Phase I clinical and pharmacokinetic study of oral S-1 in patients with advanced solid tumors

Purpose: To investigate the side effects, determine the maximum-tolerated d ose (MTD), and study the pharmacokinetics of S-1, an oral fluoropyrimidine- based antineoplastic agent consisting of the fluorouracil (5-FU) prodrug te gafur combined with two modulators, 5-chloro-2,4-dihydroxypyridine and pota ssium oxonate. Patients and Methods: Patients with advanced solid tumors received S-1 bid for 28 days, followed by 1 week of rest. 5-FU pharmacokinetics were investi gated after a single initial dose of S-1 during the first 24 hours and week ly thereafter. Results: Twenty-eight patients received S-1 at the four consecutive dose le vels of 25, 45, 35, and 40 mg/m(2), The MTD was initially found at 45 mg/m( 2), with diarrhea as the dose-limiting toxicity (DLT). Diarrhea was also th e DLT at the dose of 40 mg/m2, which was the MTD for patients exposed to ex tensive prior chemotherapy. Other toxicities were generally mild. Two patie nts had a reduction of more than 50% in tumor dimension. Plasma pharmacokin etics of 5-FU were linear; at the highest S-1 dose level, 5-FU plasma peak concentrations reached 1 to 2 mu mol/L, and the half-life of 5-FU was 3 to 4 hours. A statistically significant relationship was observed between the severity of diarrhea and pharmacokinetic parameters of 5-FU. Conclusion: The recommended dose of S-1 in chemotherapy-naive or minimally chemotherapy-exposed patients is 40 mg/m2 bid on 28 consecutive days, every 5 weeks. In heavily pretreated patients, the recommended dose is 35 mg/m(2 ) bid, Phase II trials are warranted in tumors known to be responsive to 5- FU treatment. (C) 2000 by American Society of Clinical Oncology.