Background: MRZ is an irreversible, brain-penetrant, pan-proteasome inhibitor (PI). It inhibits glioma cell proliferation and invasion in vitro, prolongs survival in in vivo mg tumor models, with little effect on normal neuronal stem cells, suggesting minimal neurotoxicity (Neuro Oncol 2015 Dec 17. pii: nov299). Intravenous (IV) MRZ has been administered to ~300 patients (pts) with solid tumors and hematologic cancers. This trial is evaluating the safety, pharmacodynamics, and efficacy of MRZ and BEV in BEV-naïve pts with G4 mg who are in first or second relapse with no prior anti-angiogenic or PI therapy. Methods: Phase 1, dose-escalation (3+3 design) followed by dose-expansion at recommended Phase 2 Dose (RP2D); three dose cohorts - MRZ 0.55 (n = 6 pts), 0.7 (n = 3 pts), and 0.8 mg/m² (n = 3 pts). MRZ infused IV (10 min) on Days 1, 8, & 15; BEV IV 10 mg/kg on Days 1 & 15 (over 28-Day Cycles). Tumor response is assessed every other Cycle by RANO criteria; blood proteasome inhibition assessed every Cycle. Results: In dose-escalation, 12 pts enrolled: median age 53 yrs (44-61); 83% male; 83% Caucasian; Karnofsky Score > 80. As of 6 Jan 2016, duration of dosing is 5-33 weeks with treatment ongoing in 7 pts. MRZ/BEV was well tolerated; most common adverse events (AEs): headache (9), fatigue (7), hypertension (5), infusion site pain (5), and nausea (5). Grade 3 AEs related to MRZ or BEV: hypertension (2), confusional state (1), fatigue (1), hallucinations (1), and headache (1). One pt (cohort 1) had fatigue as DLT, but no DLTs at higher doses. MRZ caused > 70% inhibition of chymotrypsin-like activity on Cycle 1 Day 1 with 100% by Day 28. Transient hyperactivation of trypsin-like (T-L) and caspase-like (C-L) activities after the first 1-2 MRZ doses, followed by 40-60% inhibition of T-L and 10-30% inhibition of C-L activities in Cycle 3. RANO responses in the 3 cohorts: 4/12 partial response, 6/12 stable disease and 2/12 progressive disease. Conclusions: The MRZ/BEV combination was well tolerated with only one DLT at MRZ 0.5 mg/m². To date, rapid and pronounced pan-proteasome inhibition has been observed with 4/12 pts achieving confirmed PRs. MRZ 0.8 mg/m² is the RP2D in the ongoing dose-expansion stage. Clinical trial information: NCT02330562