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Phase II Study of Imatinib in Patients With Recurrent Gliomas of Various Histologies: A European Organisation for Research and Treatment of Cancer Brain Tumor Group Study

Eric Raymond, Alba A. Brandes, Christian Dittrich, Pierre Fumoleau, Bruno Coudert, Paul M.J. Clement, Marc Frenay, Roy Rampling, Roger Stupp, Johan M. Kros, Michael C. Heinrich, Thierry Gorlia, Denis Lacombe, Martin J. van den Bent

From the Service Inter Hospitalier de Cancérologie, Beaujon University Hospital, Clichy; Centre Georges-François Leclerc, Dijon; Antoine Lacassagne Center, Nice, France; Bellaria and Maggiore Hospitals, Azienda Unità Sanitaria Locale of Bologna, Bologna, Italy; Applied Cancer Research-Institute for Translational Research; Ludwig Boltzmann-Institute for Applied Cancer Reearch; Kaiser Franz Josef Spital, Vienna, Austria; Leuven Cancer Institute, University Hospital Leuven, Leuven; European Organisation for Research and Treatment of Cancer Data Center, Brussels, Belgium; Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom; Multidisciplinary Oncology Center, University Hospital and University of Lausanne, Lausanne, Switzerland; Erasmus University Hospital, and Daniel den Hoed Cancer Center/Erasmus University Hospital, Rotterdam, the Netherlands; and Oregon Health and Science University Cancer Institute and Portland Veterans Affairs Medical Center, Portland, OR

Corresponding author: M.J. van den Bent, MD, Neuro-Oncology Unit, Daniel den Hoed Cancer Center/Erasmus University Hospital, PO Box 5201, 3008AE Rotterdam, the Netherlands; e-mail: m.vandenbent{at}erasmusmc.nl

Purpose To evaluate the safety and the efficacy of imatinib in recurrent malignant gliomas.

Patients and Methods This was a single-arm, phase II study. Eligible patients had recurrent glioma after prior radiotherapy with an enhancing lesion on magnetic resonance imaging. Three different histologic groups were studied: glioblastomas (GBM), pure/mixed (anaplastic) oligodendrogliomas (OD), and low-grade or anaplastic astrocytomas (A). Imatinib was started at a dose of 600 mg/d with dose escalation to 800 mg in case of no toxicity; during the trial this dose was increased to 800 mg/d with escalation to 1,000 mg/d. Trial design was one-stage Fleming; both an objective response and 6 months of progression-free survival (PFS) were considered a successful outcome to treatment.

Results A total of 112 patients (51 patients with GBM, 25 patients with A, and 36 patients with OD) were enrolled. Imatinib was in general well tolerated. The median number of cycles was 2.0 (range, 1 to 43 cycles). Five patients had an objective partial response, including three patients with GBM; all had 6 months of PFS. The 6-month PFS rate was 16% (95% CI, 8.0% to 34.0%) in GBM, 4.0% (95% CI, 0.3% to 15.0%) in OD, and 9% (95% CI, 2.0% to 25.0%) in A. The exposure to imatinib was significantly lower in patients using enzyme-inducing antiepileptic drugs. The presence of ABCG2 point mutations were not correlated with pharmacokinetic findings. No somatic activating mutations of KIT or platelet-derived growth factor receptor–A or –B were found.

Conclusion In the dose range of 600 to 1,000 mg/d, single-agent imatinib is well tolerated but has limited antitumor activity in patients with recurrent gliomas.

Supported by the European Organisation for Research and Treatment of Cancer Charitable Trust and Grants No. 5U10 CA11488-32 through 5U10 CA11488-34 from the National Cancer Institute (Bethesda, MD). Additional funding was provided by Novartis Pharma AG and a Veterans Affairs Merit Review Grant (M.C.H.). The imatinib used in this study was provided free of charge by Novartis Pharma AG.

The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

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

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