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

• ClinicalTrials.gov Identifier: NCT05580562
• Recruitment Status: Recruiting
• First Posted: October 14, 2022
• Last Update Posted: April 9, 2024
• Sponsor: Chimerix
• Information provided by (Responsible Party): Chimerix

Tracking Information

• First Submitted Date: September 27, 2022
• First Posted Date: October 14, 2022
• Last Update Posted Date: April 9, 2024
• Actual Study Start Date: January 23, 2023
• Estimated Primary Completion Date: August 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 12, 2022)

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

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: October 12, 2022)

• Incidence of adverse events [ Time Frame: From date of randomization up to 44 months ]
  Incidence of 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 [ Time Frame: From date of randomization up to 44 months ]
  Percentage of participants with clinically significant laboratory results
• PFS using RANO-HGG criteria [ Time Frame: From date of randomization up to 44 months ]
  PFS using RANO-HGG criteria for participants with measurable contrast-enhancing disease
• Corticosteroid response [ Time Frame: From date of randomization up to 44 months ]
  Corticosteroid response will be measured by a confirmed 50% decrease in use of dexamethasone or equivalent
• Performance status response [ Time Frame: From date of randomization up to 44 months ]
  Performance status response will be measured by confirmed increase in Karnofsky Performance Status (KPS) or Lansky Performance Status (LPS)

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: ONC201 in H3 K27M-mutant Diffuse Glioma Following Radiotherapy (the ACTION Study)
• 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
• Brief 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment

Condition

• H3 K27M
• Glioma

Intervention

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

Study Arms

• Experimental: ONC201 Twice Weekly Group
  Intervention: Drug: ONC201
• Experimental: ONC201 Once Weekly Group
  Intervention: Drug: ONC201 + Placebo
• Placebo Comparator: Placebo Group
  Intervention: Other: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: October 12, 2022): 450
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: August 2026
• Estimated Primary Completion Date: August 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: Child, Adult, Older Adult
• Accepts Healthy Volunteers: No

Contacts

Contact: Tarapore, PhD; 1-919-806-1074; clinicaltrials@chimerix.com

• Listed Location Countries: Australia, Austria, Canada, Denmark, Germany, Israel, Italy, Korea, Republic of, Netherlands, Spain, Switzerland, United Kingdom, United States

Administrative Information

• NCT Number: NCT05580562
• Other Study ID Numbers: ONC201-108
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Chimerix
• Original Responsible Party: Same as current
• Current Study Sponsor: Chimerix
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Chimerix
• Verification Date: April 2024