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Phase I Study with Pharmacokinetics of S-1 on an Oral Daily Schedule for 28 Days in Patients with Solid Tumors¹

Department of Gastrointestinal Medical Oncology, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas

Purpose: Our purpose in the study was to determine the maximum tolerated dose and dose-limiting toxicity and investigate the clinical pharmacology of S-1, a combination of tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate.

Experimental Design: Eligible patients had advanced solid tumors, adequate organ function, and no anticancer therapy in the preceding 4 weeks. Dose level 1 was 30 mg/m²/dose, level 2 was 40 mg/m²/dose, and level 3 was 35 allmg/m²/dose, all of the levels comprising two daily doses. S-1 was administered as a single dose at each level, and its pharmacology was studied. The first course was begun 3 days later and consisted of 28 consecutive treatment days, followed by a 1-week rest.

Results: Sixteen patients were enrolled; toxicity could be assessed in all of the 16 and response in 15. At dose level 1, two of nine patients developed grade 3 hyperbilirubinemia or diarrhea. Dose-limiting toxicity (diarrhea) occurred in all three of the patients at dose level 2. The protocol was, therefore, amended to include an intermediate dose level (level 3), which caused grade 3 or 4 diarrhea or hyperbilirubinemia in three of four patients. Dose level 1 was thus considered as the maximum tolerated dose. Other grade 3 or 4 toxic effects at dose level 2 or 3 were granulocytopenia, nausea, and vomiting. The pharmacology of tegafur, CDHP, potassium oxonate, and fluorouracil (a metabolite of tegafur) was characterized by rapid absorption and was consistent with first-order kinetics. One patient with colorectal cancer had a durable partial response.

Conclusions: The recommended S-1 dose for future studies is 30 mg/m² twice daily, and diarrhea is the most frequent toxic effect. Additional trials of S-1 in the treatment of patients with solid tumors are warranted.

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