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.

Abstract

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/m(2)/day (dose level I), 6 at 25 mg/m(2)/day (dose level II), and 4 at 22.5 mg/m(2)/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/m(2)/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/m(2)/day the maximum-tolerable dose and 20.0 mg/m(2)/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 hx micro mol/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/m(2)/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.

• Authors: Gianluca Masi, Alfredo Falcone, Antonello Di Paolo, Giacomo Allegrini, Romano Danesi, Cecilia Barbara, Samanta Cupini, Mario Del Tacca
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 10 Issue 5 Pg. 1657-63 (Mar 01 2004) ISSN: 1078-0432 [Print] United States
• PMID: 15014016 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article)

Chemical References

• 7-ethyl-10-hydroxycamptothecin glucuronide
• Antimetabolites, Antineoplastic
• Antineoplastic Agents, Phytogenic
• Glucuronides
• Quinazolines
• Thiophenes
• Irinotecan
• raltitrexed
• Fluorouracil
• Camptothecin

Topics

• Aged
• Antimetabolites, Antineoplastic (therapeutic use)
• Antineoplastic Agents, Phytogenic (administration & dosage, pharmacokinetics, toxicity)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use, toxicity)
• Camptothecin (administration & dosage, analogs & derivatives, pharmacokinetics, therapeutic use, toxicity)
• Colorectal Neoplasms (drug therapy, pathology)
• Diarrhea (chemically induced)
• Female
• Fluorouracil (therapeutic use)
• Glucuronides (therapeutic use)
• Humans
• Infusions, Intravenous
• Irinotecan
• Male
• Middle Aged
• Nausea (chemically induced)
• Neoplasm Metastasis
• Patient Selection
• Quinazolines (therapeutic use)
• Thiophenes (therapeutic use)
• Vomiting (chemically induced)