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Phase
II trial of R115777 (Zarnestra) in patients with recurrent glioma not taking
enzyme inducing antiepileptic drugs (EIAED): a North American Brain Tumor
Consortium (NABTC) report
Timothy
F Cloughesy, John Kuhn, Patrick Wen, Susan M Chang, David Schiff, Harry
Greenberg, Larry Junck, Ian Robins, Lisa M DeAngelis, Al Yung, Morris Groves,
Karen Fink, Lauren E Abrey, Frank Lieberman, Minesh P Mehta, Jeff J Raizer, Ken
Hess, Michael Prados
UCLA, Los
Angeles, CA; UT San Antonio, San Antonio, TX; Dana-Farber Cancer Center, Boston,
MA; UCSF, San Francisco, CA; University of Pittsburgh, Pittsburgh, PA;
University of Michigan, Ann Arbor, MI; University of Wisconsin, Madison, WI;
Memorial Sloan-Kettering Cancer Ctr, New York, NY; M.D. Anderson Cancer Center,
Houston, TX; UT Southwestern, Dallas, TX.
Novel
specific focal molecular therapies are needed in the treatment of recurrent
malignant glioma.
R115777 is an oral farnesyl transferase (FT) inhibitor that has activity in
other cancer types, and may be an effective therapy for glioma.
The objectives of this phase II study of R115777 are to determine efficacy in
patients with progressive maligant gliomas as measured by 6 month progression
free survival and objective tumor response, to evaluate safety of R115777 in
this patient population, and to correlate treatment response with inhibition of
FTase in peripheral blood monocytes (PBM) and with phamacokinetics (PK).
Adult patients were enrolled with evidence of a recurrent malignant glioma, KPS
at 60 or greater, adequate organ function, prior failure of radiation, and
limits on prior therapies.
Patients were not receiving enzyme-inducing anti-epileptic drugs (EIAED).
The dose of R115777started at the accepted MTD of 300mg po bid for 21 days on
and 7 days off in repeating 28-day cycles.
Forty-two patients were enrolled, and receiveddrug.
The median age was 50 (30-75), the median KPS 90 (60-100).
There were 25 males, 17 females.
Histologies included 5 AA, 3 AO, 33 GBM; all were evaluable for toxicity and
response.
In the 33 patients with GBM, three have shown PRs and two additional had SD >
6 months and 15% of patients are progression free at 6 months.
Overall survival is pending.
Grade 3-4 adverse events included 1 depressed consciousness, 1 constipation, 3
granulocytopenia, 1 leukopenia, 1 photophobia, 1 skin rash, and 1
thrombocytopenia.
Three patients were taken off study due to toxicity.
Preliminary PK data show Cmax and AUC data similar to patients with AML
receiving this same dosing schedule.
Complete PK and FTase inhibition results will be provided.
R115777 is tolerable at 300mg bid 21/7 in this patient population.
There is some modest evidence of activity against recurrent GBM who are not on
EIAED.
Analysis of PK and FTase data might provide rationale for the responses and
adverse events seen in this study.
© Copyright 2002
American
Society of Clinical Oncology
Source:
http://www.asco.org/ac/1,1003,_12-002324-00_18-002002-00_19-00317-00_29-00A-00_42-00ONeill-00_43-00-00_44-00-00_45-00
Author-00_46-00Title-00_47-00Title-00_48-00and-00_49-00and,00.asp?cat=CNS+Tumors&parent=CENTRAL+NERVOUS+SYSTEM+TUMORS
&returnpid=2323
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