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01-01-2011 | Clinical Study – Patient Study

Effect of CYP3A-inducing anti-epileptics on sorafenib exposure: results of a phase II study of sorafenib plus daily temozolomide in adults with recurrent glioblastoma

Authors: David A. Reardon, James J. Vredenburgh, Annick Desjardins, Katherine Peters, Sridharan Gururangan, John H. Sampson, Jennifer Marcello, James E. Herndon II, Roger E. McLendon, Dorothea Janney, Allan H. Friedman, Darell D. Bigner, Henry S. Friedman

Published in: Journal of Neuro-Oncology | Issue 1/2011

Abstract

Sorafenib, an oral VEGFR-2, Raf, PDGFR, c-KIT and Flt-3 inhibitor, is active against renal cell and hepatocellular carcinomas, and has recently demonstrated promising activity for lung and breast cancers. In addition, various protracted temozolomide dosing schedules have been evaluated as a strategy to further enhance its anti-tumor activity. We reasoned that sorafenib and protracted, daily temozolomide may provide complementary therapeutic benefit, and therefore performed a phase 2 trial among recurrent glioblastoma patients. Adult glioblastoma patients at any recurrence after standard temozolomide chemoradiotherapy received sorafenib (400 mg twice daily) and continuous daily temozolomide (50 mg/m²/day). Assessments were performed every eight weeks. The primary endpoint was progression-free survival at 6 months (PFS-6) and secondary end points were radiographic response, overall survival (OS), safety and sorafenib pharmacokinetics. Of 32 enrolled patients, 12 (38%) were on CYP3-A inducing anti-epileptics (EIAEDs), 17 (53%) had 2 or more prior progressions, 15 had progressed while receiving 5-day temozolomide, and 12 (38%) had failed either prior bevacizumab or VEGFR inhibitor therapy. The most common grade ≥ 3 toxicities were palmer-planter erythrodysesthesia (19%) and elevated amylase/lipase (13%). Sorafenib pharmacokinetic exposures were comparable on day 1 regardless of EIAED status, but significantly lower on day 28 for patients on EIAEDs (P = 0.0431). With a median follow-up of 93 weeks, PFS-6 was 9.4%. Only one patient (3%) achieved a partial response. In conclusion, sorafenib can be safely administered with daily temozolomide, but this regimen has limited activity for recurrent GBM. Co-administration of EIAEDs can lower sorafenib exposures in this population.

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Title: Effect of CYP3A-inducing anti-epileptics on sorafenib exposure: results of a phase II study of sorafenib plus daily temozolomide in adults with recurrent glioblastoma
Authors: David A. Reardon
James J. Vredenburgh
Annick Desjardins
Katherine Peters
Sridharan Gururangan
John H. Sampson
Jennifer Marcello
James E. Herndon II
Roger E. McLendon
Dorothea Janney
Allan H. Friedman
Darell D. Bigner
Henry S. Friedman
Publication date: 01-01-2011
Publisher: Springer US
Published in: Journal of Neuro-Oncology / Issue 1/2011
Print ISSN: 0167-594X
Electronic ISSN: 1573-7373
DOI: https://doi.org/10.1007/s11060-010-0217-6

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Effect of CYP3A-inducing anti-epileptics on sorafenib exposure: results of a phase II study of sorafenib plus daily temozolomide in adults with recurrent glioblastoma

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

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