in our study than in the Japanese study (80 mg/m²/d for 21 days). A multi-institutional phase II study of this active combination is currently accruing patients.