ACTR-45. A PHASE 1, MULTICENTER, OPEN-LABEL STUDY OF MARIZOMIB (MRZ) WITH TEMOZOLOMIDE (TMZ) AND RADIOTHERAPY (RT) IN NEWLY DIAGNOSED WHO GRADE IV MALIGNANT GLIOMA (GLIOBLASTOMA, ndGBM)

Abstract

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 -- is being evaluated in ndGBM patients (NCT02903069). The phase 1 study (MRZ at 0.55, 0.7, 0.8, 1.0, and 1.2 mg/m²) is accruing in separate concomitant (MRZ+TMZ+RT) and adjuvant (MRZ+RT) treatment cohorts (3 + 3 design), followed by dose-expansion at the recommended phase 2 dose in concomitant followed by adjuvant treatment cohorts. Concomitant treatment (42 days (D)): MRZ (10 min IV infusion) D1, 8, 15, 29, 36; RT total dose 60 Gy; TMZ (75 mg/m², PO QD). Adjuvant treatment (28D-cycle): MRZ D1, 8, 15; TMZ (150–200 mg/m², PO QDX5). Tumor response (RANO criteria) measured at beginning and end of concomitant treatment, and every other cycle during adjuvant treatment; MRZ and TMZ PK in concomitant treatment D1-2, 8–9. Mean age 55 yrs (60% male) for 20 patients in 14Apr2017 interim analysis (cohorts 1–3 have completed accrual in concomitant treatment, cohorts 1 and 2 have completed accrual and 2 patients are enrolled in adjuvant cohort 3); one DLT (fatigue) in the 0.7 mg/m² adjuvant cohort. Most common treatment-related AEs (≥4 pts): fatigue, nausea, vomiting, decreased appetite, dizziness, hallucination; three Grade 3 SAEs (fatigue, hallucination, vomiting; all MRZ-related); two Grade 2 SAEs (nausea, confusional state, MRZ-related). Seventeen of the 20 patients included in this interim analysis remain on study: 7 of 9 concomitant patients are continuing in adjuvant treatment (longest beginning adjuvant cycle 7); of 11 adjuvant pts, two beginning cycle 9. The study is ongoing at 1.0 mg/m² for both concomitant and adjuvant dose-escalation cohorts. Together the data demonstrate that the combination of MRZ with standard of care in ndGBM is well tolerated and may provide novel therapeutic benefit in this unmet need.