ORIGINAL ARTICLE Javier Sastre Æ Luis Paz-Ares Æ Antonio Carcas Rosario Alfonso Æ Cristina Gra´valos Æ Jesus Frı´as Pedro Guerra Æ Linda Pronk Æ Herna´ n Corte´s-Funes Eduardo Dı´az-Rubio 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 Received: 16 April 2004 / Accepted: 26 August 2004 / Published online: 26 October 2004 Ó Springer-Verlag 2004 Abstract Purpose: Irinotecan (CPT-11) and 5-fluoro- uracil (5-FU) are effective cytotoxic agents in the treat- ment 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 fail- ure 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/m 2 ) plus a fixed dose of 5-FU CI 250 mg/m 2 per day over 14 days. If the MTD was not reached at CPT-11 level 6, then 5-FU was increased to 300 mg/m 2 . 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/m 2 , 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/m 2 + 5-FU 250 mg/m 2 CI over 14 days was identified as the recommended dose. In step 2, CPT-11 dose had to be reduced to 300 mg/m 2 due to toxicity. The weekly schedule of CPT-11 75 mg/m 2 + 5-FU 250 mg/m 2 CI was feasible with only one patient expe- riencing severe diarrhoea. No interactions were found in the kinetics parameters of CPT-11 or 5-FU for the dif- ferent dose levels studied. Conclusion: CPT-11 300 mg/ m 2 + 5-FU 250 mg/m 2 protracted infusion is the rec- ommended dose for phase II trials, neutropenia and diarrhoea being the dose-limiting toxicities. Keywords CPT-11 Æ 5-Fluorouracil Æ Phase I Æ Solid tumours Æ Pharmacokinetic Introduction Irinotecan (CPT-11) and 5-fluorouracil (5-FU) are effective cytotoxic agents in the treatment of solid tumours such as colorectal cancer [1–3], lung cancer [4, 5] and gastric adenocarcinoma [6]. CPT-11 is a semi- synthetic derivative of the natural alkaloid camptothecin that is hydrolysed in vivo to SN-38, an active metabolite that exerts its cytotoxic action by inhibiting the nuclear enzyme DNA topoisomerase I. Several phase I clinical trials on CPT-11 monotherapy have been carried out in Europe, United States and Japan, which showed that diarrhoea and neutropenia are the main dose-limiting toxicities (DLT) of the drug regardless of the schedule of administration [7–12]. CPT-11 350 mg/m 2 every 3 weeks has been the most commonly developed schedule in European countries because the highest dose-intensity was reached with this regimen compared with the weekly schedule. Because colorectal cancer is usually a slow-growing tumour, with few cells actively dividing at the same time, the use of continuous infusion (CI) of 5-FU has been J. Sastre (&) Æ R. Alfonso Æ E. Dı´az-Rubio Servicio de Oncologı´a Me´dica, Hospital Clı´nico San Carlos de Madrid, Madrid, Spain E-mail: jsastre.hcsc@salud.madrid.org Fax: +34-91-3303544 L. Paz-Ares Æ C. Gra´valos Æ H. Corte´s-Funes Servicio de Oncologı´a Me´dica, Hospital 12 de Octubre de Madrid, Madrid, Spain A. Carcas Æ J. Frı´as Æ P. Guerra Departamento de Farmacologı´a de la Universidad Auto´noma de Madrid, Madrid, Spain L. Pronk Aventis Pharma, Madrid, Spain Cancer Chemother Pharmacol (2005) 55: 453–460 DOI 10.1007/s00280-004-0915-x