ONC201 in H3 K27M-mutant Diffuse Glioma Following Radiotherapy (the ACTION Study)

Inclusion Criteria:

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

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

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

4. At least one, high-quality, contrast-enhanced MRI of the brain obtained prior tostarting radiotherapy for submission to sponsor's imaging vendor for central read.For participants who had a surgical resection, this scan must be post-resection; forparticipants 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 weeksafter completion of frontline radiotherapy. If unable to obtain contrast-enhancedimaging due to lack of venous access after multiple attempts, a patient may still beeligible after collection of a nonenhanced MRI of the brain. [Site to also provideall available MRIs completed prior to initiating treatment with study intervention.]

6. Received frontline radiotherapy

7. Initiated radiotherapy within 12 weeks from the initial diagnosis of H3K27M-mutant diffuse glioma.

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

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

10. Karnofsky Performance Status or Lansky Performance Status ≥ 70 at time ofrandomization.

11. Stable or decreasing dose of corticosteroids and anti-seizure medications for 7 daysprior to randomization, if applicable. Stable steroid dose is defined as ≤ 2 mg/dayincrease (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 epicenterand 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 torandomization:

9. ONC201 or ONC206 at any time.

10. Systemic bevacizumab (includes biosimilars) at any time since the initialdiagnosis of H3 K27M-mutant diffuse glioma.

11. Temozolomide within past 3 weeks.

12. Tumor treating fields at any time.

13. DRD2 antagonist within past 2 weeks.

14. Any investigational therapy within past 4 weeks.

15. Strong CYP3A4 inhibitors within 3 days.

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

17. Laboratory test results meeting any of the following parameters within 2 weeks priorto randomization:

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

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

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

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

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

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

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

25. Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection requiring systemic therapy or psychiatric illness/social situations thatwould limit compliance with study requirements.

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