title: A phase I/II and pharmacokinetic study of irinotecan in combination with capecitabine as first-line therapy for advanced colorectal cancer.
abstract: OBJECTIVE
  The aim of this study was to determine in patients with previously untreated advanced colorectal cancer the maximum tolerated dose (MTD) and safety profile of irinotecan in combination with capecitabine, to identify a recommended dose and to determine the response rate and time to disease progression. In addition, we aimed to explore the pharmacokinetic parameters of irinotecan and capecitabine when used in different sequences of administration, with irinotecan infusion either prior to or after the first intake of capecitabine.
  
  
  METHODS
  One hundred patients were included: 43 patients were recruited into an extended phase I trial of alternating escalation in dose of both drugs where irinotecan was administered intravenously (i.v) on day 1 after first intake of capecitabine taken from days 1-14 twice daily, with cycles repeated every 3 weeks. After the determination of recommended dose a further 57 patients were treated in a phase II evaluation with the reverse sequence of drugs on day 1. Pharmacokinetic analysis was performed in patients treated at the recommended dose in two cohorts of patients in which the sequence of the first administration of each drug was reversed.
  
  
  RESULTS
  The MTD of the combination was determined as irinotecan 300 mg/m2, with capecitabine 2000 mg/m2/day. Dose limiting toxicities were neutropenia and diarrhoea. The recommended dose is irinotecan intravenous (i.v.) 250 mg/m2 day 1 and capecitabine 2000 mg/m2/day days 1-14, every 3 weeks. Treatment was well tolerated, with diarrhoea the most common serious toxicity. Response rate in the phase II cohort was 42% [95% confidence interval (CI) 29% to 56%]. Median duration of response was 7.7 months (95% CI 7.5-8.9). Median time to progression was 8.3 months (95% CI 5.8-10). No significant effect on irinotecan pharmacokinetics was observed whatever the intake of capecitabine before or after irinotecan infusion. An effect of irinotecan on capecitabine and some capecitabine metabolites was observed, but irinotecan did not effect 5-fluorouracil (5-FU) pharmacokinetics.
  
  
  CONCLUSIONS
  Irinotecan in combination with capecitabine is a well tolerated regimen with an activity comparable to, but more convenient than, irinotecan-5-FU i.v. combinations in patients with previously untreated advanced colorectal cancer. The pharmacokinetic data suggest that the sequence of administration does not impact significantly on the metabolism of the two drugs.
authors.affiliation: CR UK Institute for Cancer Studies, University of Birmingham, Birmingham, UK.
authors.forename: D W
authors.initials: DW
authors.lastname: Rea
authors.forename: J W R
authors.initials: JW
authors.lastname: Nortier
authors.forename: W W
authors.initials: WW
authors.lastname: Ten Bokkel Huinink
authors.forename: S
authors.initials: S
authors.lastname: Falk
authors.forename: D J
authors.initials: DJ
authors.lastname: Richel
authors.forename: T
authors.initials: T
authors.lastname: Maughan
authors.forename: G
authors.initials: G
authors.lastname: Groenewegen
authors.forename: J M
authors.initials: JM
authors.lastname: Smit
authors.forename: N
authors.initials: N
authors.lastname: Steven
authors.forename: J M
authors.initials: JM
authors.lastname: Bakker
authors.forename: D
authors.initials: D
authors.lastname: Semiond
authors.forename: D J
authors.initials: DJ
authors.lastname: Kerr
authors.forename: C J A
authors.initials: CJ
authors.lastname: Punt
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000069287:Capecitabine; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged
chemical_list: D003841:Deoxycytidine; D000069287:Capecitabine; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin