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

Trial ID: 2022-502051-56-00
Protocol: ONC201-108
Sponsor: Chimerix Inc.

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Diseases & Conditions

Malignant glioma

Objectives

The primary objective of this study is to evaluate the **efficacy** of ONC201 administered following radiotherapy in participants with H3 K27M-mutant diffuse glioma. This objective is clinically relevant as it aims to determine the potential therapeutic benefits of ONC201 in improving outcomes for patients with this aggressive and difficult-to-treat brain tumor subtype.

Secondary objectives include:

To evaluate the **safety** and tolerability of ONC201 versus placebo, which is crucial for understanding the risk-benefit profile of the treatment.
To assess the efficacy of ONC201 administered following radiotherapy using RANO-HGG criteria in participants with H3 K27M mutant diffuse glioma, providing a standardized measure of treatment response.
To evaluate the clinical benefits of treatment with ONC201, which may include improvements in symptoms or disease progression.
To evaluate the impact of ONC201 on health-related quality of life (QoL) and neurological function, which are important considerations for patient-centered care and overall treatment success.

Participants

The clinical trial involves a total of **346 participants** diagnosed with **H3 K27M-mutant diffuse glioma**. The study population includes both male and female subjects, encompassing a pediatric and young adult age range, specifically from 2 to 21 years old. Participants were selected based on their ability to understand study procedures and provide informed consent, with a body weight of at least 10 kg at the time of randomization. The trial includes individuals who have completed standard frontline radiotherapy within 2 to 6 weeks prior to randomization and have a Karnofsky or Lansky Performance Status of 70 or higher. Participants are required to have stable or decreasing doses of corticosteroids and anti-seizure medications for 7 days prior to randomization. The trial population is considered vulnerable, given the inclusion of pediatric subjects. The selection criteria ensure that participants have a histologically confirmed diagnosis of H3 K27M-mutant diffuse glioma, with the mutation detected through appropriate laboratory testing. The study does not specify any particular lifestyle considerations such as diet or physical activity.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **ONC201** in participants with **H3 K27M-mutant diffuse glioma** following the completion of radiotherapy. This study is a **randomized, double-blind, placebo-controlled** trial, ensuring that neither the participants nor the investigators know which treatment the participants are receiving, thereby minimizing bias. The trial is expected to run until December 15, 2026, with recruitment having commenced on March 31, 2023. Participants will be involved in the study for a maximum treatment period of 12 months, during which they will receive either ONC201 or a placebo in capsule form, administered orally.

The sequence of study visits begins with an inclusion (screening) visit, where eligibility is confirmed based on criteria such as a histologically diagnosed **H3 K27M-mutant diffuse glioma**, completion of standard frontline radiotherapy, and a stable or decreasing dose of corticosteroids and anti-seizure medications. Following randomization, participants will undergo regular follow-up visits to monitor their health status, assess the progression of the disease, and evaluate any adverse events. The primary endpoints of the study include overall survival and progression-free survival using RANO-HGG criteria. Secondary endpoints focus on the incidence of adverse events, changes in clinical laboratory parameters, and quality of life assessments.

The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted to gather comprehensive data on the treatment's efficacy and safety. Participants may be subject to early termination from the study if they experience severe adverse events, if there is evidence of disease progression, or if they withdraw consent. The trial's rigorous design and structured visit schedule aim to provide robust data on the potential benefits of ONC201 for this specific patient population.

Treatment

The clinical trial involves the administration of **ONC201**, an experimental medication, for the treatment of newly diagnosed **H3 K27M-mutant diffuse glioma** following the completion of radiotherapy. **ONC201** is provided in a **capsule** form and is administered **orally**. The active substance in **ONC201** is **2,4,6,7,8,9-hexahydro-4-((2-methylphenyl)methyl)-7-(phenylmethyl)imidazo(1,2-a)pyrido(3,4-e)pyrimidin-5(1H)-one**, a chemical compound. The maximum daily dose of **ONC201** is **625 mg**, and the treatment period extends up to **12 weeks**. The medication is manufactured by **CHIMERIX, INC.** and is classified as an orphan drug under designation number **EU/3/22/2661**. Participant compliance with the dosing schedule is monitored throughout the study.

The study also includes a **placebo** group to serve as a comparator treatment. The placebo is designed to match the **ONC201** capsules in appearance but does not contain the active substance. The placebo is administered **orally** in the same manner and frequency as the experimental medication, ensuring the study remains double-blind. The use of a placebo allows for the assessment of the efficacy of **ONC201** by comparing outcomes between the treatment and control groups. Participants are randomly assigned to either the **ONC201** or placebo group, maintaining the integrity of the study's design.

Efficacy

The efficacy of ONC201 in the treatment of newly diagnosed H3 K27M-mutant diffuse glioma will be assessed through a series of primary and secondary endpoints. The primary endpoints include overall survival and progression-free survival, evaluated using the RANO-HGG criteria. These endpoints will provide critical insights into the effectiveness of ONC201 in prolonging life and delaying disease progression in participants.

Secondary endpoints will further explore the impact of ONC201 on various clinical parameters. These include the incidence of adverse events, changes in clinical laboratory parameters, and progression-free survival for participants with measurable contrast-enhancing disease. Additionally, the study will assess corticosteroid response, performance status response, and changes in quality of life (QoL) assessments. QoL will be measured using the EORTC-QLQ-C30, QLQ-BN20, and MDASI-BT for participants aged 18 and older, and the PedsQL Brain Tumor Module for those aged 2 to under 18. Changes in the Neurologic Assessment in Neuro Oncology (NANO) results will also be evaluated.

The collection and analysis of these efficacy parameters will be conducted at specified timepoints throughout the trial, ensuring a comprehensive evaluation of ONC201's therapeutic potential. The study is designed as a randomized, double-blind, placebo-controlled, multicenter trial, which will enhance the reliability and validity of the findings.

Inclusion and Exclusion 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 ≥ 11 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 (IHC or NGS in a CLIA-certified or equivalent laboratory). [Site to provide (as available): ≥ 11 unstained 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.]
Received 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).

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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: a. Dordaviprone (ONC201) or ONC206 at any time; b. bevacizumab (includes biosimilars) at any time; c. Temozolomide within past 3 weeks; d. Tumor treating fields at any time; e. DRD2 antagonist within past 2 weeks; f. Any investigational therapy within past 4 weeks; g. Strong CYP3A4/5 inhibitors within 3 days; h. 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: a. Absolute neutrophil count <1.0 × 10^9/L or platelets <75 × 10^9/L; b. 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); c. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 × ULN; d. 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.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Austria	Recruiting	31 Mar 2023	10
Denmark	Recruiting	31 Mar 2023	30
Germany	Recruiting	31 Mar 2023	25
Italy	Recruiting	31 Mar 2023	40
The Netherlands	Recruiting	31 Mar 2023	—
Spain	Recruiting	31 Mar 2023	45
Netherlands	—	—	20