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

Study Overview
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Brief Summary
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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
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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

Conditions
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Glioma, H3 K27M

Intervention / Treatment
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* Drug: ONC201
* Drug: ONC201 + Placebo
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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). 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.] 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. At least one, high-quality, contrast-enhanced MRI of the brain obtained 2 to 6 weeks after completion of frontline radiotherapy. [Site to also provide all available MRIs completed prior to initiating treatment with study intervention.] 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. Karnofsky Performance Status or Lansky Performance Status ≥ 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 an alternative steroid). Exclusion Criteria: Primary spinal tumor. Diffuse intrinsic pontine glioma (DIPG), defined as tumors with a pontine epicenter and diffuse involvement of the pons. Evidence of leptomeningeal spread of disease or cerebrospinal fluid 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 within 3 days. Strong CYP3A4/5 inducers (includes enzyme-inducing antiepileptic drugs) within 2 weeks. Laboratory test results meeting any of the following parameters within 2 weeks prior to randomization: Absolute neutrophil count < 1.0 × 109/L or platelets < 75 × 109/L. 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). Aspartate aminotransferase (AST) or alanine aminotransferase (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 msec (based on mean from triplicate electrocardiograms) 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 hours 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.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ONC201 Twice Weekly Group<br> | Drug: ONC201<br>* 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.<br>|
| Experimental: ONC201 Once Weekly Group<br> | Drug: ONC201 + Placebo<br>* 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<br>|
| Placebo Comparator: Placebo Group<br> | Other: Placebo<br>* Participants will receive placebo (same number of capsules as the ONC201 dose) on dosing days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Overall Survival is defined as the time from randomization to death due to any cause. | From date of randomization until date of death from any cause, assessed up to approximately 44 months | 
| Progression free survival (PFS) as assessed by using RANO-HGG criteria | PFS is defined as time from randomization to disease progression (PD) or death. | From date of randomization until the date of first documented progression assessed up to approximately 44 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Incidence of overall, treatment-related, Grade 3 or higher in severity, serious, fatal, those resulting in treatment discontinuation, and events of special interest | From date of randomization up to 44 months | 
| Change from baseline in clinical laboratory parameters | Percentage of participants with clinically significant laboratory results | From date of randomization up to 44 months | 
| PFS using RANO-HGG criteria | PFS using RANO-HGG criteria for participants with measurable contrast-enhancing disease | From date of randomization up to 44 months | 
| Corticosteroid response | Corticosteroid response will be measured by a confirmed 50% decrease in use of dexamethasone or equivalent | From date of randomization up to 44 months | 
| Performance status response | Performance status response will be measured by confirmed increase in Karnofsky Performance Status (KPS) or Lansky Performance Status (LPS) | From date of randomization up to 44 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DMG, H3 K27M, H3 K28M, H3 K27-altered, histone, H3F3A, HIST1H3B, HIST1H3C, H3.1, H3.3, thalamus, thalamic, midline