Table 2.

Eligibility criteria

Inclusion criteria
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.
Body weight ≥10 kg at time of randomization.
Histologically diagnosed H3 K27M-mutant diffuse glioma (new diagnosis, nonrecurrent). Detection of a missense K27M mutation in any histone H3-encoding gene detected by local testing of tumor tissue (IHC or NGS in a CLIA-certified or equivalent laboratory). Site to provide (as available): ≥ 10 unstained FFPE slides from tumor tissue
Completed standard frontline radiotherapy (54 to 60 Gy at 1.8 to 2.2 Gy/fraction) ≤ 6 weeks prior to randomization.
At least 1, 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.
At least 1 high-quality, contrast-enhanced MRI of the brain obtained within 2–6 weeks after completion of frontline radiotherapy. Site to also provide (if available): pre-surgery/biopsy, post-surgery, and radiation planning MRIs.
KPS/LPS ≥70 at time of randomization
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 alternative steroid).
Exclusion criteria
Primary spinal tumor.
DIPG, defined as tumors with a pontine epicenter and diffuse involvement of the pons.
Evidence of leptomeningeal spread of disease or CSF dissemination.
Any known concurrent malignancy.
New lesion(s) outside of the radiation field.
Received whole-brain radiotherapy.
Received proton therapy for glioma.
Use of any of the following treatments within the specified time periods prior to randomization: • ONC201 or ONC206 at any time. • Bevacizumab (includes biosimilars) at any time. • Temozolomide within past 3 weeks. • Tumor-treating fields at any time. • DRD2 antagonist within past 2 weeks. • Any investigational therapy within past 4 weeks. • Strong CYP3A4/5 inhibitors (see Appendix 8) within 3 days. • Strong CYP3A4/5 inducers (includes enzyme-inducing antiepileptic drugs; see Appendix 8) within 2 weeks.
Laboratory test results meeting any of the following parameters within 2 weeks prior to randomization: • ANC < 1.0 × 109/L or platelets < 75 × 109/L. • Total bilirubin > 1.5 × ULN (participants with Gilbert’s syndrome may be included with total bilirubin > 1.5 × ULN if direct bilirubin is ≤ 1.5 × ULN). • AST or ALT > 2.5 × ULN. • Creatinine clearance ≤ 60 mL/min as calculated by the Cockcroft Gault equation (or estimated glomerular filtration rate < 60 mL/min/1.73 m2.
QTc > 480 ms (based on mean from triplicate ECGs) during screening
Known hypersensitivity to any excipients used in the study intervention formulation.
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 h prior to receiving the first dose of study intervention.
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.
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.

ANC, Absolute neutrophil count; ALT, alanine aminotransferase alanine aminotransferase; AST, aspartate aminotransferase; CLIA, clinical laboratory improvement amendments; CSF, cerebrospinal fluid; DIPG, diffuse intrinsic pontine glioma; DRD2, dopamine receptor D2; ECG, electrocardiogram; FFPE, formalin-fixed paraffin-embedded; ICH, immunohistochemistry; KPS, Karnofsky Performance Status; LPS, Lansky Performance Status NGS, next-generation sequencing; MRI, magnetic resonance imaging; ULN, upper limit of normal.