title: Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme.
abstract: OBJECTIVE
  We performed a phase II study to evaluate the combination of imatinib mesylate, an adenosine triphosphate mimetic, tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, in patients with recurrent glioblastoma multiforme (GBM).
  
  
  METHODS
  Patients with GBM at any recurrence received imatinib mesylate plus hydroxyurea (500 mg twice a day) orally on a continuous, daily schedule. The imatinib mesylate dose was 500 mg twice a day for patients on enzyme-inducing antiepileptic drugs (EIAEDs) and 400 mg once a day for those not on EIAEDs. Assessments were performed every 28 days. The primary end point was 6-month progression-free survival (PFS).
  
  
  RESULTS
  Thirty-three patients enrolled with progressive disease after prior radiotherapy and at least temozolomide-based chemotherapy. With a median follow-up of 58 weeks, 27% of patients were progression-free at 6 months, and the median PFS was 14.4 weeks. Three patients (9%) achieved radiographic response, and 14 (42%) achieved stable disease. Cox regression analysis identified concurrent EIAED use and no more than one prior progression as independent positive prognostic factors of PFS. The most common toxicities included grade 3 neutropenia (16%), thrombocytopenia (6%), and edema (6%). There were no grade 4 or 5 events. Concurrent EIAED use lowered imatinib mesylate exposure. Imatinib mesylate clearance was decreased at day 28 compared with day 1 in all patients, suggesting an effect of hydroxyurea.
  
  
  CONCLUSIONS
  Imatinib mesylate plus hydroxyurea is well tolerated and associated with durable antitumor activity in some patients with recurrent GBM.
authors.affiliation: Department of Medicine, Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA. reard003@mc.duke.edu
authors.forename: David A
authors.initials: DA
authors.lastname: Reardon
authors.forename: Merrill J
authors.initials: MJ
authors.lastname: Egorin
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Quinn
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Rich
authors.forename: Sridharan
authors.initials: S
authors.lastname: Gururangan
authors.forename: Idharan
authors.initials: I
authors.lastname: Gururangan
authors.forename: James J
authors.initials: JJ
authors.lastname: Vredenburgh
authors.forename: Annick
authors.initials: A
authors.lastname: Desjardins
authors.forename: Sith
authors.initials: S
authors.lastname: Sathornsumetee
authors.forename: James M
authors.initials: JM
authors.lastname: Provenzale
authors.forename: James E
authors.initials: JE
authors.lastname: Herndon
authors.forename: Jeannette M
authors.initials: JM
authors.lastname: Dowell
authors.forename: Michael A
authors.initials: MA
authors.lastname: Badruddoja
authors.forename: Roger E
authors.initials: RE
authors.lastname: McLendon
authors.forename: Theodore F
authors.initials: TF
authors.lastname: Lagattuta
authors.forename: Kimberly P
authors.initials: KP
authors.lastname: Kicielinski
authors.forename: Gregor
authors.initials: G
authors.lastname: Dresemann
authors.forename: John H
authors.initials: JH
authors.lastname: Sampson
authors.forename: Allan H
authors.initials: AH
authors.lastname: Friedman
authors.forename: August J
authors.initials: AJ
authors.lastname: Salvado
authors.forename: Henry S
authors.initials: HS
authors.lastname: Friedman
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001549:Benzamides; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018450:Disease Progression; D004334:Drug Administration Schedule; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D016019:Survival Analysis
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D006918:Hydroxyurea