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RECRUITING

NCT05580562

PHASE3

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

Sponsor: Jazz Pharmaceuticals

View on ClinicalTrials.gov

Summary

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 whether treatment with ONC201 following frontline radiotherapy will extend overall survival and progression-free survival in this population. Eligible participants will have histologically diagnosed H3 K27M-mutant diffuse glioma and have completed standard frontline radiotherapy.

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

Key Details

Gender

All

Age Range

Any - Any

Study Type

INTERVENTIONAL

Enrollment

450

Start Date

2023-01-23

Completion Date

2026-08

Last Updated

2025-08-26

Healthy Volunteers

Conditions

H3 K27M Glioma

Interventions

DRUG

Dordaviprone (ONC201)

Participants ≥ 52.5 kg will receive 625 mg of ONC201 (5 × 125-mg capsules) dosing days; participants \< 52.5 kg will receive a dose (and corresponding number of capsules) scaled by body weight and rounded to 125-mg increments.

DRUG

Dordaviprone (ONC201) + Placebo

Participants ≥ 52.5 kg will receive 625 mg of ONC201 (5 × 125-mg capsules) or matching placebo on dosing days; participants \< 52.5 kg will receive a dose (and corresponding number of capsules) scaled by body weight and rounded to 125-mg increments

OTHER

Placebo

Participants will receive placebo (same number of capsules as the ONC201 dose) on dosing days

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). \[Site to provide (as available): ≥ 10 unstained formalin-fixed paraffin-embedded (FFPE) slides from tumor tissue.\] 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. 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.

Locations (162)

Banner MD Anderson Cancer Center

Phoenix, Arizona, United States

Barrow Neurological Institute

Phoenix, Arizona, United States

Phoenix Childrens Hospital

Phoenix, Arizona, United States

Mayo Clinic Arizona

Phoenix, Arizona, United States

UC San Diego Moores Cancer Center

La Jolla, California, United States

Kaiser Permanente Los Angeles Medical Center

Los Angeles, California, United States

UCLA University of California Los Angeles

Los Angeles, California, United States

Children's Hospital of Orange County

Orange, California, United States

University of California Irvine

Orange, California, United States

UCSF Benioff Children's Hospital

San Francisco, California, United States

University of California San Francisco

San Francisco, California, United States

Providence Saint John's Cancer Institute

Santa Monica, California, United States

Stanford Cancer Center

Stanford, California, United States

Yale University

New Haven, Connecticut, United States

MedStar Georgetown University Hospital

Washington D.C., District of Columbia, United States

Mayo Clinic Jacksonville

Jacksonville, Florida, United States

Miami Cancer Institute

Miami, Florida, United States

St Joseph's Children's Hospital of Tampa

Tampa, Florida, United States

Moffitt Cancer Center

Tampa, Florida, United States

Cleveland Clinic Florida

Weston, Florida, United States

Children's Healthcare of Atlanta

Atlanta, Georgia, United States

Kapi'olani Medical Center for Women and Children

Honolulu, Hawaii, United States

Feinberg School of Medicine Northwestern University

Chicago, Illinois, United States

Indiana University School of Medicine - Indianapolis

Indianapolis, Indiana, United States

University of Iowa Hospitals & Clinics

Iowa City, Iowa, United States

Norton Healthcare

Louisville, Kentucky, United States

Ochsner Medical Center - New Orleans

New Orleans, Louisiana, United States

University of Maryland School of Medicine

Baltimore, Maryland, United States

Massachusetts General Hospital Cancer Center

Boston, Massachusetts, United States

Dana Farber Cancer Institute

Boston, Massachusetts, United States

University of Michigan Hospital

Ann Arbor, Michigan, United States

University of Minnesota

Minneapolis, Minnesota, United States

Mayo Clinic - Cancer Center - Rochester

Rochester, Minnesota, United States

Washington University School of Medicine/St. Louis Children's Hospital

St Louis, Missouri, United States

Benefis Hospital Sletten Cancer Institute

Great Falls, Montana, United States

University of Nebraska Medical Center

Omaha, Nebraska, United States

Jersey Shore University Medical Center

Neptune City, New Jersey, United States

Overlook Medical Center

Summit, New Jersey, United States

Albany Medical Center

Albany, New York, United States

Children's Hospital at Montefiore Medical Center