A phase I, dose-finding study of irinotecan (CPT-11) short i.v. infusion combined with fixed dose of 5-fluorouracil (5-FU) protracted i.v. infusion in adult patients with advanced solid tumours

Purpose Irinotecan (CPT-11) and 5-fluorouracil (5-FU) are effective cytotoxic agents in the treatment of solid tumours. Continuous i.v. infusion (CI) of 5-FU is significantly more active and better tolerated than bolus i.v. 5-FU. This phase I pharmacokinetic and clinical study evaluated escalating CPT-11 doses administered every 3 weeks combined with a fixed dose of 5-FU CI over 14 days to find the maximum tolerated dose (MTD) of this combined chemotherapy.Patients and methods Patients with solid tumours showing failure with previous standard treatment or for whom no established curative therapy existed received CPT-11 i.v. over 90 min (six dose levels were evaluated: 150, 175, 200, 250, 300 and 350 mg/m²) plus a fixed dose of 5-FU CI 250 mg/m² per day over 14 days. If the MTD was not reached at CPT-11 level 6, then 5-FU was increased to 300 mg/m². In step 2, 5-FU was administered as a true protracted infusion at the recommended dose found during step 1. In step 3, the recommended dose of CPT-11 was divided and administered in a weekly schedule for 4 weeks combined with a fixed dose of 5-FU CI 250 mg/m², and then followed by 2–5 weeks rest.Results Neutropenia and diarrhoea were the main toxicities, leading to early termination of infusion in three of six patients in level 7. Therefore, CPT-11 350 mg/m² + 5-FU 250 mg/m² CI over 14 days was identified as the recommended dose. In step 2, CPT-11 dose had to be reduced to 300 mg/m² due to toxicity. The weekly schedule of CPT-11 75 mg/m² + 5-FU 250 mg/m² CI was feasible with only one patient experiencing severe diarrhoea. No interactions were found in the kinetics parameters of CPT-11 or 5-FU for the different dose levels studied.Conclusion CPT-11 300 mg/m² + 5-FU 250 mg/m² protracted infusion is the recommended dose for phase II trials, neutropenia and diarrhoea being the dose-limiting toxicities.