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Phase II Trial of Tipifarnib in Patients With Recurrent Malignant Glioma Either Receiving or Not Receiving Enzyme-Inducing Antiepileptic Drugs: A North American Brain Tumor Consortium Study

Timothy F. Cloughesy, Patrick Y. Wen, H. Ian Robins, Susan M. Chang, Morris D. Groves, Karen L. Fink, Larry Junck, David Schiff, Lauren Abrey, Mark R. Gilbert, Frank Lieberman, John Kuhn, Lisa M. DeAngelis, Minesh Mehta, Jeff J. Raizer, W.K. Alfred Yung, Ken Aldape, John Wright, Kathleen R. Lamborn, Michael D. Prados

From the University of California, Los Angeles, Los Angeles; Neuro-Oncology Service, University of California, San Francisco, CA; Dana-Farber/Brigham and Women's Cancer Center, Boston, MA; University of Wisconsin Hospital, Madison, WI; Department of Neuro-Oncology, M.D. Anderson Cancer Center, Houston; Department of Neurology, University of Texas, Southwestern Medical Center, Dallas; University of Texas, Health Science Center, San Antonio, San Antonio TX; Department of Neurology, University of Michigan Hospital, Ann Arbor, MI; University of Virginia Health System, Charlottesville, VA; Memorial Sloan-Kettering Cancer Center, New York, NY; University of Pittsburgh Cancer Institute, Pittsburgh, PA; Northwestern University Feinberg School of Medicine, Chicago, IL; and Cancer Therapy Evaluation Program, National Cancer Institute, National Institutes of Health, Bethesda, MD

Address reprint requests to Timothy F. Cloughesy, MD, UCLA Neuro-Oncology Program, David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Reed Bldg, Room 1-230, Los Angeles, CA 90095; e-mail: tcloughe{at}ucla.edu

PURPOSE: A phase II study was undertaken in patients with recurrent malignant glioma to determine the efficacy and safety of tipifarnib, a farnesyltransferase inhibitor, dosed at the respective maximum-tolerated dose (MTD) for patients receiving and not receiving enzyme-inducing antiepileptic drugs (EIAEDs). Because tipifarnib undergoes extensive hepatic metabolism, MTD is doubled in patients on EIAEDs. The population included 67 patients with glioblastoma multiforme (GBM) and an exploratory group of 22 patients with anaplastic glioma (AG).

PATIENTS AND METHODS: Patients received tipifarnib (300 and 600 mg bid for 21 days every 4 weeks in non-EIAED and EIAED patients, respectively). All patients were assessable for efficacy and safety.

RESULTS: Two AG patients (9.1%) and eight GBM patients (11.9%) had progression-free survival (PFS) more than 6 months. Among the latter eight GBM patients, six of 36 patients (16.7%; 95% CI, 7% to 32%) were not receiving EIAEDs and two of 31 patients (6.5%; 95% CI, 1% to 20%) were receiving EIAEDs. Four patients had partial responses in group A GBM and one patient had a partial response group B GBM. An exploratory comparison of PFS between GBM groups A and B was statistically significant (P = .01). Patients not receiving EIAEDs had a higher incidence and increased severity of hematologic events. However, the incidence and severity of rash (the previously determined dose-limiting toxicity in patients receiving EIAEDs) seemed similar in EIAED and non-EIAED subgroups.

CONCLUSION: Tipifarnib (300 mg bid for 21 days every 4 weeks) shows modest evidence of activity in patients with recurrent GBM who are not receiving EIAEDs and is generally well tolerated in this population.

Supported by grants to the following institutions: University of California, Los Angeles, Grants No. U01CA62399 and General Clinical Research Center M01-RR0865, and a grant from Art of the Brain; University of California, San Francisco, Grants No. U01CA62422 and GCRC M01-RR00079; The University of Texas M.D. Anderson Cancer Center, Grants No. CA62412 and CA16672; Dana-Farber Cancer Center, Grant No. U01CA62407-08; University of Texas, Southwestern Medical Center, Grants No. CA62455-08 and GCRC M01-RR00633; University of Pittsburgh, Grants No. U01CA62405 and GCRC M01-RR00056; University of Texas, San Antonio, Grant No. CA62426; University of Michigan, Grants No. U01CA62399 and GCRC M01-RR00042; Memorial Sloan-Kettering Cancer Center, Grant No. 5-U01CA62399-09; University of Wisconsin Hospital, Grants No. U01CA62421-08 and GCRC M01 RR03186.

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

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