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Phase I/II Study of Imatinib Mesylate for Recurrent Malignant Gliomas: North American Brain Tumor Consortium Study 99-08

Authors' Affiliations: ¹ Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts; ² University of Texas M.D. Anderson Cancer Center, Houston, Texas; ³ University of California-San Francisco Medical Center, San Francisco, California; ⁴ Novartis Pharmaceuticals, Florham Park, New Jersey; ⁵ Memorial Sloan-Kettering Cancer Center, New York, New York; ⁶ University of California-Los Angeles Medical Center, Los Angeles, California; ⁷ University of Texas Southwestern Medical Center, Dallas, Texas; ⁸ University of Michigan, Ann Arbor, Michigan; ⁹ University of Pittsburgh, Pittsburgh, Pennsylvania; ¹⁰ Neuro-Oncology Branch, NIH, Bethesda, Maryland; ¹¹ University of Wisconsin, Madison, Wisconsin; and ¹² Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, Maryland

Requests for reprints: Patrick Y. Wen, Center for Neuro-Oncology, Dana-Farber/Brigham and Women's Cancer Center, SW430D, 44 Binney Street, Boston, MA 02115. Phone: 617-632-2166; Fax: 617-632-4773; E-mail: pwen{at}partners.org.

Purpose: Phase I: To determine the maximum tolerated doses, toxicities, and pharmacokinetics of imatinib mesylate (Gleevec) in patients with malignant gliomas taking enzyme-inducing antiepileptic drugs (EIAED) or not taking EIAED. Phase II: To determine the therapeutic efficacy of imatinib.

Experimental Design: Phase I component used an interpatient dose escalation scheme. End points of the phase II component were 6-month progression-free survival and response.

Results: Fifty patients enrolled in the phase I component (27 EIAED and 23 non-EIAED). The maximum tolerated dose for non-EIAED patients was 800 mg/d. Dose-limiting toxicities were neutropenia, rash, and elevated alanine aminotransferase. EIAED patients received up to 1,200 mg/d imatinib without developing dose-limiting toxicity. Plasma exposure of imatinib was reduced by 68% in EIAED patients compared with non-EIAED patients. Fifty-five non-EIAED patients (34 glioblastoma multiforme and 21 anaplastic glioma) enrolled in the phase II component. Patients initially received 800 mg/d imatinib; 15 anaplastic glioma patients received 600 mg/d after hemorrhages were observed. There were 2 partial response and 6 stable disease among glioblastoma multiforme patients and 0 partial response and 5 stable disease among anaplastic glioma patients. Six-month progression-free survival was 3% for glioblastoma multiforme and 10% for anaplastic glioma patients. Five phase II patients developed intratumoral hemorrhages.

Conclusions: Single-agent imatinib has minimal activity in malignant gliomas. CYP3A4 inducers, such as EIAEDs, substantially decreased plasma exposure of imatinib and should be avoided in patients receiving imatinib for chronic myelogenous leukemia and gastrointestinal stromal tumors. The evaluation of the activity of combination regimens incorporating imatinib is under way in phase II trials.

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