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

Summary

This is a randomized, double-blind, placebo-controlled international phase III study in participants with newly diagnosed H3 K27M-mutant diffuse glioma to assess whether treatment with ONC201 following frontline radiotherapy extends overall survival and progression-free survival.

ONC201 is a first-in-class small molecule imipridone that inhibits dopamine receptor D2 (DRD2) and activates mitochondrial caseinolytic protease P (ClpP). This drug decreases the activity of the Akt and ERK cellular signaling pathways and induces cell death. Gliomas with the H3 K27M mutation express more genes, like DRD2, that cause normal cells to become cancerous.

 

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 or next-generation sequencing in a CLIA-certified or equivalent laboratory).
  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.
  6. Completed standard frontline radiotherapy within 2 to 6 weeks prior to randomization. Standard frontline radiotherapy is defined as a dose of 54 to 60 Gy at 1.8 to 2.2 Gy/fraction. Radiotherapy must be initiated within 12 weeks from initial diagnosis of H3 K27M-mutant diffuse glioma and within 8 weeks of most recent surgical resection/biopsy.
  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 alternative steroid).

For the most up-to-date criteria, please visit clinicaltrials.gov.

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. Bevicizumab (includes biosimilars) at any time.
    3. Tumor treating fields at any time.
    4. DRD2 antagonist within past two weeks.
    5. Any investigational therapy within the past four weeks.
    6. Strong CYP3A4/5 inhibitors within three days.
    7. Strong CYP3A4/5 inducer (includes enzyme-inducing anti-epileptic drugs) within two weeks.
  9. Laboratory test results meeting any of the following parameters within two weeks prior to randomization:
    1. Absolute neutrophil count < 1.0 × 109/L or platelets < 75 × 109/L.
    2. 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).
    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 [ECGs]) 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 three 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.
Investigator(s)

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