Phuphanich S.,New Approaches to Brain Tumor Therapy NABTT Consortium |
Supko J.G.,New Approaches to Brain Tumor Therapy NABTT Consortium |
Carson K.A.,New Approaches to Brain Tumor Therapy NABTT Consortium |
Grossman S.A.,New Approaches to Brain Tumor Therapy NABTT Consortium |
And 6 more authors.
Journal of Neuro-Oncology | Year: 2010
Bortezomib selectively binds and inhibits the 20S proteasome enzyme's active sites. This study was conducted to determine the side effects and maximum tolerated dose (MTD) of bortezomib in patients with recurrent malignant glioma. Separate dose escalations were conducted in patients taking or not taking enzyme-inducing anti-seizure drugs (+/-EIASD). The starting dose in both groups was 0.9 mg/m2 intravenously twice weekly for the first three of each 4 week cycle. Imaging assessment of response was carried out and Plasma 20S proteasome activity inhibition and imaging was conducted to monitor efficacy. The 66 patients enrolled had a median age of 51 years, median KPS of 90%, and 77% had glioblastoma multiforme. The MTD in the -EIASD group was 1.70 mg/m 2 based on grade 3 thrombocytopenia, sensory neuropathy and fatigue. In the +EIASD group escalation was terminated at 2.5 mg/m2 without meeting meet the MTD criteria. However, proteasome inhibition in this group did not change at doses above 1.90 mg/m2 suggesting that further escalations would be unlikely to increase a biologic effect. Mean proteasome inhibition plateaued in +EIASD patients receiving 2.1 mg/m2 of bortezomib at 77 ± 12% and in -EIASD patients treated with a dose of 1.7 mg/m2 at 79 ± 6%. Two partial responses were observed. This study determined that EIASDs effect the MTD of bortezomib and the dose required for maximal inhibition of whole blood 20S proteasome. Some evidence of clinical activity was noted in this phase I study in patients with recurrent high grade gliomas. © 2010 Springer Science+Business Media, LLC.