UC Irvine

Abstract OBJECTIVE: To investigate the toxicity, tolerability and efficacy of the combination of ixazomib and standard chemoradiation therapy for newly diagnosed MGMT methylated GBM patients.

BACKGROUND

GBM is the most aggressive primary malignant brain tumor. Standard therapy with temozolomide and radiotherapy after the surgery offers limited overall survival (OS). The median OS in patients with MGMT methylation is still less than 2 years. Our recent phase II clinical trial found that the addition of bortezomib, a proteasome inhibitor, to the standard therapy, offered mild survival benefit (19 months) for the entire group of GBM patients. However, significant improvement of OS and progression free survival (PFS) were found in the MGMT methylated patients when compared to MGMT unmethylated patients (OS: 49.4 vs 15.6 months, p=0.0002; PFS: 24.7 vs 5.1 months, p=0.00004) [Kong et al. Int J Radiation Oncology Biol Phys 2018]. Ixazomib is a newer generation of proteasome inhibitor and has demonstrated similar selectivity and potency to bortezomib in biochemical and cell-based assays. While bortezomib can be administered via injection, ixazomib is taken orally, which is more convenient. HYPOTHESIS: Adding ixazomib to standard therapy improve the survival of the patients with newly diagnosed MGMT-methylated GBM compared to standard therapy. STUDY DESIGN: This is a randomized, active controlled, open label phase I/II study of Ixazomib plus standard therapy versus standard therapy. Primary and secondary endpoints are PFS, 12, 24, 36 and 48 month survival rates and response duration. The study consists of two parts: In part I, the maximum tolerated dose (MTD) is decided by using 3 + 3 design with dose limiting toxicity (DLT) method. In part II, randomize the patients to the combination therapy or the standard therapy arm. Safety will be assessed by CTCAE V4.03. We will use Kaplan-Meier estimates for survival data and a stratified log-rank test for the randomization strata.