ACTR-50. MARIZOMIB (MRZ) WITH BEVACIZUMAB (BEV) IN WHO GRADE IV MALIGNANT GLIOMA (G4 MG): FULL ENROLLMENT RESULTS FROM THE PHASE 1, MULTICENTER, OPEN-LABEL STUDY

Abstract

MRZ is an irreversible, brain-penetrant, pan-proteasome inhibitor (PI) with anti-MG efficacy preclinically in vitro and in vivo. The safety, pharmocokinetics, and activity of MRZ+BEV is evaluated in BEV-naive G4 MG patients (pts) in first or second relapse (no prior anti-angiogenic or PI therapy), in a 3+3 dose-escalation (MRZ 0.55 (6 pts), 0.7 (3 pts), and 0.8 mg/m2 (3 pts)) followed by dose-expansion (0.8 mg/m2, 24 pts). Treatments administered IV, 28-day cycles: MRZ (10 min) days 1, 8, & 15; BEV (10 mg/kg) days 1 & 15. Tumor response assessed every other cycle by RANO criteria; MRZ and BEV pharmacokinetics, and proteasome inhibition in circulating blood cells also evaluated. Data reported as of 17 May 2016; median age 55 yrs (range 27-76 yrs), 64% male, Karnofsky score >=70. Duration of dosing 0.5-11.6 months to date; treatment ongoing in 16 pts. Study treatment-related Grade >=3 AEs: fatigue, headache, hypertension, hallucination, confusional state, ataxia; one Grade 4 SAE (appendicitis perforated, not related to study treatment), one Grade 5 SAE (intracranial hemorrhage, BEV-related). One pt (cohort 1) had DLT (fatigue); no other DLTs occurred. N=36 for the intent-to-treat population; 30 pts efficacy evaluable by RANO criteria. Overall response (>= partial response, PR) 39% (14/36, including 5 with complete target lesion response and 2 unconfirmed PRs); 11 stable disease, 5 progressive disease. PFS 6-months is 39%; median OS not yet reached. MGMT status known for 15 of 36 pts; 14 unmethylated (uMGMT), 1 methylated. Seven of 14 uMGMT pts achieved >=PR; 49% PFS 6-months in uMGMT subgroup. Preliminary activity in uMGMT subgroup suggests therapeutic advantage provided by brain-penetrant PI in comparison with BEV single agent (Taal et al., 2014). MRZ+BEV combination is well tolerated with promising early signs of efficacy in recurrent G4 MG pts.