The ACTION study: ONC201 in diffuse glioma with H3 K27M mutation after radiotherapy

Argentina, Australia, Austria, Brazil, Canada, Denmark, Germany, Hong Kong, Israel, Italy, Japan, Korea, Republic of, Netherlands, Singapore, Spain, Switzerland, United Kingdom, United States (ICTRP)

Identifiant de l'essai ICTRP
NCT05580562 (ICTRP)

Titre officiel (approuvé par le comité d'éthique)
ONC201 for the Treatment of Newly Diagnosed H3 K27M-mutant Diffuse Glioma Following Completion of Radiotherapy: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study (BASEC)

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

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

Maladie en cours d'investigation
H3 K27MGlioma (ICTRP)

Intervention étudiée
Drug: Dordaviprone (ONC201)Drug: Dordaviprone (ONC201) + PlaceboOther: Placebo (ICTRP)

Type d'essai
Interventional (ICTRP)

Plan de l'étude
Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Triple (Participant, Care Provider, Investigator). (ICTRP)

Critères d'inclusion/exclusion
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. (ICTRP)

non disponible

Critères d'évaluation principaux et secondaires
Overall survival (OS);Progression free survival (PFS) as assessed by using RANO-HGG criteria (ICTRP)

Incidence of adverse events;Change from baseline in clinical laboratory parameters;PFS using RANO-HGG criteria;Corticosteroid response;Performance status response (ICTRP)

Date d'enregistrement
non disponible

Inclusion du premier participant
non disponible

Sponsors secondaires
non disponible

Contacts supplémentaires
Tarapore, PhD, clinicaltrials@chimerix.com, 1-919-806-1074 (ICTRP)

ID secondaires
ONC201-108 (ICTRP)

Résultats-Données individuelles des participants
non disponible

Informations complémentaires sur l'essai
https://clinicaltrials.gov/ct2/show/NCT05580562 (ICTRP)