Originally published as JCO Early Release 10.1200/JCO.2005.01.917 on September 6 2005

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Phase I Pharmacokinetic Study of S-1 Plus Cisplatin in Patients With Advanced Gastric Carcinoma

From the Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; and Taiho Pharma USA, Inc, Princeton, NJ

Address reprint requests to Jaffer A. Ajani, MD, The University of Texas M.D. Anderson Cancer Center, Box 426, 1515 Holcombe Blvd, Houston, TX 77030; e-mail: jajani{at}mdanderson.org

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/m² (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 1A. 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.

Supported by a grant from Taiho Pharma USA, Inc, Princeton, NJ.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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