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.
OBJECTIVE
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).


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.


CONCLUSIONS
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.
Cloughesy
Timothy F
TF
UCLA Neuro-Oncology Program, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095, USA. tcloughe@ucla.edu
Wen
Patrick Y
PY
Robins
H Ian
HI
Chang
Susan M
SM
Groves
Morris D
MD
Fink
Karen L
KL
Junck
Larry
L
Schiff
David
D
Abrey
Lauren
L
Gilbert
Mark R
MR
Lieberman
Frank
F
Kuhn
John
J
DeAngelis
Lisa M
LM
Mehta
Minesh
M
Raizer
Jeff J
JJ
Yung
W K Alfred
WK
Aldape
Ken
K
Wright
John
J
Lamborn
Kathleen R
KR
Prados
Michael D
MD
D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000008:administration & dosage* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D004790:Enzyme Induction / Q000187:drug effects*; D004827:Epilepsy / Q000209:etiology / Q000517:prevention & control; D005260:Female; D005909:Glioblastoma / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology; D005910:Glioma / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009656:North America; D015363:Quinolones / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
D000927:Anticonvulsants; D000970:Antineoplastic Agents; D015363:Quinolones; C402769:tipifarnib