CPT-11: clinical experience in phase I studies.

Phase I studies of CPT-11 (irinotecan) have been conducted in Europe, the United States, and Japan to determine the maximum tolerated dose (MTD) and the most appropriate intravenous administration schedule for further evaluation in phase II investigations. Diarrhea and/or neutropenia were the major dose-limiting toxicities in all the phase I studies. In Japanese and US investigations, the CPT-11 MTD was defined as 240 to 250 mg/m2 using a once every 3 weeks schedule and 100 and 150 mg/m2 using a weekly schedule. The weekly intermittent schedule was associated with greater dose intensity and was thus chosen in Japan (100 mg/2 every week) and in the United States (150 mg/m2/wk for 4 weeks followed by 2 weeks rest) for further evaluation in phase II studies. Preliminary results of an ongoing US study showed that CPT-11 could be administered in doses of at least 175 mg/m2 on an every other week basis. In European studies, the MTD was 90 to 100 mg/m2/d with IV infusion over 3 consecutive days every 3 weeks and 100 to 115 mg/m2 with a weekly infusion for 3 weeks every 4 weeks. European experience with a single infusion every 3 weeks showed diarrhea to be dose limiting at 350 mg/m2, but concomitant administration of high-dose loperamide allowed administration of CPT-11 at doses of up to 600 mg/m2. This latter schedule was better tolerated, achieved the highest dose intensity, and was considered to confer greater convenience in an outpatient setting when compared with the other European regimens. European phase II studies were therefore commenced using a CPT-11 schedule comprising a single intravenous infusion every 3 weeks at a dose of 350 mg/m2.