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A Phase I and Pharmacokinetic Study of Irinotecan Given as a 7-Day Continuous Infusion in Metastatic Colorectal Cancer Patients Pretreated with 5-Fluorouracil or Raltitrexed

¹ Division of Medical Oncology, Department of Oncology, Civil Hospital, Livorno, and ² Division of Pharmacology and Chemotherapy, Department of Oncology, Transplants, and Advanced Technologies in Medicine, University of Pisa, Pisa, Italy

Purpose: The purpose is to determine the plasma pharmacokinetics, the maximum-tolerable dose and to preliminary evaluate the antitumor activity of irinotecan administered as a 7-day continuous infusion every 21 days in metastatic colorectal cancer patients pretreated with 5-fluorouracil or raltitrexed.

Experimental Design: A total of 13 patients entered the study. Three received irinotecan at 20 mg/m²/day (dose level I), 6 at 25 mg/m²/day (dose level II), and 4 at 22.5 mg/m²/day (dose level III). In 8 patients, plasma levels of irinotecan and its metabolites SN-38 and SN-38 glucuronide (SN-38glu) were measured by high-performance liquid chromatography and main pharmacokinetic parameters, including steady-state concentration, area under the time-concentration curve, and clearance, were calculated and normalized to the dose level of 22.5 mg/m²/day.

Results: Dose-limiting toxicity was grade 3–4 diarrhea, which occurred in 4 of 6 patients at dose level II and in 2 of 4 patients at dose level III. Therefore, we defined 22.5 mg/m²/day the maximum-tolerable dose and 20.0 mg/m²/day the recommended dose for Phase II studies. Hematological toxicity was rare. The pharmacokinetic data provided evidence that continuous infusion increased the metabolism of irinotecan to SN-38 with respect to standard 30/90-min administration. Indeed, the steady-state concentration of irinotecan, SN-38, and SN-38glu were 42.7 ± 25.2, 14.9 ± 1.9, and 31.7 ± 3.5 nmol/liter, respectively, and the area under the time-concentration curves of irinotecan, SN-38, and SN-38glu were 6.94 ± 0.41, 1.92 ± 0.30, and 4.23 ± 0.52 hxµmol/liter, respectively. Twelve patients were evaluable for activity, and we observed 3 (25%) partial responses, 2 (17%) minor responses, and 4 (33%) disease stabilizations.

Conclusions: The administration of irinotecan as a 7-day continuous infusion every 21 days is feasible with diarrhea being the dose-limiting toxicity; recommended dose for Phase II studies is 20.0 mg/m²/day. The comparison of the present data with those obtained after a standard 30–90 min. i.v. infusion of irinotecan demonstrates that continuous infusion improves the transformation of irinotecan to SN-38 and also results in increased glucuronidation of the active metabolite. Antitumor activity in pretreated metastatic colorectal cancer patients is encouraging.

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