Originally published as JCO Early Release 10.1200/JCO.2008.17.6644 on December 15 2008

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Widemann, B. C. Articles by Fox, E. Search for Related Content PubMed PubMed Citation Articles by Widemann, B. C. Articles by Fox, E. Social Bookmarking                            What's this?

Phase I Trial and Pharmacokinetic Study of Ixabepilone Administered Daily for 5 Days in Children and Adolescents With Refractory Solid Tumors

From the Pediatric and Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD.

Corresponding author: Brigitte C. Widemann, MD, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, 10 Center Dr, Bldg 10/Rm 1-5742, Bethesda, MD 20892; e-mail: widemanb{at}mail.nih.gov.

Purpose The objectives of this phase I trial were to determine the maximum-tolerated dose (MTD), toxicity profile, dose-limiting toxicities (DLTs), pharmacokinetics, and preliminary response rate for ixabepilone, a microtubule-stabilizing agent, administered intravenously daily for 5 days in children and adolescents.

Patients and Methods Patients 2 and 18 years with relapsed or refractory solid tumors were enrolled onto sequential cohorts to the following five dose levels: 3.0 (n = 3), 4.5 (n = 4), 6.0 (n = 3), 8.0 (n = 6), and 10 (n = 3) mg/m²/d. Eligibility criteria, dose levels, definitions of DLT and MTD, and pharmacokinetic sampling times were designed to be as similar as possible to the adult phase I trial of ixabepilone on the same schedule.

Results Nineteen children (median age, 10 years; range, 2 to 18 years) were enrolled, and 18 (12 with sarcomas) were assessable for toxicity. DLTs (grade 4 neutropenia for > 5 days and grade 3 fatigue) were observed in two of three patients receiving 10 mg/m²/d. The MTD of ixabepilone administered daily for 5 days every 21 days was 8 mg/m²/d. Myelosuppression, GI, and hepatic toxicities were common non-DLTs. Peripheral neuropathy was uncommon. Ixabepilone clearance was 475 ± 247 mL/min/m², volume of distribution at steady-state was 12.2 ± 5.4 L/kg, and half-life was 14 hours.

Conclusion The recommended dose of ixabepilone for phase II trials in solid tumors is 8 mg/m²/d daily for 5 days every 21 days. This dose is 33% higher than the MTD in adults receiving the same dosing schedule. Pharmacokinetic parameters in children and adolescents were highly variable but similar to adults.

Supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research.

Presented in part at the 41st Annual Meeting of the American Society for Clinical Oncology, May 13-17, 2005, Orlando, FL.

The views expressed do not necessarily represent views of the National Institutes of Health or the US government.

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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?