Phase I Study of APR-246 in Combination With Venetoclax and Azacitidine in TP53-Mutant Myeloid Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 51
- 试验地点
- 8
- 主要终点
- To Evaluate the Tolerabililty and the Incidence of Treatment-Emergent Adverse Events of Administration of APR 246 in Combination With Venetoclax and Azacitidine in Patients With TP53 Mutant Myeloid Malignancies.
研究概览
简要总结
This clinical trial is a Phase I, open-label, dose-finding and cohort expansion study to determine the safety and preliminary efficacy of APR-246 in combination with venetoclax and azacitidine in patients with myeloid malignancies.
详细描述
This study will enroll adult male and female patients of age ≥ 18 years with documented diagnosis of AML, according to WHO classification, and documented TP53 mutation which is not benign or likely benign, who also meet the eligibility requirements of this protocol.
The study will include a safety lead-in dose-finding portion followed by expansion portion. During the safety lead-in portion of the study, two cohorts will independently enroll patients following a 3 + 3 design. Each cohort will enroll up to 6 patients.
The expansion portion will begin once the recommended phase II dose (RP2D) of APR-246 in combination with venetoclax and in combination with venetoclax and azacitidine have been determined in order to assess the antitumor activity of these combinations.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 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
- •Signed informed consent and ability to comply with protocol requirements.
- •Documented diagnosis of AML according to World Health Organization WHO) classification
- •Adequate organ function as defined by the following laboratory values:
- •Creatinine clearance > 30 mL/min
- •Total serum bilirubin < 1.5 × ULN
- •Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3 × ULN
- •Age ≥18 years
- •At least one TP53 mutation
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
- •Projected life expectancy of ≥ 12 weeks.
- •Negative serum or urine pregnancy test
- •Females of childbearing potential and males with female partners of childbearing potential must be willing to use an effective form of contraception
排除标准
- •Prior treatment for TP53-mutant AML (*dependent upon treatment arm assigned).
- •Known history of HIV or active hepatitis B or active hepatitis C infection.
- •Any of the following cardiac abnormalities:
- •Myocardial infarction within six months prior to registration;
- •New York Heart Association Class III or IV heart failure or known left ventricular ejection fraction (LVEF) < 40%;
- •A history of familial long QT syndrome;
- •Symptomatic atrial or ventricular arrhythmias
- •QTcF ≥ 470 msec, unless due to underlying bundle branch block and/or pacemaker and with approval of the medical monitor.
- •Concomitant malignancies for which patients are receiving active therapy
- •Known active CNS involvement from AML.
- •Malabsorption syndrome
- •Pregnancy or lactation.
- •Active uncontrolled systemic infection (viral, bacterial or fungal).
研究组 & 干预措施
APR-246
APR-246 4.5 g/day
干预措施: APR-246 (Drug)
APR-246
APR-246 4.5 g/day
干预措施: Venetoclax (Drug)
APR-246
APR-246 4.5 g/day
干预措施: Azacitidine (Drug)
结局指标
主要结局
To Evaluate the Tolerabililty and the Incidence of Treatment-Emergent Adverse Events of Administration of APR 246 in Combination With Venetoclax and Azacitidine in Patients With TP53 Mutant Myeloid Malignancies.
时间窗: From baseline until event occures, i.e. through study completion, an average of 1 year
2. Frequency of treatment-emergent adverse events (TEAEs), and serious adverse events (SAEs) related to APR-246 in combination with venetoclax and azacitidine during the trial.
次要结局
未报告次要终点