Combination Therapy for the Treatment of Diffuse Midline Gliomas

--COHORTS 1, 2, AND 3 CLOSED--- INCLUSION CRITERIA: COHORT 1A AND 1B: * New diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors. In cohort 1B, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including diffuse midline glioma Histone 3 lysine 27 - mutant (H3K27M); World Health Organization (WHO) grade III and IV H3 wildtype gliomas. * Must be within 6 weeks of diagnosis to begin standard of care radiation therapy on study. COHORT 2A AND 2B: * Diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors, who have complete standard-of-care radiation therapy. In Cohort 2B, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including diffuse midline glioma H3K27M mutant; WHO grade III and IV H3 wildtype gliomas. * Participants must be within 4-14 weeks of completion of radiation. Radiation should have started within 6 weeks of diagnosis. COHORT 3A AND 3B: * Diagnosis of recurrent DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors, who have complete standard-of-care radiation therapy. In cohort 3B, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including diffuse midline glioma H3K27M mutant; WHO grade III and IV H3 wildtype gliomas. * Participants must have evidence of progression and not have received any treatment for this progression and have not previously received re-irradiation. COHORT 4A AND 4B: * Diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors. In cohort 4B\^1, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG diffuse midline glioma H3K27-altered. * Not currently eligible for any other clinical trials that include administration of ONC201. Cohort 4A\^1 and 4B\^1 (participants with newly diagnosed DMG prior to radiation): Must be able to begin standard of care radiation therapy on study within 6 weeks of diagnosis. Cohort 4A\^2 and 4B\^2 (participants with newly diagnosed DMG who have completed radiation): Participants must be within 4-14 weeks of completion of radiation and not have received additional therapy beyond completion of radiation therapy. Radiation should have started within 6 weeks of diagnosis. Cohort 4A\^3 and 4B\^3 (participants with DMG at progression): Participants must have evidence of progression and not have received any treatment for this progression and have not previously received re-irradiation. COHORT 5 * Diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors. In cohort 5\^1, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG diffuse midline glioma H3K27-altered. * Not currently eligible for any other clinical trials that include administration of ONC201. * Multifocal and leptomeningeal disease will be eligible for Cohort 5. * Participant's tumor must demonstrate one of the following molecular alterations considered targetable by an approved agent: * BRAFV600E * PDGFRA (DNA point mutation or amplification with \>=5 copy numbers) * FGFR1 (DNA point mutation, gene fusions, or amplification with \>=5 copy numbers) * NF1 Cohort 5\^1 (participants pre-radiation): Must be able to begin standard of care radiation therapy on study within 6 weeks of diagnosis. Cohort 5\^2 (participants post-radiation): Participants must be within 4-14 weeks of completion of radiation and not have received additional therapy beyond completion of radiation therapy. Radiation should have started within 6 weeks of diagnosis. Cohort 5\^3 (participants with progression): Participants must have evidence of progression and not have received any treatment for this progression and have not previously received re-irradiation. All Cohorts (except Cohort 6): * Age 2 to 39 years * Participants must have recovered from all acute side effects of prior therapy and be beyond the window for expected ongoing acute toxicities. Any number of prior therapies are allowed. * Prior ONC201 exposure is allowed, except in participants who have participated in Chimerix trials investigating ONC201 in the upfront setting. Participants who participated in trials investigating ONC201 in the upfront setting will not be eligible at any time, with the exception if participants received ONC201 as part of PNOC022 or other expanded access programs such as German sources of ONC201. * Participant body weight must be above the minimum necessary for the participant to receive ONC201 (at least 10 kilograms (kg)) * From the projected start of scheduled study treatment, the following time periods must have elapsed: At least 7 days after last dose of a biologic agent or beyond time during which adverse events are known to occur for a biologic agent, 5 half-lives from any investigational agent, 4 weeks from cytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 6 weeks from antibodies (21 days for bevacizumab when used for tumor-directed therapy, guidance on use for pseudo-progression is below), or, or 4 weeks (or 5 half-lives, whichever is shorter) from other anti-tumor therapies. o The use of bevacizumab to control radiation therapy-induced edema is allowed (if used for tumor-directed therapy, please see required time period above). * Dosing limitations are as follows: * \* Bevacizumab (or equivalent) for up to a maximum of 5 doses, dosing per institutional standard. There is no required washout period. * Prior use of temozolomide during radiation at maximum of the standard pediatric dosing (defined as 90 mg/m2 /dose continuously during radiation therapy for 42 days) or dexamethasone is allowed. Any other agent given throughout radiation therapy must be discussed with the study chairs prior to beginning the agent. * C