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Phase I and Pharmacologic Study of Irinotecan Administered as a 96-Hour Infusion Weekly to Adult Cancer Patients

From the Developmental Therapeutics Department, Medicine Branch, Division of Clinical Sciences, and Investigational Drug Branch, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute; Department of Radiology, National Naval Medical Center, Bethesda, MD; and Cancer Research Center, Case Western Reserve University, School of Medicine, Cleveland, OH.

Address reprint requests to Chris Takimoto MD, PhD, Medicine Branch, National Cancer Institute, Bldg 8, Rm 5101, National Naval Medical Center, 8901 Wisconsin Ave, Bethesda, MD 20889-5105; email ctakim{at}helix.nih.gov

PURPOSE: We conducted a phase I and pharmacologic study of a weekly 96-hour infusion of irinotecan to determine the maximum-tolerated dose, define the toxicity profile, and characterize the clinical pharmacology of irinotecan and its metabolites.

PATIENTS AND METHODS: In 26 adult patients with solid tumors, the duration and dose rate of infusion were escalated in new patients until toxicity was observed.

RESULTS: In 11 patients who were treated with irinotecan at 12.5 mg/m²/d for 4 days weekly for 2 of 3 weeks, dose-limiting grade 3 diarrhea occurred in three patients and grade 3 thrombocytopenia occurred in two patients. The recommended phase II dose is 10 mg/m²/d for 4 days given weekly for 2 of 3 weeks. At this dose, the steady-state plasma concentration (Css) of total SN-38 (the active metabolite of irinotecan) was 6.42 ± 1.10 nmol/L, and the Css of total irinotecan was 28.60 ± 17.78 nmol/L. No patient experienced grade 3 or 4 neutropenia during any cycle. All other toxicities were mild to moderate. The systemic exposure to SN-38 relative to irinotecan was greater than anticipated, with a molar ratio of the area under the concentration curve (AUC) of SN-38 to irinotecan of 0.24 ± 0.08. One objective response lasting 12 months in duration was observed in a patient with metastatic colon cancer.

CONCLUSION: The recommended phase II dose of irinotecan of 10 mg/m²/d for 4 days weekly for 2 of 3 weeks was extremely well tolerated. Further efficacy testing of this pharmacologic strategy of administering intermittent low doses of irinotecan is warranted.

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