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- Title
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.
- Authors
Sastre, Javier; Paz-Ares, Luis; Carcas, Antonio; Alfonso, Rosario; Grávalos, Cristina; Frías, Jesus; Guerra, Pedro; Pronk, Linda; Cortés-Funes, Hernán; Díaz-Rubio, Eduardo; Grávalos, Cristina; Frías, Jesus; Cortés-Funes, Hernán; Díaz-Rubio, Eduardo
- Abstract
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 11 trials, neutropenia and diarrhoea being the dose-limiting toxicities.
- Subjects
TUMORS; PATHOLOGY; PHARMACOKINETICS; PHARMACOLOGY; DRUG therapy; CANCER patients; THERAPEUTICS; DRUGS; ANTIMETABOLITES; ANTINEOPLASTIC agents; BIOTRANSFORMATION (Metabolism); CAMPTOTHECIN; CLINICAL trials; COMPARATIVE studies; FLUOROURACIL; INTRAVENOUS therapy; RESEARCH methodology; MEDICAL cooperation; NEUTROPENIA; RESEARCH; TIME; EVALUATION research
- Publication
Cancer Chemotherapy & Pharmacology, 2005, Vol 55, Issue 5, p453
- ISSN
0344-5704
- Publication type
journal article
- DOI
10.1007/s00280-004-0915-x