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PMID: 17293590 Published · ppublish English Clinical Trial, Phase I Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Phase I trial of imatinib in children with newly diagnosed brainstem and recurrent malignant gliomas: a Pediatric Brain Tumor Consortium report.

Neuro-oncology ·Vol. 9 ·No. 2 ·2007-04-00 ·Pages 145-60

Pollack IF, Jakacki RI, Blaney SM, Hancock ML, Kieran MW, Phillips P, Kun LE, Friedman H, Packer R, Banerjee A, Geyer JR, Goldman S, Poussaint TY, Krasin MJ, Wang Y, Hayes M, Murgo A, Weiner S, Boyett JM

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.

MeSH Terms
Adolescent Adult Antineoplastic Agents/pharmacokinetics,toxicity Benzamides Brain Stem Neoplasms/drug therapy,mortality,radiotherapy Child Child, Preschool Disease-Free Survival Dose-Response Relationship, Drug Female Glioma/drug therapy,mortality,radiotherapy Humans Imatinib Mesylate Male Piperazines/pharmacokinetics,toxicity Pyrimidines/pharmacokinetics,toxicity Recurrence Survival Analysis
Chemicals
Antineoplastic Agents Benzamides Piperazines Pyrimidines Imatinib Mesylate
Authors & Affiliations
19 authors, click to expand affiliations / ORCID
Pollack Ian F
Department of Neurosurgery, Children's Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213, USA. ian.pollack@chp.edu
Jakacki Regina I
Blaney Susan M
Hancock Michael L
Kieran Mark W
Phillips Peter
Kun Larry E
Friedman Henry
Packer Roger
Banerjee Anu
Geyer J Russell
Goldman Stewart
Poussaint Tina Young
Krasin Matthew J
Wang Yanfeng
Hayes Michael
Murgo Anthony
Weiner Susan
Boyett James M
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Article Info
Journal
Neuro-oncology
Abbr.
Neuro Oncol
ISSN
1522-8517
DOI
10.1215/15228517-2006-031
Email
ian.pollack@chp.edu
Published
2007-04-00
Epub
2007-00-09
Pages
145-60
Language
English
Region
England
NLM ID
100887420
PMCID
PMC1871662
Subset
IM
Grants
NCRR NIH HHS · M01 RR000188 · United States
NCI NIH HHS · U01 CA081457 · United States
NCRR NIH HHS · M01 RR00188-37 · United States
NCI NIH HHS · U01 CA81457 · United States
External Links
PubMed source DOI: 10.1215/15228517-2006-031 PMC Full Text View journal details
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