Originally published as JCO Early Release 10.1200/JCO.2008.19.6642 on August 17 2009

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Tyrosine Kinase Inhibitor Enhances the Bioavailability of Oral Irinotecan in Pediatric Patients With Refractory Solid Tumors

From the Departments of Oncology, Radiological Sciences, Pharmaceutical Sciences, Biostatistics, and Molecular Pharmacology, St Jude Children's Research Hospital; the Departments of Pharmacy and Pharmaceutical Sciences, College of Pharmacy, and the Department of Pediatrics, College of Medicine, University of Tennessee Health Sciences Center, Memphis, TN.

Corresponding author: Wayne L. Furman, MD, Department of Oncology, St Jude Children's Research Hospital, 262 Danny Thomas Pl, Memphis, TN 38105-3678; e-mail: wayne.furman{at}stjude.org.

Purpose To assess the maximum-tolerated dosages (MTDs), and dose-limiting toxicities (DLTs) of the epidermal growth factor receptor inhibitor gefitinib and of intravenous (IV) irinotecan when administered together in children with refractory solid tumors. To assess the effect of gefitinib on the pharmacokinetics of IV irinotecan and on the bioavailability of a single oral dose of irinotecan.

Patients and Methods IV irinotecan (15 or 20 mg/m²) was given daily for 5 days of 2 consecutive weeks. Oral gefitinib (150 or 112.5 mg/m²) was concomitantly given daily for 12 or 21 days. A single oral dose of irinotecan was given on day 9 of course 2 to allow pharmacokinetic analysis.

Results The study enrolled 29 patients with recurrent solid tumors. The 21-day regimen of oral gefitinib with irinotecan was not tolerated. Diarrhea was the most common DLT. The MTD of the combination regimen was 15 mg/m²/d of IV irinotecan for 5 days of 2 consecutive weeks and 112.5 mg/m²/d of gefitinib given for 12 days. Gefitinib increased the bioavailability of oral irinotecan by four-fold over that observed in historical controls (median, 0.09 v 0.42; P < .000001), reducing the apparent clearance (an inverse measure of exposure) of irinotecan and SN-38 by 37% and 38%, respectively (P < .0001). A partial response was observed in a patient with refractory Ewing sarcoma.

Conclusion IV irinotecan given with 12 days of oral gefitinib is well tolerated in children. We observed one partial response. Gefitinib significantly enhances the bioavailability of oral irinotecan. This combination warrants further investigation, particularly with orally administered irinotecan.

Supported by Grants No. CA23099 and CA21765 from the National Institutes of Health, by a grant from Astra Zeneca, and by the American Lebanese Syrian Associated Charities.

Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Clinical Trials repository link available on JCO.org.

Clinical trial information can be found for the following: NCT00186979 [ClinicalTrials.gov] .

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