Table 1.

Objectives and endpoints

Objectives	Endpoints
Primary
To evaluate the efficacy of ONC201 administered following radiotherapy in participants with H3 K27M-mutant diffuse glioma	• OS • PFS using RANO-HGG criteria
Secondary
To evaluate the safety and tolerability of ONC201 versus placebo	• Incidence of AEs: overall, treatment-related, Grade 3 or higher in severity, serious, fatal, those resulting in treatment discontinuation, and events of special interest • Change from baseline in clinical laboratory parameters • Distribution of graded clinical laboratory parameters
To evaluate the efficacy of ONC201 administered following radiotherapy using RANO-HGG criteria in participants with H3 K27M-mutant diffuse glioma	• PFS using RANO-HGG criteria for participants with measurable contrast-enhancing disease
To evaluate clinical benefits of treatment with ONC201	• Corticosteroid response • Time to first corticosteroid response • Duration of first corticosteroid response • Cumulative duration of corticosteroid responses • Corticosteroid dose and change from baseline over time • Time to corticosteroid use deterioration • Performance status response • Time to first performance status response • Duration of first performance status response • Cumulative duration of performance status responses • Performance status and change from baseline over time • Time to performance status deterioration
To evaluate the impact of ONC201 on health-related QoL and neurological function	• Change from baseline in QoL assessments   ◦ ≥18 years of age: EORTC-QLQ-C30, QLQ-BN20, and MDASI-BT   ◦ 2 to <18 years of age: PedsQL Brain Tumor Module • Change from baseline NANO results
Exploratory
To assess plasma concentrations and estimate PK parameters for ONC201	• Plasma concentrations of ONC201 • PK parameters for ONC201
To evaluate the exposure-response relationship	• Correlation between extent of exposure to ONC201 and select efficacy and safety endpoints
To evaluate the efficacy of ONC201 using RANO-LGG criteria	• PFS using RANO-LGG criteria
To evaluate the impact of molecular profile on outcomes	• Correlation between the molecular profile of the tumor and efficacy (OS and PFS)
To compare outcomes among selected subgroups	• OS, PFS • Incidence of AEs
To evaluate the impact of ONC201 treatment on health care resource utilization	• Health care resource utilization

Abbreviations: AE, adverse events; HGG, high-grade glioma; LGG, low-grade glioma; NANO, Neurologic Assessment in Neuro-Oncology; OS, overall survival; RANO, response assessment in neuro-oncology; PFS, progression-free survival; PK, pharmacokinetic.