Phase I trial of imatinib in children with newly diagnosed brainstem and recurrent malignant gliomas: A Pediatric Brain Tumor Consortium report1

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.

Pediatric Brain Tumors: Current Treatment Strategies and Future Therapeutic Approaches

“…Although survival analysis was not primary objective of that study, estimates of PFS was not superior to other studies. 97 Other small molecule inhibitors currently under investigation include inhibitors of the farnesyltransferase (lonafarnib), Notch (MK 0752) and mammalian target of rapamycin ([mTOR] temsirolismus, everolismus) signaling pathways as well as anti-angiogenic agents like bevacizumab. These agents are tested as single agent, as well as in combination with conventional chemotherapy and radiation.…”

Antigen-Specific Immune Responses and Clinical Outcome After Vaccination With Glioma-Associated Antigen Peptides and Polyinosinic-Polycytidylic Acid Stabilized by Lysine and Carboxymethylcellulose in Children With Newly Diagnosed Malignant Brainstem and Nonbrainstem Gliomas

“…[1][2][3][4] Other than irradiation, no therapy has demonstrated clinical benefit. [3][4][5][6][7][8] Similarly, children with newly diagnosed nonbrainstem high-grade gliomas have a poor prognosis, with 5-year survival rates around 10% with the use of irradiation and conventional chemotherapy.…”

Platelet-derived growth factor receptor expression and amplification in choroid plexus carcinomas

“…Indeed, early clinical studies suggest efficacy of imatinib mesylate in combination with hydroxyurea for the treatment of gliomas. 14,15 Results from pilot trials employing imatinib mesylate for the treatment of children with solid tumors 16 as well as recurrent malignant gliomas 17 point toward a favorable safety profile of imatinib mesylate in that age group.…”