Phase II study of imatinib mesylate (Gleevec®) for recurrent meningiomas (North American Brain Tumor Consortium Study 01–08)

¹ Dana Farber/Brigham and Women’s Cancer Center, Boston, MA, USA
² University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
³ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco Medical Center, San Francisco, CA, USA
⁴ University of California Los Angeles Medical Center, Los Angeles, CA, USA
⁵ Memorial Sloan Kettering Cancer Center, New York, NY, USA
⁶ Neuro-Oncology Branch, National Institutes of Health, Bethesda, MD, USA
⁷ University of Wisconsin, Madison, WI, USA
⁸ University of Texas Southwestern Medical Center, Dallas, TX, USA
⁹ Massachusetts General Hospital, Boston, MA, USA
¹⁰ University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

^* To whom correspondence should be addressed. E-mail: Patrick_Wen{at}dfci.harvard.edu.

	Abstract

Platelet-derived growth factor (PDGF) and its receptors (PDGFR) are frequently co-expressed in meningiomas, potentially contributing to their pathogenesis. The North American Brain Tumor Consortium (NABTC) conducted a phase II study to evaluate the therapeutic potential of imatinib mesylate (Gleevec®), a PDGFR inhibitor, in patients with recurrent meningiomas. Patients were stratified into benign (WHO grade I) meningiomas or atypical (WHO grade II) and malignant (WHO grade III) meningiomas. The primary endpoint was 6-month progressionfree survival (6M-PFS). Patients requiring enzyme-inducing anti-epileptic drugs were ineligible. Patients received imatinib at a dose of 600 mg/day for the first 4-week cycle and then gradually increased to 800 mg/day for subsequent cycles, if there were no unacceptable toxicities. Plasma concentrations of imatinib and its active metabolite, CGP74588, were assessed. Twenty-three heavily pretreated patients were enrolled into the study (13 benign, 5 atypical, and 5 malignant meningiomas), of whom 22 were eligible. The study was closed prematurely due to slow accrual. Tissue was available only from a minority of patients but in these specimens there was uniform distribution of PDGFR, the drug target. Imatinib was generally well tolerated. Of 19 patients evaluable for response, 10 progressed at the first scan, and 9 were stable. There were no complete or partial responses (PR). Overall median PFS was 2 months (range 0.7–34 months); 6M-PFS was 29.4%. For benign meningiomas, median PFS was 3 months (range 1.1–34 months); 6M-PFS was 45%. For atypical and malignant meningiomas, median PFS was 2 months (range 0.7–3.7 months); 6M-PFS was 0%. Cycle 1 trough concentrations of imatinib and CGP74588 were 2129±1600 ng/ml and 517±326 ng/ml, respectively. Single-agent imatinib was well-tolerated but had no significant activity in recurrent meningiomas. Trough plasma concentrations of imatinib exceeded those associated with imatinib activity in CML.

Key Words: imatinib, meningioma, pharmacokinetics, toxicities

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