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Phase II Study of Imatinib Mesylate Plus Hydroxyurea in Adults With Recurrent Glioblastoma Multiforme

From the Departments of Medicine, Pharmacology and Cancer Institute, University of Pittsburgh, Pittsburgh, PA; Franz-Hospital Dülmen, Dülmen, Germany; Novartis Pharmaceuticals, Florham Park, NJ; and Departments of Surgery, Neurology, Pediatrics, Radiology, Pathology, and Cancer Center Biostatistics, Duke University Medical Center, Durham, NC

Address reprint requests to David A. Reardon, MD, the Brain Tumor Center at Duke, Duke University Medical Center, Box 3624, Durham, NC 27710; e-mail: reard003{at}mc.duke.edu

PURPOSE: We performed a phase II study to evaluate the combination of imatinib mesylate, an adenosine triphosphate mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme (GBM).

PATIENTS AND METHODS: Patients with GBM at any recurrence received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule. The imatinib mesylate dose was 500 mg twice a day for patients on enzyme-inducing antiepileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Assessments were performed every 28 days. The primary end point was 6-month progression-free survival (PFS).

RESULTS: Thirty-three patients enrolled with progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. With a median follow-up of 58 weeks, 27% of patients were progression-free at 6 months, and the median PFS was 14.4 weeks. Three patients (9%) achieved radiographic response, and 14 (42%) achieved stable disease. Cox regression analysis identified concurrent EIAED use and no more than one prior progression as independent positive prognostic factors of PFS. The most common toxicities included grade 3 neutropenia (16%), thrombocytopenia (6%), and edema (6%). There were no grade 4 or 5 events. Concurrent EIAED use lowered imatinib mesylate exposure. Imatinib mesylate clearance was decreased at day 28 compared with day 1 in all patients, suggesting an effect of hydroxyurea.

CONCLUSION: Imatinib mesylate plus hydroxyurea is well tolerated and associated with durable antitumor activity in some patients with recurrent GBM.

Supported by National Institutes of Health Grants No. NS20023, CA11898, MO1 RR 30, General Clinical Research Center Program, National Center for Research Resources; NCI Specialized Program of Research Excellence P30CA47904 and a grant from Novartis Pharmaceuticals.

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

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