Phase I trial of tipifarnib in patients with recurrent malignant glioma taking enzyme-inducing antiepileptic drugs: A North American brain tumor consortium study Journal Article
| Authors: | Cloughesy, T. F.; Kuhn, J.; Robins, H. I.; Abrey, L.; Wen, P.; Fink, K.; Lieberman, F. S.; Mehta, M.; Chang, S.; Yung, A.; DeAngelis, L.; Schiff, D.; Junck, L.; Groves, M.; Paquette, S.; Wright, J.; Lamborn, K.; Sebti, S. M.; Prados, M. |
| Article Title: | Phase I trial of tipifarnib in patients with recurrent malignant glioma taking enzyme-inducing antiepileptic drugs: A North American brain tumor consortium study |
| Title Series: | 38th Annual Meeting of the American-Society-of-Clinical-Oncology |
| Abstract: | 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 antielpileptic 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 tipifarnilb 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. |
| Keywords: | advanced cancer; paclitaxel; metabolism; guanosine triphosphate; ras; growth; glioblastoma-multiforme; therapeutic strategy; transferase inhibitor r115777; farnesyltransferase inhibitors |
| Journal Title: | Journal of Clinical Oncology |
| Volume: | 23 |
| Issue: | 27 |
| Dates: | MAY 18-21, 2002 |
| Location: | ORLANDO, FL |
| ISSN: | 0732-183X |
| Publisher: | American Society of Clinical Oncology |
| Date Published: | 2005-09-20 |
| Start Page: | 6647 |
| End Page: | 6656 |
| Language: | English |
| DOI: | 10.1200/jco.2005.10.068 |
| ACCESSION: | WOS:000232233100029 |
| PROVIDER: | wos |
| PUBMED: | 16170172 |
| Notes: | --- - Article; Proceedings Paper - 38th Annual Meeting of the American-Society-of-Clinical-Oncology - MAY 18-21, 2002 - ORLANDO, FL - "Source: Wos" |
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