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 HighWire Citing Articles via Google Scholar Google Scholar Articles by Daw, N. C. Articles by Stewart, C. F. Search for Related Content PubMed PubMed Citation Articles by Daw, N. C. Articles by Stewart, C. F. Social Bookmarking                            What's this?

Phase I and Pharmacokinetic Study of Topotecan Administered Orally Once Daily for 5 Days for 2 Consecutive Weeks to Pediatric Patients With Refractory Solid Tumors

From the Departments of Hematology-Oncology, Molecular Pharmacology, and Pharmaceutical Sciences, St Jude Children's Research Hospital; and the University of Tennessee Health Science Center, Memphis, TN.

Address reprint requests to Najat C. Daw, MD, Department of Hematology-Oncology, Mail Stop 260, St Jude Children's Research Hospital, 332 N Lauderdale, Memphis, TN 38105-2794; e-mail: najat.daw{at}stjude.org

PURPOSE: We conducted a phase I trial of the injectable formulation of topotecan given orally once daily for 5 days for 2 consecutive weeks (qd x 5 x 2) in pediatric patients with refractory solid tumors.

PATIENTS AND METHODS: Cohorts of two to six patients received oral topotecan at 0.8, 1.1, 1.4, 1.8, and 2.3 mg/m²/d every 28 days for a maximum of six courses. Twenty patients (median age, 10.6 years) received a total of 51 courses. Eight patients received topotecan capsules during course 2 only.

RESULTS: Dose-limiting toxicity occurred at 2.3 mg/m²/d and consisted of prolonged grade 4 neutropenia (n = 2), grade 3 stomatitis as a result of radiation recall (n = 1), grade 3 hemorrhage (epistaxis) in the presence of grade 4 thrombocytopenia (n = 1), and grade 3 diarrhea in the presence of Clostridium difficile infection (n = 1). Dose-limiting, prolonged grade 4 neutropenia and thrombocytopenia occurred in one patient at 1.4 mg/m²/d. Infrequent toxicities were mild nausea, vomiting, elevated liver ALT or AST, and rash. The maximum-tolerated dosage was 1.8 mg/m²/d; the mean (± standard deviation) area under the plasma concentration-time curve for topotecan lactone at this dosage was 20.9 ± 8.4 ng/mL · h. The population mean (± standard error) oral bioavailability of the injectable formulation was 0.27 ± 0.03; that of capsules was 0.36 ± 0.06 (P = .16). Disease stabilized in nine of 19 assessable patients for 1.5 to 6 months.

CONCLUSION: Oral topotecan (1.8 mg/m²/d) on a qd x 5 x 2 schedule is well tolerated and warrants additional testing in pediatric patients.

Supported in part by Cancer Center Support (CORE) grant CA21765 and grant CA23099 from the National Cancer Institute, by the American Lebanese Syrian Associated Charities (ALSAC), and by GlaxoSmithKline.

Presented in part at the 37th Annual Meeting of the American Society of Clinical Oncology, May 12-15, 2001, San Francisco, CA, and the 39th Annual Meeting, May 31-June 3, 2003, Chicago, IL.

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

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

This article has been cited by other articles:

				D. P. Lee, J. M. Skolnik, and P. C. Adamson Pediatric Phase I Trials in Oncology: An Analysis of Study Conduct Efficiency J. Clin. Oncol., November 20, 2005; 23(33): 8431 - 8441. [Abstract] [Full Text] [PDF]

				A. Rapisarda, J. Zalek, M. Hollingshead, T. Braunschweig, B. Uranchimeg, C. A. Bonomi, S. D. Borgel, J. P. Carter, S. M. Hewitt, R. H. Shoemaker, et al. Schedule-dependent Inhibition of Hypoxia-inducible Factor-1{alpha} Protein Accumulation, Angiogenesis, and Tumor Growth by Topotecan in U251-HRE Glioblastoma Xenografts Cancer Res., October 1, 2004; 64(19): 6845 - 6848. [Abstract] [Full Text] [PDF]