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Treatment with ONC201 for patients with H3 K27M-mutant diffuse glioma after radiotherapy

ONC201 for the Treatment of Newly Diagnosed H3 K27M-mutant Diffuse Glioma Following Completion of Radiotherapy: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study

Phase 3 Interventional Jazz Pharmaceuticals · NCT05580562

This study is testing if the drug ONC201 can help people with a specific type of brain tumor live longer and stay healthier after they finish their initial radiation treatment.

Quick facts

PhasePhase 3
Study typeInterventional
Enrollment510 (estimated)
SexAll
SponsorJazz Pharmaceuticals Industry-sponsored
Drugs / interventionsbevacizumab, radiation
Locations162 sites (Phoenix, Arizona and 161 other locations)
Trial IDNCT05580562 on ClinicalTrials.gov

What this trial studies

This Phase 3 clinical trial evaluates the effectiveness of ONC201 in extending overall survival and progression-free survival in patients with newly diagnosed H3 K27M-mutant diffuse glioma who have completed standard frontline radiotherapy. The study is randomized, double-blind, and placebo-controlled, involving multiple international sites. Participants will be assigned to receive either ONC201, a placebo, or a combination of both following their radiotherapy treatment.

Who should consider this trial

Good fit: Ideal candidates are individuals with newly diagnosed H3 K27M-mutant diffuse glioma who have completed standard radiotherapy.

Not a fit: Patients with other types of gliomas or those who have not undergone prior radiotherapy may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could significantly improve survival outcomes for patients with a specific type of aggressive brain tumor.

How similar studies have performed: While this approach is novel for this specific mutation, similar studies targeting other glioma mutations have shown promising results.

Eligibility criteria

Show full inclusion / exclusion criteria 
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). \[Site to provide (as available): ≥ 11 unstained formalin-fixed paraffin-embedded (FFPE) slides from tumor tissue.\]
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. Dordaviprone (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.

Where this trial is running

Phoenix, Arizona and 161 other locations

+112 more sites — see ClinicalTrials.gov for the full list.

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions H3 K27MGliomaH3 K28MH3 K27-alteredhistoneH3F3AHIST1H3BHIST1H3C
Last reviewed 2026-06-13 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.