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Phase I and Pharmacokinetic Study of Intravenous Irinotecan Plus Oral Ciclosporin in Patients With Fluorouracil-Refractory Metastatic Colon Cancer

John D. Chester, Simon P. Joel, Susan L. Cheeseman, Geoffrey D. Hall, Michael S. Braun, Jackie Perry, Theresa Davis, Christopher J. Button, Matthew T. Seymour

From the Cancer Research UK Clinical Centre at Leeds, Cookridge Hospital, Leeds LS16 6QB, and Department of Medical Oncology, St. Bartholomew’s Hospital, West Smithfield, London EC1A 7BE, United Kingdom.

Address reprint requests to Matt Seymour, MA, MD, FRCP, Cookridge Hospital, Leeds LS16 6QB, UK; email: Matt.Seymour{at}cancer.org.uk.

Purpose: To assess the safety and toxicity profile of escalating doses of intravenous irinotecan, in combination with a fixed dose of oral ciclosporin (Cs) and to determine the pharmacokinetic profile of irinotecan and its metabolites.

Patients and Methods: Patients with fluorouracil-refractory metastatic colorectal cancer received escalating doses of intravenous irinotecan from 40 to 125 mg/m² every 2 weeks in combination with a fixed dose of oral Cs (5 mg/kg bid for 3 days). Pharmacokinetic analysis of plasma irinotecan and its metabolites SN38 and SN38G was performed during paired cycles with and without Cs.

Results: Thirty-seven patients were treated. Dose-limiting toxicity of grade 4 neutropenia was seen at an irinotecan dose of 125 mg/m². There was no grade 4 diarrhea, and only one patient experienced grade 3 diarrhea. Toxicities caused by Cs were generally mild. Pharmacokinetic studies demonstrated that irinotecan clearance was reduced from 13.4 to 5.8 L/h/m² and area under the curve (AUC)_0-tn was increased 2.2-fold by the coadministration of Cs. Similar significant increases in AUC_0-24h were seen for both SN38 and SN38G (2.2-fold and 2.3-fold, respectively) in the presence of Cs. Antitumor activity was seen at every irinotecan dose level.

Conclusion: The maximum tolerated irinotecan dose and recommended dose for phase II studies is 100 mg/m² every 2 weeks. Dose-limiting diarrhea was not seen during this study, supporting the hypothesis that pharmacokinetic modulation of irinotecan by Cs may improve its therapeutic index. Further studies using this combination are warranted.

Supported by Cancer Research UK and by the Cookridge Hospital Gastrointestinal Research Unit Fund.

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