A Single-Center Experience of Dopamine Antagonist ONC201 for Recurrent Histone H3 Lysine 27-to-Methionine (H3K27M)-Mutant Glioblastoma in Adults.

This study aimed to report a single-center experience of three adult subjects receiving ONC201 as part of the ONC018-expanded access clinical trial (NCT03134131). ONC201 is an oral investigational antagonist against the D2 dopamine receptor that has shown encouraging results for malignant gliomas harboring the histone H3 lysine 27-to-methionine (H3K27M) mutation in the H3 histone complex. Responses have been reported in pediatric subjects with such tumors. An expanded access clinical trial (ONC018) was available to eligible patients allowing them access to this agent pending FDA review. Our site enrolled three subjects in the ONC018 trial. We present the demographic, clinical, and molecular characteristics of our enrolled subjects. We report the tolerability, adverse events, and outcome measures including survival, Karnofsky Performance Status (KPS), and quality-of-life measured by the MD Anderson symptom inventory instrument (MDASI). Three subjects were registered at our site onto ONC018 with the age range of 18-44 years, two of three were female, residing in Norway, India, and the United States. Tumor locations were brainstem, corpus callosum, and thalamus. Pathology includes glioblastoma (3/3), methylguanine-DNA methyltransferase (MGMT) methylated (2/3), isocitrate dehydrogenase 1 (IDH1) mutant (0/3), epidermal growth factor receptor (EGFR) amplification (0/3), and α thalassemia/mental retardation syndrome X‑linked (ATRX) (3/3). Median change from baseline KPS ≤20% decrease; MDASI of 2/3 experienced decrease from baseline (median 6%), consistent with improved quality of life. No clinically significant laboratory abnormalities were found. All adverse events were grades I-II. We found that the study drug was quite tolerable. No serious adverse events nor radiographic responses were seen. Analyses of the larger study cohort and additional randomized controlled trials are necessary to provide insight into the safety and efficacy.