Glioma, H3 K27M
Conditions
Keywords
H3 K27M, H3 K28M, H3 K27-altered, histone, H3F3A, HIST1H3B, HIST1H3C, H3.1, H3.3, DMG, thalamus, thalamic, midline
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 dordaviprone (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.
Interventions
Participants ≥ 52.5 kg will receive 625 mg of dordaviprone (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.
DRUGDordaviprone (ONC201) + Placebo
Participants ≥ 52.5 kg will receive 625 mg of dordaviprone (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
OTHERPlacebo
Participants will receive placebo (same number of capsules as the dordaviprone dose) on dosing days
Sponsors
Jazz Pharmaceuticals
Chimerix, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
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). \[Site to provide (as available): ≥ 11 unstained formalin-fixed paraffin-embedded (FFPE) slides from tumor tissue.\] 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. Dordaviprone (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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall survival (OS) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) using RANO 2.0 Criteria for All Participants | 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. |
| PFS Using RANO 2.0 Criteria for Participants with Measurable Contrast-Enhancing Disease | From date of randomization up to 44 months | PFS is defined as time from randomization to disease progression (PD) or death. |
| Incidence of adverse events | 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 | From date of randomization up to 44 months | Percentage of participants with clinically significant laboratory results |
| Distribution of Graded Clinical Laboratory Parameter | From date of randomization up to 44 months | Breakdown of how many participants fall into each severity grade. Grade 1 for mild up to Grade 4 for severe or life threatening. |
| Corticosteroid response | From date of randomization up to 44 months | Corticosteroid response will be measured by a confirmed 50% decrease in use of dexamethasone or equivalent |
| Time to First Corticosteroid Response | From date of randomization up to 44 months | Time from the first dose to the nominal analysis timepoint when the response criteria are first met. |
| Duration of First Corticosteroid Response | From date of randomization up to 44 months | Time from first response to end of first response. |
| Cumulative Duration of Corticosteroid Responses | From date of randomization up to 44 months | Total durations of response, irrespective of censoring, to account for participants with multiple responses during the study. |
| Corticosteroid Dose and Change from Baseline Over Time | From date of randomization up to 44 months | — |
| Time to Corticosteroid Use Deterioration | From date of randomization up to 44 months | Time from first dose of study intervention to time when corticosteroid daily dose ≥ baseline daily dose + 2 mg at 2 consecutive analysis time points or death. |
| Performance status response | 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). |
| Time to first performance status response | From date of randomization up to 44 months | time from the first dose of study intervention to the nominal analysis timepoint when the response criteria are first met. |
| Duration of first performance status response | From date of randomization up to 44 months | Time from response to end of response. |
| Cumulative duration of performance status responses | From date of randomization up to 44 months | Total durations of response, irrespective of censoring, to account for patients with multiple responses during the study |
| Performance status and change from baseline over time | From date of randomization up to 44 months | — |
| Time to performance status deterioration | From date of randomization up to 44 months | As time from the first dose of study intervention to time when KPS/LPS score \< baseline or death. |
| Change from Baseline in European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life-Core Questionnaire (QLQ-C30) | Day 1 (pre-dose), up to 44 months | The EORTC QLQ-C30 will be administered to participants ≥ 18 years. It evaluates the following scales: functional, symptom, global health, quality of life, and financial impact. |
| Change from Baseline in Quality of Life-Core Questionnaire Brain Module (QLQ-BN20) | Day 1 (pre-dose), up to 44 months | The QLQ-bN20 will be administered to participants ≥ 18 years of age and will measure health related quality of life. |
| Change from Baseline in MD Anderson Symptom Inventory Brain Tumor Module (MDASI-BT) | Day 1 (pre-dose), up to 44 months | The MDASI-BT will be administered to participants ≥ 18 years of age. It is a 22-item assessment that measures brain tumor related symptoms and impact on daily function. It will assess six areas on a scale of 0-10 (10 indicating worse or more severe symptoms): affective, cognitive, focal neurologic deficit, constitutional, generalized symptom, and gastrointestinal. |
| Change from Baseline in Pediatric Quality of Life Inventory (PedsQL) Brain Tumor Module | Day 1 (pre-dose), up to 44 months | The PedsQL will be administered to participants 2 to \< 18 years of age. It measures 4 scales: physical, emotional, social, and school functioning. |
| Change from Baseline in Neurologic Assessment in Neuro-Oncology (NANO) Score | Day 1 (pre-dose), up to 44 months | The NANO score evaluates gait, strength, ataxia in the upper extremity, sensation, visual field, facial strength, language, level of consciousness, and behavior. |
Countries
Argentina, Australia, Austria, Brazil, Canada, Denmark, Germany, Hong Kong, Israel, Italy, Japan, Netherlands, Singapore, South Korea, Spain, Switzerland, United Kingdom, United States
Contacts
CONTACTClinical Trial Disclosure & Transparency
Outcome results
None listed