title: Phase 1 trial of gefitinib plus sirolimus in adults with recurrent malignant glioma.
abstract: OBJECTIVE
  To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of gefitinib, a receptor tyrosine kinase inhibitor of the epidermal growth factor receptor, plus sirolimus, an inhibitor of the mammalian target of rapamycin, among patients with recurrent malignant glioma.
  
  
  METHODS
  Gefitinib and sirolimus were administered on a continuous daily dosing schedule at dose levels that were escalated in successive cohorts of malignant glioma patients at any recurrence who were stratified based on concurrent use of CYP3A-inducing anticonvulsants [enzyme-inducing antiepileptic drugs, (EIAED)]. Pharmacokinetic and archival tumor biomarker data were also assessed.
  
  
  RESULTS
  Thirty-four patients with progressive disease after prior radiation therapy and chemotherapy were enrolled, including 29 (85%) with glioblastoma multiforme and 5 (15%) with anaplastic glioma. The MTD was 500 mg of gefitinib plus 5 mg of sirolimus for patients not on EIAEDs and 1,000 mg of gefitinib plus 10 mg of sirolimus for patients on EIAEDs. DLTs included mucositis, diarrhea, rash, thrombocytopenia, and hypertriglyceridemia. Gefitinib exposure was not affected by sirolimus administration but was significantly lowered by concurrent EIAED use. Two patients (6%) achieved a partial radiographic response, and 13 patients (38%) achieved stable disease.
  
  
  CONCLUSIONS
  We show that gefitinib plus sirolimus can be safely coadministered on a continuous, daily dosing schedule, and established the recommended dose level of these agents in combination for future phase 2 clinical trials.
authors.affiliation: AstraZeneca Pharmaceuticals, Wilmington, Delaware, USA. reard003@mc.duke.edu
authors.forename: David A
authors.initials: DA
authors.lastname: Reardon
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Quinn
authors.forename: James J
authors.initials: JJ
authors.lastname: Vredenburgh
authors.forename: Sridharan
authors.initials: S
authors.lastname: Gururangan
authors.forename: Allan H
authors.initials: AH
authors.lastname: Friedman
authors.forename: Annick
authors.initials: A
authors.lastname: Desjardins
authors.forename: Sith
authors.initials: S
authors.lastname: Sathornsumetee
authors.forename: James E
authors.initials: JE
authors.lastname: Herndon
authors.forename: Jeannette M
authors.initials: JM
authors.lastname: Dowell
authors.forename: Roger E
authors.initials: RE
authors.lastname: McLendon
authors.forename: James M
authors.initials: JM
authors.lastname: Provenzale
authors.forename: John H
authors.initials: JH
authors.lastname: Sampson
authors.forename: Robert P
authors.initials: RP
authors.lastname: Smith
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Swaisland
authors.forename: Judith S
authors.initials: JS
authors.lastname: Ochs
authors.forename: Peggy
authors.initials: P
authors.lastname: Lyons
authors.forename: Sandy
authors.initials: S
authors.lastname: Tourt-Uhlig
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.forename: Henry S
authors.initials: HS
authors.lastname: Friedman
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D000077156:Gefitinib; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011799:Quinazolines / Q000008:administration & dosage*; D012008:Recurrence; D020123:Sirolimus / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D011799:Quinazolines; D000077156:Gefitinib; D020123:Sirolimus