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.
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.
authors.affiliation: Department of Surgery, Duke University Medical Center, Durham, NC, 27710, USA. reard003@mc.duke.edu
authors.forename: David A
authors.initials: DA
authors.lastname: Reardon
authors.forename: James J
authors.initials: JJ
authors.lastname: Vredenburgh
authors.forename: Annick
authors.initials: A
authors.lastname: Desjardins
authors.forename: Katherine
authors.initials: K
authors.lastname: Peters
authors.forename: Sridharan
authors.initials: S
authors.lastname: Gururangan
authors.forename: John H
authors.initials: JH
authors.lastname: Sampson
authors.forename: Jennifer
authors.initials: J
authors.lastname: Marcello
authors.forename: James E
authors.initials: JE
authors.lastname: Herndon
authors.forename: Roger E
authors.initials: RE
authors.lastname: McLendon
authors.forename: Dorothea
authors.initials: D
authors.lastname: Janney
authors.forename: Allan H
authors.initials: AH
authors.lastname: Friedman
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: Henry S
authors.initials: HS
authors.lastname: Friedman
mesh_terms: D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D012008:Recurrence; D000077157:Sorafenib; D000077204:Temozolomide
chemical_list: D000927:Anticonvulsants; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D003606:Dacarbazine; D000077157:Sorafenib; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D000077204:Temozolomide