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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@ucla.edu
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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.
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