Background: Proteasome inhibition sensitizes glioma cells to TMZ and RT, providing a novel therapeutic strategy for ndGBM. MRZ, an irreversible, brain-penetrant, pan-proteasome inhibitor with anti-glioma preclinical activity was combined with standard-of-care (SOC) TMZ/RT in ndGBM (NCT02903069), to determine the recommended dose (RD). Methods: Patients enrolled in separate concomitant (TMZ/RT+MRZ) and adjuvant (TMZ+MRZ) cohorts in dose-escalation (3+3 design, MRZ at 0.55, 0.7, 0.8, and 1.0 mg/m²), followed by dose-expansion at RD in concomitant followed by adjuvant treatment. MRZ (10 min IV infusion): Concomitant D1, 8, 15, 29, 36; Adjuvant (28D-cycle) D1, 8, 15. Results: (as of 01Feb2018): Dose-escalation completed (N = 33; 15 concomitant and 18 adjuvant); mean age 56 yrs, 73% male. Dose-limiting toxicities (DLT): one (fatigue) at 0.7 mg/m²adjuvant cohort, 3 (ataxia/diarrhea; ataxia/confusion; myocardial infarction) in concomitant and 2 (delirium/ataxia; ataxia/fatigue) in adjuvant cohorts at 1.0 mg/m². Grade ≥3 treatment-emergent AEs (TEAE) in 11 of 12 patients at 1.0 mg/m²including one Grade 4 and one Grade 5 TEAE; at ≤0.8 mg/m² MRZ, Grade 3 TEAEs in 9 of 21 patients; severe TEAEs generally ameliorated with dose reductions, allowing patients to stay on therapy. Most common TEAE (≥20% patients, all grades): fatigue, nausea, vomiting, hallucination, ataxia, headache. Currently 15 active of 20 patients enrolled in dose-expansion; 9 patients from dose-escalation also remain active, with 5 longest patients on study 12-18 months. Conclusions: MRZ demonstrated a steep dose-response; TEAEs/DLTs predominately CNS adverse events (ataxia, hallucinations), dose-related, short-lasting, reversible and ameliorated by subsequent dose reductions. The RD is 0.8 mg/m² MRZ in combination with SOC. MRZ at the RD with adjuvant TMZ+Optune is now enrolling to assess the safety of this combination. Based on the safety and tolerability of MRZ in this study and earlier results in recurrent GBM, an EORTC-sponsored phase 3 study will open in Spring 2018 to assess the overall survival benefit of MRZ added to SOC in ndGBM. Clinical trial information: NCT02903069