Annals of Oncology Advance Access originally published online on June 6, 2005
Annals of Oncology 2005 16(7):1123-1132; doi:10.1093/annonc/mdi227
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© 2005 European Society for Medical Oncology
A phase I/II and pharmacokinetic study of irinotecan in combination with capecitabine as first-line therapy for advanced colorectal cancer
1 CR UK Institute for Cancer Studies, University of Birmingham, Birmingham, UK; 2 Leiden University Medical Centre, Leiden; 3 Netherlands Cancer Institute, Amsterdam, The Netherlands; 4 Taunton and Somerset Hospital, Somerset, UK; 5 Academic Medical Centre, Amsterdam, The Netherlands; 6 Clinical Trials Unit Velindre Hospital NHS Trust, Whithchurch, UK; 7 University Medical Centre Utrecht, Utrecht; 8 Gelre Hospitals, Apeldoorn, The Netherlands; 9 University of Oxford, Oxford, UK; 10 Aventis Pharma B.V., The Netherlands; 11 Aventis Pharma, S.A., France; 12 Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
* Correspondence to: Prof. Dr C. J. A. Punt, Department of Medical Oncology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500HB Nijmegen, The Netherlands. Tel: +31-24-3610353; Fax: +31-24-3540788; Email: c.punt{at}onco.umcn.nl
Purpose:: 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.
Patients and 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.
Key words: capecitabine, colorectal cancer, irinotecan, phase I, phase II pharmacokinetics
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