A Phase I, Multicenter, Open-Label, Dose-Escalation and Expansion, Safety, Pharmacokinetic, Pharmacodynamic, and Clinical Activity Study of Orally Administered AG-120 in Subjects With Advanced Hematologic Malignancies With an IDH1 Mutation
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 291
- 试验地点
- 30
- 主要终点
- Maximum Tolerated Dose and/or the recommended Phase II dose of AG-120 in subjects with advanced hematologic malignancies.
研究概览
简要总结
The purpose of this Phase I, multicenter study is to evaluate the safety, pharmacokinetics, pharmacodynamics and clinical activity of AG-120 in advanced hematologic malignancies that harbor an IDH1 mutation. The first portion of the study is a dose escalation phase where cohorts of patients will receive ascending oral doses of AG-120 to determine maximum tolerated dose (MTD) and/or the recommended Phase II dose. The second portion of the study is a dose expansion phase where four cohorts of patients will receive AG-120 to further evaluate the safety, tolerability, and clinical activity of the recommended Phase II dose. Additionally, the study includes a substudy evaluating the safety and tolerability, clinical activity, pharmacokinetics, and pharmacodynamics of AG-120 in subjects with relapsed or refractory myelodysplastic syndrome with an IDH1 mutation. Anticipated time on study treatment is until disease progression or unacceptable toxicity occurs.
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
- •Subject must be ≥18 years of age.
- •Subjects must have documented IDH1 R132 gene-mutated advanced hematologic malignancy based on local or central evaluation.
- •Subjects must be amenable to serial bone marrow biopsies, peripheral blood sampling, and urine sampling during the study.
- •Subjects must have ECOG PS of 0 to
- •Platelet count ≥20,000/µL (Transfusions to achieve this level are allowed).
- •Subjects must have adequate hepatic function as evidenced by: Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤3.0 × ULN, unless considered due to leukemic disease and serum total bilirubin ≤1.5 x upper limit of normal (ULN), unless considered due to Gilbert's disease or leukemic disease
- •Subjects must have adequate renal function as evidenced by a serum creatinine ≤2.0 × ULN or creatinine clearance >40mL/min based on Cockroft-Gault glomerular filtration rate (GFR)
- •Subjects must be recovered from any clinically relevant toxic effects of any prior surgery, radiotherapy, or other therapy intended for the treatment of cancer.
- •Female subjects with reproductive potential must have a negative serum pregnancy test within 7 days prior to the start of therapy and on the first day of study drug administration.
排除标准
- •Subjects who have undergone hematopoietic stem cell transplant (HSCT) within 60 days of the first dose of AG-120, or subjects on immunosuppressive therapy post HSCT at the time of screening, or with clinically significant graft-versus-host disease (GVHD). (The use of a stable dose of oral steroids post HSCT and/or topical for ongoing skin GVHD is permitted.)
- •Subjects who received systemic anticancer therapy or radiotherapy <14 days prior to their first day of study drug administration. (Hydroxyurea is allowed prior to enrollment and after the start of AG-120).
- •Subjects who received an investigational agent <14 days prior to their first day of study drug administration.
- •Subjects who are pregnant or breastfeeding.
- •Subjects with an active severe infection or with an unexplained fever >38.5°C during screening visits or on their first day of study drug administration (at the discretion of the Investigator, subjects with tumor fever may be enrolled).
- •Subjects with New York Heart Association (NYHA) Class III or IV congestive heart failure or LVEF <40% by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan within approximately 28 days of C1D
- •Subjects with a history of myocardial infarction within the last 6 months of screening.
- •Subjects with a known unstable or uncontrolled angina pectoris.
- •Subjects with a known history of severe and/or uncontrolled ventricular arrhythmias.
- •Subjects with known unstable or uncontrolled angina pectoris.
- •Subjects with heart-rate corrected QT (QTc) interval ≥450 ms or other factors that increase the risk of QT prolongation or arrhythmic events.
- •Patients taking medications that are known to prolong the QT interval
- •Subjects with known infection with human immunodeficiency virus (HIV) or active hepatitis B or C.
- •Subjects with clinical symptoms suggesting active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid is only required if there is a clinical suspicion of CNS involvement by leukemia during screening.
- •Subjects with immediately life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, and/or disseminated intravascular coagulation.
研究组 & 干预措施
AG-120
AG-120 administered continuously as a single agent dosed orally every day of a 28-day cycle.
干预措施: AG-120 (Drug)
结局指标
主要结局
Maximum Tolerated Dose and/or the recommended Phase II dose of AG-120 in subjects with advanced hematologic malignancies.
时间窗: up to 26 weeks, on average
Assess clinical activity of AG-120 in subjects with relapsed or refractory AML who are enrolled in the Expansion Phase.
时间窗: up to 26 weeks, on average
Safety/tolerability: incidence of adverse events.
时间窗: up to 26 weeks, on average
Safety/tolerability of treatment with AG-120 in subjects with relapsed or refractory myelodysplastic syndrome.
时间窗: up to 26 weeks, on average
Assess clinical activity of AG-120 in subjects with relapsed or refractory myelodysplastic syndrome.
时间窗: up to 26 weeks, on average
次要结局
- Pharmacokinetics of AG-120 in subjects with advanced hematologic malignancies.(up to 26 weeks, on average)
- Serial blood sampling at specified time points for determination of plasma concentration-time profiles and PK parameters (Tmax) of AG-120 in subjects with R/R MDS.(up to 26 weeks, on average)
- Serial blood sampling at specified time points for determination of plasma concentration-time profiles and PK parameters (AUC) of AG-120 in subjects with R/R MDS.(up to 26 weeks, on average)
- Pharmacodynamic relationship of AG-120 and 2-HG.(up to 26 weeks, on average)
- Clinical Activity of AG-120 in advanced hematologic malignancies according to the 2003 revised IWG criteria for AML or the 2006 modified IWG criteria for MDS or MDS/myeloproliferative neoplasms (MPN).(up to 26 weeks, on average)
- Dose Limiting Toxicities of AG-120 in subjects with advanced hematologic malignancies.(up to 26 weeks, on average)
- Serial blood sampling at specified time points for determination of plasma concentration-time profiles and PK parameters (Cmax) of AG-120 in subjects with R/R MDS.(up to 26 weeks, on average)
- Blood and bone marrow sampling at specified time points for determination of 2-HG levels to characterize the percent of 2-HG inhibition of AG-120 in plasma and bone marrow.(up to 26 weeks, on average)