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Phase II Trial of Irinotecan in Children With Refractory Solid Tumors: A Children's Oncology Group Study

Lisa R. Bomgaars, Mark Bernstein, Mark Krailo, Richard Kadota, Soma Das, Zhengjia Chen, Peter C. Adamson, Susan M. Blaney

From the Baylor College of Medicine, Houston, TX; IWK Health Centre, Halifax, Nova Scotia, Canada; Keck School of Medicine, University of Southern California, Los Angeles; Rady Children's Hospital, San Diego; Children's Oncology Group, Arcadia, CA; University of Chicago, Chicago, IL; and Children's Hospital of Philadelphia, Philadelphia, PA

Address reprint requests to Lisa Bomgaars, MD, Texas Children's Cancer Center, 6621 Fannin, MC 3-3320, Houston, TX 77030; e-mail: lbomgaars{at}txccc.org

Purpose A phase II study was performed to determine the efficacy of irinotecan (IRN) in children with refractory solid tumors. Secondary objectives were to evaluate toxicity, pharmacokinetics, pharmacodynamics, and UGT1A1 genotype.

Patients and Methods A total of 181 patients were enrolled, of whom 171 were eligible. Patients received IRN 50 mg/m²/d for 5 days repeated every 3 weeks. Pharmacokinetic studies and UGT1A1 genotyping were performed.

Results Of 161 patients assessable for response, one patient with hepatoblastoma had a complete response, with partial responses observed in patients with medulloblastoma (n = 4), rhabdomyosarcoma (n = 1), neuroblastoma (n = 1), and germinoma (n = 1), for an overall response rate of 5%. Grade 4 neutropenia and grade 3 to 4 diarrhea occurred in less than 7% of the courses administered. Pharmacokinetic studies were available for 79 patients. The mean ± standard deviation IRN plasma clearance was 374 ± 148 mL/min/m², with median relative extent of conversion and relative extent of glucuronidation of 0.05 (range, 0.01 to 0.25) and 2.24 (range, 0.39 to 9.6), respectively. No association between UGT1A1 genotype (n = 61) and toxicity or pharmacokinetic parameters was observed.

Conclusion IRN 50 mg/m²/d for 5 days every 21 days is well tolerated, but was not effective as a single agent in a spectrum of solid tumors, with the possible exception of patients with medulloblastoma (16% response rate). There was no association between UGT1A1*28 genotype and toxicity or pharmacokinetic parameters.

Supported by Children's Oncology Group (COG) Grant No. CA 98543. A complete listing of grant support for research conducted by CCG and Pediatric Oncology Group before initiation of the COG Grant in 2003 is available online at: http://www.childrensoncologygroup.org/admin/grantinfo.htm.

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

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