title: Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 99-08.
abstract: OBJECTIVE
  Phase I: To determine the maximum tolerated doses, toxicities, and pharmacokinetics of imatinib mesylate (Gleevec) in patients with malignant gliomas taking enzyme-inducing antiepileptic drugs (EIAED) or not taking EIAED. Phase II: To determine the therapeutic efficacy of imatinib.
  
  
  METHODS
  Phase I component used an interpatient dose escalation scheme. End points of the phase II component were 6-month progression-free survival and response.
  
  
  RESULTS
  Fifty patients enrolled in the phase I component (27 EIAED and 23 non-EIAED). The maximum tolerated dose for non-EIAED patients was 800 mg/d. Dose-limiting toxicities were neutropenia, rash, and elevated alanine aminotransferase. EIAED patients received up to 1,200 mg/d imatinib without developing dose-limiting toxicity. Plasma exposure of imatinib was reduced by approximately 68% in EIAED patients compared with non-EIAED patients. Fifty-five non-EIAED patients (34 glioblastoma multiforme and 21 anaplastic glioma) enrolled in the phase II component. Patients initially received 800 mg/d imatinib; 15 anaplastic glioma patients received 600 mg/d after hemorrhages were observed. There were 2 partial response and 6 stable disease among glioblastoma multiforme patients and 0 partial response and 5 stable disease among anaplastic glioma patients. Six-month progression-free survival was 3% for glioblastoma multiforme and 10% for anaplastic glioma patients. Five phase II patients developed intratumoral hemorrhages.
  
  
  CONCLUSIONS
  Single-agent imatinib has minimal activity in malignant gliomas. CYP3A4 inducers, such as EIAEDs, substantially decreased plasma exposure of imatinib and should be avoided in patients receiving imatinib for chronic myelogenous leukemia and gastrointestinal stromal tumors. The evaluation of the activity of combination regimens incorporating imatinib is under way in phase II trials.
authors.affiliation: Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts, USA. pwen@partners.org
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Wen
authors.forename: W K Alfred
authors.initials: WK
authors.lastname: Yung
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Lamborn
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Dahia
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Wang
authors.forename: Bin
authors.initials: B
authors.lastname: Peng
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Abrey
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Raizer
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Cloughesy
authors.forename: Karen
authors.initials: K
authors.lastname: Fink
authors.forename: Mark
authors.initials: M
authors.lastname: Gilbert
authors.forename: Susan
authors.initials: S
authors.lastname: Chang
authors.forename: Larry
authors.initials: L
authors.lastname: Junck
authors.forename: David
authors.initials: D
authors.lastname: Schiff
authors.forename: Frank
authors.initials: F
authors.lastname: Lieberman
authors.forename: Howard A
authors.initials: HA
authors.lastname: Fine
authors.forename: Minesh
authors.initials: M
authors.lastname: Mehta
authors.forename: H Ian
authors.initials: HI
authors.lastname: Robins
authors.forename: Lisa M
authors.initials: LM
authors.lastname: DeAngelis
authors.forename: Morris D
authors.initials: MD
authors.lastname: Groves
authors.forename: Vinay K
authors.initials: VK
authors.lastname: Puduvalli
authors.forename: Victor
authors.initials: V
authors.lastname: Levin
authors.forename: Charles
authors.initials: C
authors.lastname: Conrad
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Maher
authors.forename: Kenneth
authors.initials: K
authors.lastname: Aldape
authors.forename: Michael
authors.initials: M
authors.lastname: Hayes
authors.forename: Laurie
authors.initials: L
authors.lastname: Letvak
authors.forename: Merrill J
authors.initials: MJ
authors.lastname: Egorin
authors.forename: Renaud
authors.initials: R
authors.lastname: Capdeville
authors.forename: Richard
authors.initials: R
authors.lastname: Kaplan
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Murgo
authors.forename: Charles
authors.initials: C
authors.lastname: Stiles
authors.forename: Michael D
authors.initials: MD
authors.lastname: Prados
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001549:Benzamides; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D005838:Genotype; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011743:Pyrimidines / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: D000927:Anticonvulsants; D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate