Phase I trial of tipifarnib in patients with recurrent malignant glioma taking enzyme-inducing antiepileptic drugs: a North American Brain Tumor Consortium Study.
OBJECTIVE
To determine the maximum-tolerated dose (MTD), toxicities, and clinical effect of tipifarnib, a farnesyltransferase (FTase) inhibitor, in patients with recurrent malignant glioma taking enzyme-inducing antiepileptic drugs (EIAEDs). This study compares the pharmacokinetics and pharmacodynamics of tipifarnib at MTD in patients on and off EIAEDs.


METHODS
Recurrent malignant glioma patients were treated with tipifarnib using an interpatient dose-escalation scheme. Pharmacokinetics and pharmacodynamics were assessed.


RESULTS
Twenty-three assessable patients taking EIAEDs received tipifarnib in escalating doses from 300 to 700 mg bid for 21 of 28 days. The dose-limiting toxicity was rash, and the MTD was 600 mg bid. There were significant differences in pharmacokinetic parameters at 300 mg bid between patients on and not on EIAEDs. When patients on EIAEDs and not on EIAEDs were treated at MTD (600 and 300 mg bid, respectively), the area under the plasma concentration-time curve (AUC)(0-12 hours) was approximately two-fold lower in patients on EIAEDs. Farnesyltransferase inhibition was noted at all tipifarnib dose levels, as measured in peripheral-blood mononuclear cells (PBMC).


CONCLUSIONS
Toxicities and pharmacokinetics differ significantly when comparing patients on or off EIAEDs. EIAEDs significantly decreased the maximum concentration, AUC(0-12 hours), and predose trough concentrations of tipifarnib. Even in the presence of EIAEDs, the levels of tipifarnib were still sufficient to potently inhibit FTase activity in patient PBMCs. The relevance of these important findings to clinical activity will be determined in ongoing studies with larger numbers of patients.
Cloughesy
Timothy F
TF
Henry E. Singleton Brain Cancer Research Program, University of California, Los Angeles, CA, USA. tcloughe@ucla.edu
Kuhn
John
J
Robins
H Ian
HI
Abrey
Lauren
L
Wen
Patrick
P
Fink
Karen
K
Lieberman
Frank S
FS
Mehta
Minesh
M
Chang
Susan
S
Yung
Alfred
A
DeAngelis
Lisa
L
Schiff
David
D
Junck
Larry
L
Groves
Morris
M
Paquette
Steve
S
Wright
John
J
Lamborn
Kathleen
K
Sebti
Said M
SM
Prados
Michael
M
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D015363:Quinolones / Q000008:administration & dosage* / Q000493:pharmacokinetics; D018570:Risk Assessment; D016879:Salvage Therapy; D016019:Survival Analysis; D016896:Treatment Outcome
D000927:Anticonvulsants; D015363:Quinolones; C402769:tipifarnib