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.
abstract: OBJECTIVE
  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.
  
  
  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/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 experiencing severe diarrhoea. No interactions were found in the kinetics parameters of CPT-11 or 5-FU for the different dose levels studied.
  
  
  CONCLUSIONS
  CPT-11 300 mg/m(2) + 5-FU 250 mg/m(2) protracted infusion is the recommended dose for phase II trials, neutropenia and diarrhoea being the dose-limiting toxicities.
authors.affiliation: Servicio de Oncología Médica, Hospital Clínico San Carlos de Madrid, Madrid, Spain. jsastre.hcsc@salud.madrid.org
authors.forename: Javier
authors.initials: J
authors.lastname: Sastre
authors.forename: Luis
authors.initials: L
authors.lastname: Paz-Ares
authors.forename: Antonio
authors.initials: A
authors.lastname: Carcas
authors.forename: Rosario
authors.initials: R
authors.lastname: Alfonso
authors.forename: Cristina
authors.initials: C
authors.lastname: Grávalos
authors.forename: Jesus
authors.initials: J
authors.lastname: Frías
authors.forename: Pedro
authors.initials: P
authors.lastname: Guerra
authors.forename: Linda
authors.initials: L
authors.lastname: Pronk
authors.forename: Hernán
authors.initials: H
authors.lastname: Cortés-Funes
authors.forename: Eduardo
authors.initials: E
authors.lastname: Díaz-Rubio
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D009503:Neutropenia / Q000139:chemically induced
chemical_list: D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin