A Phase 1, Safety Lead-In and Randomized, Open-label, Perioperative Study of Vorasidenib in Combination With Pembrolizumab in Subjects With Recurrent or Progressive IDH-1 Mutant Glioma
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 60
- 试验地点
- 33
- 主要终点
- Safety Lead-in Phase: Percentage of Participants With Dose-limiting Toxicities (DLTs)
研究概览
简要总结
Vorasidenib in combination with pembrolizumab in participants with recurrent or progressive isocitrate dehydrogenase-1 (IDH-1) mutant Glioma.
详细描述
The study is divided into 2 phases, a Safety Lead-In phase and a randomized perioperative phase. In the Safety Lead-In Phase, the recommended combination dose (RCD) of vorasidenib will be determined. In the Randomized Perioperative Phase, the Lymphocytes infiltration in tumors will be evaluated following pre-surgical treatment with vorasidenib and pembrolizumab combination, compared to untreated control tumors. Prior to surgery, participants will be randomized to receive vorasidenib at the RCD in combination with pembrolizumab, or vorasidenib only, or no treatment (untreated control group). Following surgery, participants will have the option to receive treatment with vorasidenib in combination with pembrolizumab in 21-day cycles.
Study treatment will be administered until participant experiences unacceptable toxicity, disease progression, or other discontinuation criteria are met.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Have Karnofsky Performance Status (KPS) of ≥ 70%.
- •Have expected survival of ≥ 3 months.
- •Have histologically confirmed Grade 2 or Grade 3 glioma (per the 2016 or 2021 World Health Organization [WHO] Classification of Tumors of the central nervous system)
- •Documented IDH1-R132H gene mutation; and
- •For Astrocytomas: Absence of 1p19q co-deletion (i.e., exclusion of combined whole-arm deletions of 1p and 19q) and/or documented loss of nuclear ATRX expression or ATRX mutation by local testing. For Oligodendrogliomas: Presence of 1p19q co-deletion (i.e., combined whole-arm deletions of 1p and 19q) by local testing.
- •Have measurable, magnetic resonance imaging (MRI)-evaluable, unequivocal contrast enhancing disease as determined by institutional radiologist/Investigator at Screening on either 2D T1 post-contrast weighted images or 3D T1 post-contrast weighted images. Per mRANO criteria, measurable lesion is defined as at least 1 enhancing lesion measuring ≥ 1 cm x ≥ 1 cm. OR (in the absence of measurable enhancing disease) measurable, MRI-evaluable, unequivocal non enhancing disease as determined by institutional radiologist/Investigator at Screening on either 2D or 3D T2-weighted image or FLAIR. Per RANO 2.0 criteria, measurable lesion is defined as at least 1 non enhancing lesion measuring ≥ 1 cm × ≥ 1 cm.
- •Have recurrent or progressive disease and received prior treatment with chemotherapy, radiation, or both.
- •Surgical resection is indicated for treatment, but surgery is not urgently indicated (e.g., for whom surgery within the next 6-9 weeks is appropriate). (NOTE: This criterion only applies to participants enrolled in the perioperative phase of the study. Participants in the Safety Lead-In should not require surgery).
排除标准
- •Have received prior systemic anti-cancer therapy within 1 month of the first dose of IMP, radiation within 12 months of the first dose of IMP, or an investigational agent < 14 days prior to the first dose of IMP. In addition, the first dose of IMP should not occur before a period of ≥ 5 half-lives of the investigational agent has elapsed.
- •Have received 2 or more courses of radiation.
- •Have received any prior treatment with an isocitrate dehydrogenase (IDH) inhibitor; anti-programmed cell death 1 (PD1), anti-programmed cell death ligand 1 (PD-L1), or anti-PD-ligand 2 (L2) agent, or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137); any other checkpoint inhibitor; bevacizumab; or any prior vaccine therapy.
- •Note: Other inclusion and exclusion criteria may apply.
研究组 & 干预措施
Safety Lead-In Phase: Vorasidenib + Pembrolizumab
Participants will receive vorasidenib orally, once daily (QD) in combination with pembrolizumab 200 mg intravenous (IV) infusion, once every 3 weeks (Q3W) in each 21-day cycle until disease progression, unacceptable toxicity or other discontinuation criteria are met.
干预措施: Vorasidenib (Drug)
Safety Lead-In Phase: Vorasidenib + Pembrolizumab
Participants will receive vorasidenib orally, once daily (QD) in combination with pembrolizumab 200 mg intravenous (IV) infusion, once every 3 weeks (Q3W) in each 21-day cycle until disease progression, unacceptable toxicity or other discontinuation criteria are met.
干预措施: Pembrolizumab (Drug)
Randomized Perioperative Phase: Vorasidenib + Pembrolizumab
Participants will receive vorasidenib recommended combination dose (RCD) determined in the Safety Lead-in phase, orally, QD from Day 1 to 28 in combination with pembrolizumab 200 mg IV infusion, Q3W on Days 1 and 22 of a 28-day cycle prior to surgery.
干预措施: Vorasidenib (Drug)
Randomized Perioperative Phase: Vorasidenib + Pembrolizumab
Participants will receive vorasidenib recommended combination dose (RCD) determined in the Safety Lead-in phase, orally, QD from Day 1 to 28 in combination with pembrolizumab 200 mg IV infusion, Q3W on Days 1 and 22 of a 28-day cycle prior to surgery.
干预措施: Pembrolizumab (Drug)
Randomized Perioperative Phase: Vorasidenib Only
Participants will receive vorasidenib orally, QD from Day 1 to 28 of a 28-day cycle prior to surgery.
干预措施: Vorasidenib (Drug)
Randomized Perioperative Phase: Untreated Control Group
Participants will not receive any treatment prior to surgery.
结局指标
主要结局
Safety Lead-in Phase: Percentage of Participants With Dose-limiting Toxicities (DLTs)
时间窗: First 21 days of dosing (Cycle 1) in safety lead-in phase
Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
时间窗: approximately up to 19 months
Percentage of Tumor-infiltrating Lymphocyte (TIL) Cells in Surgically Resected Tumors Following Treatment With Vorasidenib + Pembrolizumab Compared to Untreated Control Tumors
时间窗: approximately 2 months
TIL is defined as the percentage of tumor-infiltrating lymphocyte cells on a logarithmic scale.
次要结局
- AUC: Area Under the Plasma Concentration-Time Curve of Vorasidenib(approximately 16 months)
- Concentration of 2-hydroxygluarate (2-HG) in Surgically Resected Tumors(approximately 2 months)
- Concentration of Vorasidenib in Surgically Resected Tumors(approximately 2 months)
- Clinical Activity Associated With Vorasidenib in Combination With Pembrolizumab According to Modified Response Assessment in Neuro-oncology (mRANO) Criteria(Up to approximately 16 months)
- Overall Survival (OS)(Up to approximately 55 months)
- Time to response(Up to approximately 55 months)
- Cmax: Maximum Observed Plasma Concentration of Vorasidenib(approximately 16 months)