NCT05580562招募中3 期
ONC201 for the Treatment of Newly Diagnosed H3 K27M-mutant Diffuse Glioma Following Completion of Radiotherapy: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study
适应症
干预措施
相关药物
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 510
- 试验地点
- 300
- 主要终点
- Overall survival (OS)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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 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.]
- •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. 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.]
- •Received frontline radiotherapy
- •Initiated radiotherapy within 12 weeks from the initial diagnosis of H3 K27M-mutant diffuse glioma.
- •Completed radiotherapy within 2 to 6 weeks prior to randomization
- •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).
- •Karnofsky Performance Status or Lansky Performance Status ≥ 70 at time of randomization.
- •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).
排除标准
- •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:
- •Dordaviprone (ONC201) or ONC206 at any time.
- •Systemic bevacizumab (includes biosimilars) at any time since the initial diagnosis of H3 K27M-mutant diffuse glioma.
- •Temozolomide within past 3 weeks.
- •Tumor treating fields at any time.
- •DRD2 antagonist within past 2 weeks.
- •Any investigational therapy within past 4 weeks.
- •Strong CYP3A4 inhibitors within 3 days.
- •Strong CYP3A4 inducers (includes enzyme-inducing antiepileptic drugs) within 2 weeks.
- •Laboratory test results meeting any of the following parameters within 2 weeks prior to randomization:
- •Absolute neutrophil count < 1.0 × 109/L or platelets < 75 × 109/L.
- •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).
- •Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × ULN.
- •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) during screening.
- •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.
研究组 & 干预措施
Placebo Group
Placebo Comparator
干预措施: Placebo (Other)
Dordaviprone Twice Weekly Group
Experimental
干预措施: Dordaviprone (ONC201) (Drug)
Dordaviprone Once Weekly Group
Experimental
干预措施: Dordaviprone (ONC201) + Placebo (Drug)
结局指标
主要结局
Overall survival (OS)
时间窗: 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
时间窗: 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.
次要结局
- Incidence of adverse events(From date of randomization up to 44 months)
- Change from baseline in clinical laboratory parameters(From date of randomization up to 44 months)
- PFS using RANO-HGG criteria(From date of randomization up to 44 months)
- Corticosteroid response(From date of randomization up to 44 months)
- Performance status response(From date of randomization up to 44 months)
- 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 Using RANO 2.0 Criteria for Participants with Measurable Contrast-Enhancing Disease(From date of randomization up to 44 months)
- Distribution of Graded Clinical Laboratory Parameter(From date of randomization up to 44 months)
- Time to First Corticosteroid Response(From date of randomization up to 44 months)
- Duration of First Corticosteroid Response(From date of randomization up to 44 months)
- Cumulative Duration of Corticosteroid Responses(From date of randomization up to 44 months)
- 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 to first performance status response(From date of randomization up to 44 months)
- Duration of first performance status response(From date of randomization up to 44 months)
- Cumulative duration of performance status responses(From date of randomization up to 44 months)
- 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)
- 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)
- Change from Baseline in Quality of Life-Core Questionnaire Brain Module (QLQ-BN20)(Day 1 (pre-dose), up to 44 months)
- Change from Baseline in MD Anderson Symptom Inventory Brain Tumor Module (MDASI-BT)(Day 1 (pre-dose), up to 44 months)
- Change from Baseline in Pediatric Quality of Life Inventory (PedsQL) Brain Tumor Module(Day 1 (pre-dose), up to 44 months)
- Change from Baseline in Neurologic Assessment in Neuro-Oncology (NANO) Score(Day 1 (pre-dose), up to 44 months)
研究者
研究点 (300)
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相关资讯
FDA Grants First Accelerated Approval for H3 K27M-Mutated Diffuse Midline Glioma with Dordaviprone- The FDA has granted accelerated approval to dordaviprone (Modeyso) for adult and pediatric patients aged 1 year and older with H3 K27M-mutated diffuse midline glioma following disease progression after prior therapy.
- This represents the first FDA approval of a systemic therapy specifically for H3 K27M-mutant diffuse midline glioma, addressing a significant unmet medical need.
- Clinical trials demonstrated a 22% overall response rate with a median duration of response of 10.3 months among 50 patients with recurrent disease.
- The protease activator received multiple FDA designations including Priority Review, Orphan Drug, Rare Pediatric Disease, and Fast Track status.last yearFDA Grants Priority Review to Dordaviprone for Recurrent H3 K27M-Mutant Diffuse Glioma• The FDA has accepted and granted priority review to Chimerix's new drug application for dordaviprone, a treatment for recurrent H3 K27M-mutant diffuse glioma.
• Dordaviprone, a first-in-class imipridone, targets mitochondrial protease ClpP and DRD2, offering a novel approach to treating this aggressive brain cancer.
• The FDA has set a PDUFA target action date of August 18, 2025, and does not currently plan to hold an advisory committee meeting.
• Clinical data from pooled analyses showed a 20% overall response rate and a median duration of response of 11.2 months, supporting the application.last year