A Phase 1b/2a, Open-label, Non-randomized Study of Birinapant in Combination With 5-azacitidine in Subjects With Myelodysplastic Syndrome Who Are Naïve, Refractory or Have Relapsed to 5-azacitidine Therapy
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 21
- 试验地点
- 7
- 主要终点
- Maximum tolerated dose (MTD)
研究概览
简要总结
This is a dose escalation followed by dose expansion study of TL32711 in combination with 5-Azacitidine in subjects with Myelodysplastic syndrome who are naïve, have relapsed or have failed prior 5-azacitidine therapy. Pre-clinical and mechanistic studies support that 5-Azacitidine may modulate pathways that enable birinapant-mediated anti-tumor activity.
详细描述
This is a Phase 1b/2a, open-label, non-randomized study in male and female subjects with MDS who are naïve, refractory or have relapsed to 5-Azacitidine therapy.
Primary Objective is to determine the maximum tolerated dose (MTD), recommended Phase 2 dose, and pharmacodynamics (PD) of birinapant (TL32711) when administered in combination with 5-azacitidine (5 AZA) in subjects with myelodysplastic syndrome (MDS) who are naïve, refractory or have relapsed to 5-AZA therapy.
Secondary Objectives are to determine the clinical activity using the International Working Group (IWG) (Cheson, 2006) Response Criteria for MDS during the Phase 1b dose escalation stage of the study and in the Phase 2a expansion cohort, to determine the pharmacokinetics (PK) of birinapant when administered with 5-AZA in plasma and to assess exploratory translational biomarkers of anti-tumor activity of birinapant in combination therapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •Men or women more than 18 years of age.
- •Patients with high-risk Myelodysplastic Syndrome
- •Performance status of greater or equal to 2 by the Eastern Cooperative Oncology Group (ECOG) scale.
- •Subjects with high-risk MDS who are naïve to 5-Azacitidine or have previously received 5-AZA or decitabine as first-line cytotoxic therapy. Subjects with prior 5-Azacitidine therapy were evaluated to be either refractory or relapsed as determined by the Investigator, according to IWG response criteria.Subjects with relapsed or refractory disease may have only received prior 5-Azacitidine or decitabine.
- •Hydroxyurea for patients with rapidly proliferative disease can be used up to 24 hours prior to therapy but not concomitantly with 5-Azacitidine.
- •Adequate liver, pancreatic and renal function.
- •Women of childbearing potential must have a negative serum pregnancy test at screening within 48 hours prior to the first dose
- •Women of childbearing potential must agree to use 2 methods of adequate contraception
排除标准
- •Subjects with life-threatening toxicity or non tolerability to prior 5-Azacitidine therapy.
- •Subjects with hypoplastic Myelodysplastic syndrome.
- •Subjects with >30% bone marrow blast cells.
- •Subjects with malignant hepatic tumors or secondary malignancy within 2 years
- •Known diagnosis of human immunodeficiency virus or chronic active Hepatitis B or C.
- •Uncontrolled hypertension
- •Impaired cardiac function, uncontrolled cardiac arrhythmias despite medications,
- •QT interval corrected for heart rate (QTcB) more than 480 msec
- •Lack of recovery of prior adverse events to Grade ≤1 severity (National Cancer Institute Common Terminology Criteria for Adverse Events version 4) (except alopecia) due to therapy administered prior to the initiation of study drug dosing.
- •Nursing or pregnant women.
- •Known allergy to any of the formulation components of birinapant.
- •Known or suspected hypersensitivity to 5-Azacitidine or mannitol.
- •Any concurrent disease and/or medical condition that, in the opinion of the Investigator, would prevent the subject's participation.
- •History of Bell's Palsy.
研究组 & 干预措施
Treatment
5-Azacitidine plus birinapant
干预措施: Birinapant (Drug)
Treatment
5-Azacitidine plus birinapant
干预措施: 5-Azacitidine (Drug)
结局指标
主要结局
Maximum tolerated dose (MTD)
时间窗: 6 months
次要结局
未报告次要终点