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Ajani, J.A. et al.

Ajani, Faust, Ikeda, Yao, Anbe, Carr, Houghton, Urrea,

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/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.[1]

References

Phase I pharmacokinetic study of S-1 plus cisplatin in patients with advanced gastric carcinoma. Ajani, J.A., Faust, J., Ikeda, K., Yao, J.C., Anbe, H., Carr, K.L., Houghton, M., Urrea, P. J. Clin. Oncol. (2005) [Pubmed]

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