ONC206 for Treatment of Newly Diagnosed, Recurrent Diffuse Midline Gliomas, and Other Recurrent Malignant CNS Tumors

PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of bitopic dopamine receptor D2 (DRD2) antagonist/human Caseinolytic protease P (ClpP) agonist ONC206 (ONC206) as single agent in children and young adults with diffuse midline glioma (DMG), Histone 3 lysine 27 (H3K27) altered, who completed at least one line of prior therapy that included focal radiation therapy. (Arm A). II. To determine the MTD of ONC206 in combination with focal radiation therapy in newly diagnosed children and young adults with DMG, H3K27 altered (Arm B). III. To determine the MTD of ONC206 in combination with re-irradiation in children and young adults with progression of DMG, H3K27 altered (Arm C). IV. To determine the MTD of ONC206 in children and young adults with recurrent primary malignant CNS tumors including participants with recurrent DMGs if not eligible for other arms. (Arm D). VI. To assess the concentration of ONC206 in tumor tissue from children and young adults with DMG, H3K27 altered predominantly localized to the thalamus and compare to plasma drug levels pre-surgery. (Target validation). VII. To assess the concentration of ONC206 in tumor tissue in children and young adults with DMG, H3K27 altered predominantly localized to the pons and compare to plasma drug levels pre-surgery. (Target validation). VIII. To assess the concentration of ONC206 in tumor tissue in children and young adults with DMG, H3K27 altered in non-thalamic and non-pontine locations and compare to plasma drug levels pre-surgery. (Target validation). IX. To assess the concentration of ONC206 in tumor tissue in children and young adults with recurrent primary malignant CNS tumors and compare to plasma drug levels pre-surgery. (Target validation). SECONDARY OBJECTIVE: I. To characterize the pharmacokinetics (PK) of ONC206 in plasma in patients with DMG, H3K27 altered and recurrent primary malignant CNS tumors. EXPLORATORY OBJECTIVES: Dose Escalation/Dose Expansion: I. To assess the clinical responses within the confines of a phase 1/expansion study. II. To assess if amount of serum circulating tumor DNA (ctDNA) is correlated with clinical outcome. III. To assess if amount of cerebrospinal fluid (CSF) ctDNA is correlated with clinical outcome. IV. To assess if clinical outcomes are associated with anatomic location of tumor, H3K27 mutation status and other partner mutations. V. To assess biomarkers of response. VI. To assess the response rate to ONC206 in patients with prior ONC201 exposure. VII. To assess pharmacodynamics (PD) of ONC206. VIII. To assess PK-PD and identify the relationship between drug exposure and clinical endpoints for both safety and efficacy. IX. To characterize the PK of ONC206 in CSF in patients with DMG, H3K27 altered and recurrent primary malignant CNS tumors. Target Validation: X. To assess PD changes within tumor tissue after ONC206 administration All Phases/Arms: XI. To assess microbiome and flow cytometry studies in the context of imaging and clinical outcomes using descriptive statistics. XII. To assess Health Related Quality of Life (HRQOL) outcomes. XIII. To assess patient and/or proxy satisfaction with study participation via patient-reported outcome (PRO) measures. XIV. To assess patient and/or proxy satisfaction with study participation via patient-reported outcome (PRO) measures in the context of race ethnicity and other health related social risks. XV. To assess on therapy toxicity and survival in the context of race, ethnicity and other health related social risks. XVI. To assess if Fluoroethyl-l-tyrosine (18F-FET)-Positron Emission Tomography (PET) can support response assessment in children treated with ONC206. XVII. To assess feasibility to obtain Proton (1H) MR spectroscopy (MRS) with standard MRI. OUTLINE: This is a dose-escalation / dose expansion study of ONC206. Patients are assigned to 1 of 4 arms. ARM A (Children and young adults with DMG H3K27 altered who completed at least one line of prior therapy) Patients receive ONC206 orally (PO) up to six times per week. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity. In case the participant receives clinical benefit from the treatment, treatment could possibly proceed up to 24 months. ARM B (Newly diagnosed children and young adults with DMG H3K27 altered): Patients undergo standard of care radiation therapy daily 5 days a week and receive ONC206 as in Arm A. ARM C:(Children and young adults with DMG H3K27 altered who have evidence of progression but have not been treated for this progression and are candidates for re-irradiation): Patients undergo standard of care radiation therapy daily 5 days a week and receive ONC206 as in Arm A. ARM D (Participants with recurrent primary malignant CNS tumors including participants with recurrent DMGs who failed at least one prior therapy including radiation therapy): Patients receive ONC206 orally (PO) up to six times per week. Cycles repeat every 28 days for up to 12 months in the absence of disease progression or unacceptable toxicity. In case the participant receives clinical benefit from the treatment, treatment could possibly proceed up to 24 months. All participants will be permitted to have an optional MRS scans. After completion of study treatment, patients are followed up at 30 days and then every 3 months for up to 5 years. If co-enrolled on Pediatric Neuro-Oncology Consortium (PNOC) COMP, follow-up procedures are to be captured under the PNOC COMP protocol. Participants will be followed under the PNOC COMP protocol until death or withdrawal from study.