Inclusion Criteria:

   1. Able to understand the study procedures and agree to participate in the study by
   providing written informed consent (by participant or legally authorized
   representative), and assent when applicable.

   2. Body weight ≥ 10 kg at time of randomization.

   3. Histologically diagnosed H3 K27M-mutant diffuse glioma (new diagnosis). Detection of a
   missense K27M mutation in any histone H3-encoding gene detected by testing of tumor
   tissue (immunohistochemistry [IHC] or next-generation sequencing [NGS] in a Clinical
   Laboratory Improvement Amendments [CLIA]-certified or equivalent laboratory). [Site to
   provide (as available): ≥ 10 unstained formalin-fixed paraffin-embedded (FFPE) slides
   from tumor tissue.]

   4. At least one, high-quality, contrast-enhanced MRI of the brain obtained prior to
   starting radiotherapy for submission to sponsor's imaging vendor for central read. For
   participants who had a surgical resection, this scan must be post-resection; for
   participants who did not have a resection, this scan may be pre- or post-biopsy.

   5. At least one, high-quality, contrast-enhanced MRI of the brain obtained 2 to 6 weeks
   after completion of frontline radiotherapy. If unable to obtain contrast-enhanced
   imaging due to lack of venous access after multiple attempts, a patient may still be
   eligible after collection of a nonenhanced MRI of the brain. [Site to also provide all
   available MRIs completed prior to initiating treatment with study intervention.]

   6. Received frontline radiotherapy

      1. Initiated radiotherapy within 12 weeks from the initial diagnosis of H3
      K27M-mutant diffuse glioma.

      2. Completed radiotherapy within 2 to 6 weeks prior to randomization

      3. Completed standard fractionated radiotherapy (eg. 54 to 60 Gy in 28 to 33
      fractions given over approximately 6 weeks or hypofractionated radiotherapy (eg.
      40 Gy in 15 fractions given over approximately 3 weeks).

   7. Karnofsky Performance Status or Lansky Performance Status ≥ 70 at time of
   randomization.

   8. Stable or decreasing dose of corticosteroids and anti-seizure medications for 7 days
   prior to randomization, if applicable. Stable steroid dose is defined as ≤ 2 mg/day
   increase (based on dexamethasone dose or equivalent dose of an alternative steroid).

Exclusion Criteria:

   1. Primary spinal tumor.

   2. Diffuse intrinsic pontine glioma (DIPG), defined as tumors with a pontine epicenter
   and diffuse involvement of the pons.

   3. Evidence of leptomeningeal spread of disease or cerebrospinal fluid dissemination.

   4. Any known concurrent malignancy.

   5. New lesion(s) outside of the radiation field.

   6. Received whole-brain radiotherapy.

   7. Received proton therapy for glioma.

   8. Use of any of the following treatments within the specified time periods prior to
   randomization:

      1. ONC201 or ONC206 at any time.

      2. Systemic bevacizumab (includes biosimilars) at any time since the initial
      diagnosis of H3 K27M-mutant diffuse glioma.

      3. Temozolomide within past 3 weeks.

      4. Tumor treating fields at any time.

      5. DRD2 antagonist within past 2 weeks.

      6. Any investigational therapy within past 4 weeks.

      7. Strong CYP3A4 inhibitors within 3 days.

      8. Strong CYP3A4 inducers (includes enzyme-inducing antiepileptic drugs) within 2
      weeks.

   9. Laboratory test results meeting any of the following parameters within 2 weeks prior
   to randomization:

      1. Absolute neutrophil count < 1.0 × 109/L or platelets < 75 × 109/L.

      2. Total bilirubin > 1.5 × upper limit of normal (ULN) (participants with Gilbert's
      syndrome may be included with total bilirubin > 1.5 × ULN if direct bilirubin is
      ≤ 1.5 × ULN).

      3. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × ULN.

      4. Creatinine clearance ≤ 60 mL/min as calculated by the Cockcroft Gault equation
      (or estimated glomerular filtration rate < 60 mL/min/1.73 m2).

10. QTc > 480 msec (based on mean from triplicate electrocardiograms) during screening.

11. Known hypersensitivity to any excipients used in the study intervention formulation.

12. Pregnant, breastfeeding, or planning to become pregnant while receiving study
   intervention or within 3 months after the last dose. Participants of childbearing
   potential must have a negative serum pregnancy test within 72 hours prior to receiving
   the first dose of study intervention.

13. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
   infection requiring systemic therapy or psychiatric illness/social situations that
   would limit compliance with study requirements.

14. Any other condition (eg, medical, psychiatric, or social) that, in the opinion of the
   investigator, may interfere with participant safety or the ability to complete the
   study according to the protocol.