RATIONALE FOR THE DOSAGE AND SCHEDULE OF CPT-11 (IRINOTECAN) SELECTEDFOR PHASE-II STUDIES, AS DETERMINED BY EUROPEAN PHASE-I STUDIES

Background: CPT-11 (irinotecan), a camptothecin-derived anticancer age nt with DNA topoisomerase 1 inhibitory activity, has demonstrated a br oad spectrum of in vitro and in vivo activity in solid tumour models i ncluding multidrug-resistant tumours. This review details the rational e for the dosage schedule of CPT-11 selected for phase II studies, bas ed on the results of 3 European phase I dose-escalating trials in pati ents with solid tumours. Patients and methods: CPT-11 was administered as a 30-minute intravenous infusion once every 3 weeks (schedule 1), once daily for 3 consecutive days every 3 weeks (schedule 2) or once w eekly every 3 out of 4 weeks (schedule 3). Results: Neutropenia and di arrhoea were the major dose-limiting toxicities in all of the studies. The maximum tolerated dose of CPT-11 was 115 and 145 mg/m(2)/day for schedules 2 and 3, respectively. With schedule 1, diarrhoea became dos e-limiting at 350 mg/m(2) but was manageable with high-dose loperamide therapy. Conclusions: CPT-11 350 mg/m(2) administered as an intraveno us infusion once every 3 weeks was chosen for further evaluation in ea rly phase II studies, since this dosage regimen allowed the highest do se intensity with the least toxicity and was convenient for outpatient use. The place of higher doses (with intensive antidiarrhoeal support ) and other administration schedules (e.g., protracted infusion) warra nt further investigation.