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Results of a Phase II Upfront Window of Pharmacokinetically Guided Topotecan in High-Risk Medulloblastoma and Supratentorial Primitive Neuroectodermal Tumor

From the Departments of Pharmaceutical Sciences, Hematology-Oncology, Molecular Pharmacology, and Biostatistics, St Jude Children’s Research Hospital; Department of Pediatrics, College of Medicine, University of Tennessee, Memphis, TN; Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine, Houston TX; University of Pittsburgh Cancer Institute, Pittsburgh PA; Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN; The Oncology Unit, The Children’s Hospital at Westmead and the University of Sydney, Sydney; and Department of Hematology Oncology, Royal Children’s Hospital and the University of Melbourne, Melbourne, Australia

Address reprint requests to Amar Gajjar, MD, Department of Hematology-Oncology (Room 6024), St Jude Children’s Research Hospital, 332 N Lauderdale, Memphis, TN 38105-2794; e-mail: amar.gajjar{at}stjude.org

PURPOSE: To assess the antitumor efficacy of pharmacokinetically guided topotecan dosing in previously untreated patients with medulloblastoma and supratentorial primitive neuroectodermal tumors, and to evaluate plasma and CSF disposition of topotecan in these patients.

PATIENTS AND METHODS: After maximal surgical resection, 44 children with previously untreated high-risk medulloblastoma were enrolled, of which 36 were assessable for response. The topotecan window consisted of two cycles, administered initially as a 30-minute infusion daily for 5 days, lasting 6 weeks. Pharmacokinetic studies were conducted on day 1 to attain a topotecan lactone area under the plasma concentration-time curve (AUC) of 120 to 160 ng/mL·h. After 10 patients were enrolled, the infusion was modified to 4 hours, with dosage individualization.

RESULTS: Of 36 assessable patients, four patients (11.1%) had a complete response and six (16.6%) showed a partial response, and disease was stable in 17 patients (47.2%). Toxicity was mostly hematologic, with only one patient experiencing treatment delay. The target plasma AUC was achieved in 24 of 32 studies (75%) in the 30-minute infusion group, and in 58 of 93 studies (62%) in the 4-hour infusion group. The desired CSF topotecan exposure was achieved in seven of eight pharmacokinetic studies when the topotecan plasma AUC was within target range.

CONCLUSION: Topotecan is an effective agent against pediatric medulloblastoma in patients who have received no therapy other than surgery. Pharmacokinetically guided dosing achieved the target plasma AUC in the majority of patients. This drug warrants testing as part of standard postradiation chemotherapeutic regimens. Furthermore, these results emphasize the importance of translational research in drug development, which in this case identified an effective drug.

Supported by Cancer Center Support (CORE) grant P 30 CA 21765 and grant P01 23099 from the National Cancer Institute, and by the American Lebanese Syrian Associated Charities (ALSAC).

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

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