Irinotecan: drug schedule, research of combinations, and phase I experiences

Irinotecan (CPT11) is a synthetic camptothecin-derived, DNA topoisomerase I inhibitor. Based on phase I clinical trials, several schedules have been r ecommended for phase I studies including 350 mg/m(2) every 3 weeks in Europ e 125 mg/m(2) for 4 weeks every 6 weeks in the USA, and 100 mg/m(2) weekly or delayed until recovery, in case of grade > 2 toxicity in Japan. The prin cipal dose-limiting toxicities in those schedules are neutropenia and delay ed diarrhea. Every treatment with high doses of loperamide has made diarrhe a? a manageable toxicity and allowed nose escalation ni, to 500 mg/m(2). Re cently, two very interesting schedules have been investigated allowing to i ncrease dose-intensity: every other Il,week infusion and protracted infusio n. With those schedules, it appears that the diarrhea occurred more frequen tly with the weekly schedule. In addition, authors have observed interpatie nts; variations in rei ins of toxicity and pharmacokinetics. Those variatio ns may be related to modifications ii? the hepatic metabolism of the drug t hat may occur in patients with hepatic dysfunction;and/or in patients with concomitants medications. The understanding of the individual,metabolism of the drug would, help to determine individual nose adaptation. Based on syn ergistic preclinical interaction with several drugs, combinations of irinot ecan with other cytotoxic ir drugs such as thymidylate synthethase inhibito rs and platinum stilts are currently investigated in phase I-II studies.