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DIPG is an aggressive brainstem tumor with no effective therapy beyond the temporizing effects of radiation (RT). Preclinical studies demonstrated synergistic activity of marizomib (MRZ), an irreversible CNS-penetrant, pan-proteosome inhibitor, when administered with the HDAC inhibitor, panobinostat. In a study of adults with glioblastoma, MRZ was associated with significant CNS adverse events of interest (ataxia, balance disorder, dizziness, dysarthria, fall, gait disturbance, hallucination) in the majority of patients. We performed a novel Bayesian design, dual phase 1 trial of MRZ administered as a single agent and in combination with panobinostat to children with DIPG. Primary objectives were to determine the toxicity profile, dose limiting toxicities (DLT), and maximum tolerated dose (MTD) of MRZ at doses up to 0.8 mg/m² alone and when administered in combination with …