title: Phase I trial of imatinib in children with newly diagnosed brainstem and recurrent malignant gliomas: a Pediatric Brain Tumor Consortium report.
abstract: This study estimated the maximum tolerated dose (MTD) of imatinib with irradiation in children with newly diagnosed brainstem gliomas, and those with recurrent malignant intracranial gliomas, stratified according to use of enzyme-inducing anticonvulsant drugs (EIACDs). In the brainstem glioma stratum, imatinib was initially administered twice daily during irradiation, but because of possible association with intratumoral hemorrhage (ITH) was subsequently started two weeks after irradiation. The protocol was also amended to exclude children with prior hemorrhage. Twenty-four evaluable patients received therapy before the amendment, and three of six with a brainstem tumor experienced dose-limiting toxicity (DLT): one had asymptomatic ITH, one had grade 4 neutropenia and, one had renal insufficiency. None of 18 patients with recurrent glioma experienced DLT. After protocol amendment, 3 of 16 patients with brainstem glioma and 2 of 11 patients with recurrent glioma who were not receiving EIACDs experienced ITH DLTs, with three patients being symptomatic. In addition to the six patients with hemorrhages during the DLT monitoring period, 10 experienced ITH (eight patients were symptomatic) thereafter. The recommended phase II dose for brainstem gliomas was 265 mg/m(2). Three of 27 patients with brainstem gliomas with imaging before and after irradiation, prior to receiving imatinib, had new hemorrhage, excluding their receiving imatinib. The MTD for recurrent high-grade gliomas without EIACDs was 465 mg/m(2), but the MTD was not established with EIACDs, with no DLTs at 800 mg/m(2). In summary, recommended phase II imatinib doses were determined for children with newly diagnosed brainstem glioma and recurrent high-grade glioma who were not receiving EIACDs. Imatinib may increase the risk of ITH, although the incidence of spontaneous hemorrhages in brainstem glioma is sufficiently high that this should be considered in studies of agents in which hemorrhage is a concern.
authors.affiliation: Department of Neurosurgery, Children's Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213, USA. ian.pollack@chp.edu
authors.forename: Ian F
authors.initials: IF
authors.lastname: Pollack
authors.forename: Regina I
authors.initials: RI
authors.lastname: Jakacki
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
authors.forename: Michael L
authors.initials: ML
authors.lastname: Hancock
authors.forename: Mark W
authors.initials: MW
authors.lastname: Kieran
authors.forename: Peter
authors.initials: P
authors.lastname: Phillips
authors.forename: Larry E
authors.initials: LE
authors.lastname: Kun
authors.forename: Henry
authors.initials: H
authors.lastname: Friedman
authors.forename: Roger
authors.initials: R
authors.lastname: Packer
authors.forename: Anu
authors.initials: A
authors.lastname: Banerjee
authors.forename: J Russell
authors.initials: JR
authors.lastname: Geyer
authors.forename: Stewart
authors.initials: S
authors.lastname: Goldman
authors.forename: Tina Young
authors.initials: TY
authors.lastname: Poussaint
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Krasin
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Wang
authors.forename: Michael
authors.initials: M
authors.lastname: Hayes
authors.forename: Anthony
authors.initials: A
authors.lastname: Murgo
authors.forename: Susan
authors.initials: S
authors.lastname: Weiner
authors.forename: James M
authors.initials: JM
authors.lastname: Boyett
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D001549:Benzamides; D020295:Brain Stem Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000532:radiotherapy; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality / Q000532:radiotherapy; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D010879:Piperazines / Q000493:pharmacokinetics / Q000633:toxicity*; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000633:toxicity*; D012008:Recurrence; D016019:Survival Analysis
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate