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)
| Autor: | Bota, Daniela, Mason, Warren, Kesari, Santosh, Piccioni, David, Aregawi, Dawit, Desjardins, Annick, Winograd, Benjamin, Reich, Steven D, Levin, Nancy, Trikha, Mohit |
|---|---|
| Rok vydání: | 2017 |
| Předmět: | |
| Zdroj: | Neuro-Oncology, vol 19, iss suppl_6 Neuro-oncology, vol 19, iss Suppl 6 |
| Popis: | 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 1.2mg/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 (42days (D)): MRZ (10min IV infusion) D1, 8, 15, 29, 36; RT total dose 60 Gy; TMZ (75mg/m2, PO QD). Adjuvant treatment (28D-cycle): MRZ D1, 8, 15; TMZ (150–200mg/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 0.7mg/m2 adjuvant cohort. Most common treatment-related AEs (≥4pts): 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 1.0mg/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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|