Rationale for the dosage and schedule of CPT-11 (irinotecan) selected for phase II studies, as determined by European phase I studies

Background: CPT-11 (irinotecan), a camptothecin-derived anticancer agent with DNA topoisomerase 1 inhibitory activity, has demonstrated a broad spectrum of in vitro and in vivo activity in solid tumour models including multidrug-resistant tumours. This review details the rationale for the dosage schedule of CPT-11 selected for phase II studies, based on the results of 3 European phase I dose-escalating trials in patients 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 weekly every 3 out of 4 weeks (schedule 3). Results: Neutropenia and diarrhoea 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 dose-limiting at 350 mg/m(2) but was manageable with high-dose loperamide therapy. Conclusions: CPT-11 350 mg/m(2) administered as an intravenous infusion once every 3 weeks was chosen for further evaluation in early phase II studies, since this dosage regimen allowed the highest dose 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) warrant further investigation.