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Phase I Trial of Tipifarnib in Patients With Recurrent Malignant Glioma Taking Enzyme-Inducing Antiepileptic Drugs: A North American Brain Tumor Consortium Study

From the Henry E. Singleton Brain Cancer Research Program, University of California, Los Angeles; University of California, San Francisco, CA; University of Texas Health Science Center, San Antonio; University of Texas Southwestern Medical Center, Dallas; University of Texas M.D. Anderson Cancer Center, Houston, TX; University of Wisconsin, Madison, WI; Memorial Sloan-Kettering Cancer Center, New York, NY; Dana-Farber Cancer Institute, Boston, MA; University of Pittsburgh, Pittsburgh, PA; University of Michigan, Ann Arbor, MI; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD; and Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL

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

PURPOSE: 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.

PATIENTS AND 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).

CONCLUSION: 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.

Supported by the following Grants: University of California, Los Angeles: Grants No. U01CA62399 and GCRC# M01-RR0865 and Grant from Art of the Brain; University of California, San Francisco: Grants No. UO1CA62422 and GCRC# M01-RR00079; 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; and University of South Florida: Grant No. CA 76292.

Presented at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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