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Phase I Clinical and Pharmacokinetic Study of Oral S-1 in Patients With Advanced Solid Tumors

From the University Hospital Vrije Universiteit, Netherlands Cancer Institute, and NDDO Oncology, Amsterdam, the Netherlands, and European Organization for Research and Treatment of Cancer, Early Clinical Studies Group, Brussels, Belgium.

Address reprint requests to C.J. van Groeningen, MD, University Hospital Vrije Universiteit, Department of Medical Oncology, de Boelelaan 1117, 1081 HV Amsterdam, the Netherlands; email dr.vangroeningen{at}azvu.nl

PURPOSE: To investigate the side effects, determine the maximum-tolerated dose (MTD), and study the pharmacokinetics of S-1, an oral fluoropyrimidine-based antineoplastic agent consisting of the fluorouracil (5-FU) prodrug tegafur combined with two modulators, 5-chloro-2,4-dihydroxypyridine and potassium 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 investigated after a single initial dose of S-1 during the first 24 hours and weekly thereafter.

RESULTS: Twenty-eight patients received S-1 at the four consecutive dose levels of 25, 45, 35, and 40 mg/m². The MTD was initially found at 45 mg/m², with diarrhea as the dose-limiting toxicity (DLT). Diarrhea was also the DLT at the dose of 40 mg/m², which was the MTD for patients exposed to extensive prior chemotherapy. Other toxicities were generally mild. Two patients had a reduction of more than 50% in tumor dimension. Plasma pharmacokinetics of 5-FU were linear; at the highest S-1 dose level, 5-FU plasma peak concentrations reached 1 to 2 µmol/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/m² bid. Phase II trials are warranted in tumors known to be responsive to 5-FU treatment.

Presented in part at the Thirty-Third Annual Meeting of the American Society of Clinical Oncology, Denver, CO, May 17-20, 1997.

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