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Trial record 1 of 1 for:    ONC201-108
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ONC201 in H3 K27M-mutant Diffuse Glioma Following Radiotherapy (the ACTION Study) (ACTION)

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

Study Description
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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.

Condition or disease Intervention/treatment Phase
H3 K27M Glioma Drug: ONC201 Drug: ONC201 + Placebo Other: Placebo Phase 3

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 450 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
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
Actual Study Start Date : January 23, 2023
Estimated Primary Completion Date : August 2026
Estimated Study Completion Date : August 2026

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/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


Outcome Measures
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Primary Outcome Measures :
  1. 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.

  2. 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.


Secondary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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

  5. 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)


Eligibility Criteria
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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05580562


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

Locations
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Sponsors and Collaborators
Chimerix
More Information
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Responsible Party: Chimerix
ClinicalTrials.gov Identifier: NCT05580562    
Other Study ID Numbers: ONC201-108
First Posted: October 14, 2022    Key Record Dates
Last Update Posted: April 9, 2024
Last Verified: April 2024

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Chimerix:
H3 K27M
H3 K28M
H3 K27-altered
histone
H3F3A
HIST1H3B
HIST1H3C
 H3.1
H3.3
DMG
thalamus
thalamic
midline
Additional relevant MeSH terms:
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Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
 Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
TIC10 compound
Antineoplastic Agents