IRB Study Number 23-448
Status Recruiting
Institutes Taussig Cancer Institute, Neurological Institute
Description
Primary Objectives
• To evaluate the efficacy of ONC201 administered following radiotherapy in participants with H3 K27M-mutant diffuse glioma
Secondary Objectives
• To evaluate the safety and tolerability of ONC201 versus placebo
• To evaluate the efficacy of ONC201 administered following radiotherapy using RANO-HGG criteria in participants with H3 K27M-mutant diffuse glioma
• To evaluate clinical benefits of treatment with ONC201
• To evaluate the impact of ONC201 on health-related QoL and neurological function
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 ≥ 10 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 (immunohistochemistry [IHC] or NGS in a CLIA-certified or equivalent laboratory). [Site to provide (as available): ≥ 10 unstained formalin-fixed paraffin-embedded (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.]
Completed 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 (refer to Appendix 6 for KPS/LPS scoring).
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 alternative steroid).
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. 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 (see Appendix 8) within 3 days.
h. Strong CYP3A4/5 inducers (includes enzyme-inducing antiepileptic drugs; see Appendix 8) within 2 weeks.
[Note: Refer to Section 6.10 for additional information on concomitant therapy.]
- Laboratory test results meeting any of the following parameters within 2 weeks prior to randomization:
a. Absolute neutrophil count < 1.0 × 109/L or platelets < 75 × 109/L.
b. Total bilirubin > 1.5 × 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 [ECGs]) during screening (see Section 8.3.3 for details about QTc correction formulas).
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.
