Dose-finding phase I clinical and pharmacokinetic study of orally administered irinotecan in patients with advanced solid tumors.

PURPOSE: The aim of this study was to determine the daily maximum tolerated dose (MTD) and the dose-limiting toxicity for the following administration schedules: oral irinotecan given over 14 days every 3 weeks (part I) and oral irinotecan administered concomitantly with capecitabine over 14 days every 3 weeks (part II). In total, 42 patients (17 male and 25 female) with solid tumors refractory to standard therapy entered the study. EXPERIMENTAL DESIGN: Treatment in part I consisted of irinotecan administered orally as semisolid matrix capsules at doses of 25, 30, and 35 mg/m(2) once daily to confirm the MTD of our earlier study. In part II treatment, dose levels for irinotecan combined with capecitabine were 20/1,600, 25/1,600, 30/1,600, and 30/2,000 mg/m(2)/d. RESULTS: The median number of cycles administered per patient was 2.0 (range, 1-12) in part I and 2.0 (range, 1-13) in study part II. Gastrointestinal toxicities (grade 3 nausea, grades 3 and 4 vomiting, and grades 3 and 4 diarrhea) were dose limiting in both parts of the study. There were no grade 3 or 4 hematologic toxicities. The MTD was 30 mg/m(2)/d for irinotecan single agent and 30/1,600 mg/m(2)/d for the combination with capecitabine. Absorption of irinotecan was rapid, and peak concentrations of irinotecan and metabolite SN-38 were reached within 0 to 3 and 1.5 to 4.0 hours, respectively. CONCLUSIONS: In conclusion, oral irinotecan and capecitabine is feasible and well tolerated, and the recommended dose for phase II studies is 30/1,600 mg/m(2)/d administered daily for 14 days every 3 weeks.