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

Description
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.

Objective
Primary:
-To evaluate the efficacy of ONC201 administered following radiotherapy in participants with H3 K27M-mutant diffuse glioma

Secondary:
-To evaluate the safety and tolerability of ONC201 versus placebo
-To evaluate the efficacy of ONC201 administered following radiotherapy using RANO-HGG criteria in participants with H3 K27M-mutant diffuse glioma
-To evaluate clinical benefits of treatment with ONC201

Treatment Experimental: ONC201 Twice Weekly Group
Drug: 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.

Experimental: ONC201 Once Weekly Group
Drug: 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

Placebo Comparator: Placebo Group
Other: Placebo
Participants will receive placebo (same number of capsules as the ONC201 dose) on dosing days

Key Eligibility 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

Applicable Disease Sites
Brain/Central Nervous System

Participating Institutions
UW Health University Hospital