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

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/m 2 /day, and 10 were treated at 60 mg/m 2 /day. Results : DLTs were observed in 1 of 6 evaluable patients treated with 50 mg/m 2 /day and in 4 of 10 evaluable patients treated with 60 mg/m 2 /day. DLTs included diarrhea, nausea/vomiting, fatigue, and hyperbilirubinemia. The maximum tolerated dose was 50 mg/m 2 /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 r = 0.74, P Conclusions : The recommended Phase II dose of S-1 administered once daily for 21 consecutive days of 28 is 50 mg/m 2 . 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.