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Phase I and Pharmacokinetic Study of Once Daily Oral Administration of S-1 in Patients with Advanced Cancer¹

Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111 [S. J. C., G. Y., M. B., N. J. M.]; Division of Medical Oncology, Albany Medical College, Albany, New York 12208 [C. G. L.]; Department of Medical Oncology, Roswell Park Cancer Institute, Buffalo, New York 14263 [A. P.]; and Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492-7660 [B. R., B. D., S. P. L., A. P. D.]

Purpose: To determine the maximum tolerated dose, dose-limiting toxicities(DLTs), and pharmacokinetics of S-1, a combination of tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP), and oxonic acid, administered once daily in patients with advanced cancer.

Experimental Design: Eighteen patients with refractory malignancies were treated with S-1 administered once daily for 21 consecutive days, followed by a 1-week break. Of 16 evaluable patients, 6 were treated at a dose of 50 mg/m²/day, and 10 were treated at 60 mg/m²/day.

Results: DLTs were observed in 1 of 6 evaluable patients treated with 50 mg/m²/day and in 4 of 10 evaluable patients treated with 60 mg/m²/day. DLTs included diarrhea, nausea/vomiting, fatigue, and hyperbilirubinemia. The maximum tolerated dose was 50 mg/m²/day. Pharmacokinetic data are consistent with potent modulation of 5-fluorouracil (5-FU) by CDHP, with prolonged half-life and 5-FU AUC at least 10-fold higher than reported in previous studies of equitoxic doses of tegafur modulated by uracil. Pharmacodynamic analysis demonstrated a correlation between diarrhea grade and both 5-FU C_max (r = 0.57, P < 0.05) and 5-FU area under the curve (r = 0.74, P < 0.01).

Conclusions: The recommended Phase II dose of S-1 administered once daily for 21 consecutive days of 28 is 50 mg/m². The pharmacokinetic data presented provide evidence of 5-FU modulation by CDHP. Pharmacodynamic analyses suggest that the utility of pharmacology-based dosing of S-1 should be explored in future trials. Evaluation of once-daily dosing of S-1 in malignancies for which fluoropyrimidines have known antitumor activity is warranted.

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