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
- 5 May 2010
- journal article
- research article
- Published by Springer Science and Business Media LLC in Journal of Neuro-Oncology
- Vol. 101 (1), 57-66
- https://doi.org/10.1007/s11060-010-0217-6
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.Keywords
This publication has 63 references indexed in Scilit:
- Expression, mutation and copy number analysis of platelet-derived growth factor receptor A (PDGFRA) and its ligand PDGFA in gliomasBritish Journal of Cancer, 2009
- Extended-schedule dose-dense temozolomide in refractory gliomasJournal of Neuro-Oncology, 2009
- Phase II trial of two different irinotecan schedules with pharmacokinetic analysis in patients with recurrent glioma: North Central Cancer Treatment Group resultsJournal of Neuro-Oncology, 2008
- Sorafenib in Advanced Hepatocellular CarcinomaNew England Journal of Medicine, 2008
- A Multicenter Cohort Study of Dose-Dense Temozolomide (21 of 28 Days) for the Treatment of Recurrent Anaplastic Astrocytoma or OligoastrocytomaCancer Investigation, 2008
- Sorafenib in Advanced Clear-Cell Renal-Cell CarcinomaNew England Journal of Medicine, 2007
- AZD2171, a Pan-VEGF Receptor Tyrosine Kinase Inhibitor, Normalizes Tumor Vasculature and Alleviates Edema in Glioblastoma PatientsCancer Cell, 2007
- Temozolomide 3 weeks on and 1 week off as first-line therapy for recurrent glioblastoma: phase II study from gruppo italiano cooperativo di neuro-oncologia (GICNO)British Journal of Cancer, 2006
- Marked inactivation of O6-alkylguanine-DNA alkyltransferase activity with protracted temozolomide schedulesBritish Journal of Cancer, 2003
- Mutations of the BRAF gene in human cancerNature, 2002