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

Overview

This is a randomized, double-blind, placebo-controlled, parallel-group, international, Phase 3 study in patients with newly diagnosed H3 K27M-mutant diffuse glioma to assess whetherwith ONC201 following frontline radiotherapy will extend overall survival andgression-free survival in this population. Eligible participants will have histologically diagnosed H3 K27M-mutant diffuse glioma and have completed standard frontline radiotherapy.

Eligibility

You may be eligible for this study if you meet the following criteria:

  • Conditions:
    H3 K27M, Glioma
  • Gender: All

Inclusion Criteria:
  1. Able to understand the study procedures and agree to participate in the study byviding written informed consent (by participant or legally authorizedve), 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 aK27M mutation in any histone H3-encoding gene detected by testing of tumorue (immunohistochemistry [IHC] or next-generation sequencing [NGS] in a ClinicalLaboratory Improvement Amendments [CLIA]-certified or equivalent laboratory). [Site tovide (as available): ≥ 10 unstained formalin-fixed paraffin-embedded (FFPE) slidesumor tissue.]
  4. At least one, high-quality, contrast-enhanced MRI of the brain obtained prior tog radiotherapy for submission to sponsor's imaging vendor for central read. Forwho had a surgical resection, this scan must be post-resection; forwho 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 weeksdiotherapy. [Site to also provide all available MRIsd prior to initiating treatment with study intervention.]
  6. Completed standard frontline radiotherapy within 2 to 6 weeks prior to randomization.dard frontline radiotherapy is defined as a dose of 54 to 60 Gy at 1.8 to 2.2Gy/fraction. Radiotherapy must be initiated within 12 weeks from initial diagnosis ofH3 K27M-mutant diffuse glioma and within 8 weeks of most recent surgical/biopsy.
  7. Karnofsky Performance Status or Lansky Performance Status ≥ 70 at time ofdomization.
  8. Stable or decreasing dose of corticosteroids and anti-seizure medications for 7 daysdomization, if applicable. Stable steroid dose is defined as ≤ 2 mg/day(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 epicenterd 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 todomization
    1. ONC201 or ONC206 at any time.
    2. Bevacizumab (includes biosimilars) at any time.
    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 CYP3A4/5 inhibitors within 3 days.
    8. Strong CYP3A4/5 inducers (includes enzyme-inducing antiepileptic drugs) within 2weeks.
  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'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 studyvention or within 3 months after the last dose. Participants of childbearingust have a negative serum pregnancy test within 72 hours prior to receivinghe first dose of study intervention.
  13. Uncontrolled intercurrent illness including, but not limited to, ongoing or activequiring systemic therapy or psychiatric illness/social situations thatwould limit compliance with study requirements.
  14. Any other condition (eg, medical, psychiatric, or social) that, in the opinion of thevestigator, may interfere with participant safety or the ability to complete theudy according to the protocol.

Updated on 01 May 2024. Study ID: ONC201-108
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