Phase I/II Study of Imatinib Mesylate for Recurrent Malignant Gliomas: North American Brain Tumor Consortium Study 99-08

Abstract

Purpose: 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. Experimental Design: 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 f68% 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.

The effect of imatinib mesylate on the proliferation, invasive ability, and radiosensitivity of retinoblastoma cell lines

“…The success of IM in CML led rapidly to studies in other cancers associated with activation of two other tyrosine kinases known to be sensitive to IM, C-kit the target of IM in the GIST, and PDGFR the target of this compound in some solid tumors like glioma, osteosarcoma, and neuroblastoma. [14][15][16][17] In an effort to identify additional agents for the treatment of Rb, we performed pre-clinical studies of IM and its targets in two human Rb cell lines. In the first part of our study, we evaluated the anti-proliferative and antiinvasive effects of IM in Y79 and WERI-RB-1 human Rb cell lines.…”

Multicentre phase II studies evaluating imatinib plus hydroxyurea in patients with progressive glioblastoma

“…In study H2201, patients were not allowed to be on EIACDs whereas patients were enrolled on study H2202 if they were on EIACDs. The dose of imatinib differed between the trials to account for the effect of EIACDs on imatinib metabolism (Reardon et al, 2005;Wen et al, 2006): Patients enrolled on study H2201 received 600 mg once a day, whereas those on study H2202 received 500 mg twice a day. For both trials, patients received 500 mg of HU twice a day.…”

“…However, the uptake and distribution of imatinib in the brain is limited by P-gp/BCRP-mediated efflux (Dai et al, 2003), suggesting that combination regimens with imatinib may be more effective than imatinib monotherapy. Clinical studies evaluating imatinib as monotherapy in relapsed GBM showed response rates ranging from 3 to 6% and a progression-free survival at 6 months (PFS-6) rate of 16% (Wen et al, 2006;Raymond et al, 2008).…”

“…Enzyme-inducing anticonvulsant drugs (EIACDs; eg phenytoin, carbamazepine, phosphenytoin, oxcarbamazepine, and phenobarbital) are known to accelerate the metabolism of imatinib, resulting in a shorter plasma-elimination half-life (t 1/2 ) and a lower area under the plasma concentration time curve (AUC) (Reardon et al, 2005;Wen et al, 2006). We sought to further evaluate the efficacy and tolerability of imatinib in addition to HU among patients with recurrent GBM treated on multi-institutional phase II studies depending on the use of EIACDs or not.…”

Radixin Knockdown by RNA Interference Suppresses Human Glioblastoma Cell Growth in Vitro and in Vivo

“…Current treatment methods include surgical resection, radio-surgical, external irradiation, chemotherapy (Cheng et al, 2005;Stupp et al, 2006;Wen et al, 2006), and biological therapy (Kjaergaard et al, 2005). Despite recent advances in diagnostics and treatments, prognosis for patients with this disease remains poor (Ng et al, 2007).…”