Single-agent ONC201 in recurrent H3 K27M-mutant diffuse midline glioma.

Abstract

3615 Background: Recurrent H3 K27M-mutant diffuse midline glioma is a lethal brain tumor that predominantly affects children and young adults and has no effective therapy. ONC201 is a first-in-class orally administered, anti-cancer small molecule that selectively antagonizes the dopamine receptors DRD2/DRD3 and agonizes ClpP, a mitochondrial protease. Prior studies have indicated dysregulated dopamine receptor expression and enhanced ONC201 sensitivity among H3 K27M-mutant gliomas. Methods: Adults with midline H3 K27M-mutant glioma patients were enrolled to a dedicated Phase II clinical trial (NCT03295396), a multi-arm Phase II clinical trial (NCT02525692), and expanded access protocols under the Sponsor’s IND. Results were pooled among patients treated with ONC201 monotherapy through any of these trial with H3 K27M confirmed glioma, progressive and measurable disease by RANO, > 90 days from completion of prior radiation, no evidence of leptomeningeal dissemination, midline location other than primarily pons or spinal cord, and baseline KPS > 60. Using an enrollment cutoff of February 15, 2019 and data cutoff of July 31, 2019, there were 20 patients (NCT03295396, 12; NCT02525692, 7; expanded access, 1). Dosage was 625 mg weekly in 19 and once every 3 weeks in 1. Results: No DLTs or treatment discontinuations due to toxicity occurred. Midline gliomas can exhibit minimal contrast enhancement or exhibit a mixture of contrast-enhancing and non-contrast enhancing regions in the tumor. As a result, blinded independent central review (BICR) of tumor response by MRI was assessed by RANO-HGG and RANO-LGG for each patient to capture contrast-enhancing lesions by T1 post-contrast and non-contrast-enhancing assessments by T2/FLAIR, respectively, in the object response rate. The best response by RANO-HGG or RANO-LGG is 30% (95% CI, 11.9-54.3%). Duration of response by RANO-HGG is median 52.7 weeks (range 15.9-138.3). One patient with stable disease as of this data cutoff has continued on treatment beyond 12 months and recently underwent an investigator-reported PR by RANO-HGG that is pending confirmation. Conclusions: Single agent ONC201 is well tolerated and clinically active in recurrent H3 K27M-mutant diffuse midline glioma patients. Clinical trial information: NCT03295396, NCT02525692 .