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

This phase I trial studies the effects and best dose of ONC206 alone or in combination with radiation therapy in treating patients with diffuse midline gliomas that is newly diagnosed or has come back (recurrent) or other recurrent primary malignant CNS tumors. ONC206 is a recently discovered compound that may stop cancer cells from growing. This drug has been shown in laboratory experiments to kill brain tumor cells by causing a so called "stress response" in tumor cells. This stress response causes cancer cells to die, but without affecting normal cells. ONC206 alone or in combination with radiation therapy may be effective in treating newly diagnosed or recurrent diffuse midline gliomas and other recurrent primary malignant CNS tumors.

Inclusion Criteria: * ARM A: Children and young adults with DMG, H3K27 altered (Dose escalation: 2-21 years of age; Dose expansion: 2 years of age and above) who completed at least one line of prior therapy. Prior treatment must have included focal radiation therapy and patients must be within 4-14 weeks from completion of radiation therapy to registration (patients must start treatment within 1 week from registration), have not started any other therapies post-radiation, and have no evidence of disease progression. * ARM A: Tumor tissue confirmation of DMG, H3K27 altered is mandatory and pathology must be consistent with a DMG, H3K27 altered. * ARM A: Participants must have recovered from all acute side effects of prior therapy. * ARM A: From the projected start of scheduled study treatment, the following time periods must have elapsed: 5 half-lives from any investigational agent, 4 weeks from cytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 4 weeks from antibodies and must be at least 7 days since the completion of therapy with a biologic or small molecule agent. For any biologic or small molecule agent with known adverse events that can occur beyond 7 days after administration, the period prior to enrollment must be beyond the time during which adverse events are known to occur (these should be discussed with the study team) * ARM B: Newly diagnosed children and young adults (Dose escalation: 2-21 years of age; Dose expansion: 2 years of age and above) with a diagnosis of DMG, H3K27 altered are eligible, including spinal cord DMGs. * ARM B: Tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG, H3K27 altered. * ARM C: Children and young adults with DMGs (Dose escalation: 2-21 years of age; Dose expansion: 2 years of age and above) who have evidence of progression but have not been treated for this progression and are recommended to get re-irradiation. * ARM C: Patients must have undergone prior focal radiation therapy as part of their initial therapy and should be at least 6 months from prior radiation therapy. If timing is less than 6 months from prior focal radiation, these patients need to be discussed with the study chair(s). * ARM C: Tumor tissue confirmation is mandatory and pathology must be consistent with a DMG, H3K27 altered. * ARM C: Participants must have recovered from all acute side effects of prior therapy * ARM C: From the projected start of scheduled study treatment, the following time periods must have elapsed: 5 half-lives from any investigational agent, 4 weeks from cytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 4 weeks from antibodies and must be at least 7 days since the completion of therapy with a biologic or small molecule agent. For any biologic or small molecule agent with known adverse events that can occur beyond 7 days after administration, the period prior to enrollment must be beyond the time during which adverse events are known to occur (these should be discussed with the study team) * ARM D: Children and young adults with recurrent primary malignant CNS tumors, excluding DMGs, (Dose escalation: 2-21 years of age; Dose expansion: 2 years of age and above) who have evidence of progression but have not been treated for this progression. Participants who received a surgical resection for that progression are eligible if surgery has no curative intent. These patients need to be discussed with the study team. * ARM D: Prior tumor tissue confirmation is mandatory and pathology from the primary tumor must be consistent with malignant CNS tumor (diagnosis of ependymoma is allowed).Tissue at the time of progression is not required. * ARM D: Participants must have recovered from all acute side effects of prior therapy * ARM D: From the projected start of scheduled study treatment, the following time periods must have elapsed: 5 half-lives from any investigational agent, 4 weeks from cytotoxic therapy (except 23 days for temozolomide and 6 weeks from nitrosoureas), 4 weeks from antibodies and must be at least 7 days since the completion of therapy with a biologic or small molecule agent. For any biologic or small molecule agent with known adverse events that can occur beyond 7 days after administration, the period prior to enrollment must be beyond the time during which adverse events are known to occur (these should be discussed with the study team). Bevacizumab used for pseudoprogression does not require a wash out period. * TARGET VALIDATION: Newly diagnosed children and adults (2 years of age and above) with imaging consistent with a DMG, H3K27 altered are eligible. * TARGET VALIDATION: Children and young adults with recurrent primary malignant CNS tumors, including recurrent DMG, (2 years of age and above) who have evidence of progression but have not been treated for this progression. * TARGET VALIDATION: Participants must undergo tumor tissue collection as part of their standard of care * Participants who are receiving steroids must be on a stable or decreasing dose for at least 3 days prior to registration. * Peripheral absolute neutrophil count (ANC) \>= neutrophil 1.0 g/l. * Platelet count \>= 100 x 10\^9/L (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment). * Serum creatinine \< 1.5 Upper Limit normal (ULN) based on age and gender. * Total bilirubin \