A Phase 1b/2 Study of the BCL-2 Inhibitor Venetoclax in Combination With Standard Intensive AML Induction/Consolidation Therapy With FLAG-IDA in Patients With Newly Diagnosed or Relapsed/Refractory AML
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 116
- 试验地点
- 1
- 主要终点
- Overall response rate (ORR)
研究概览
简要总结
This phase Ib/II trial studies the best dose and side effects of venetoclax and how well it works when given with combination chemotherapy in treating patients with newly diagnosed acute myeloid leukemia or acute myeloid leukemia that has come back or does not respond to treatment. Venetoclax may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fludarabine, cytarabine, filgrastim and idarubicin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving venetoclax together with combination chemotherapy may work better in treating patients with acute myeloid leukemia.
详细描述
PRIMARY OBJECTIVES:
I. To evaluate the safety and tolerability and to determine the dose-limiting toxicity and the maximum tolerated dose MTD of the combination of fludarabine, cytarabine, filgrastim (GCSF), idarubicin (FLAG-IDA) + venetoclax for patients with acute myeloid leukemia (AML) (Phase 1b).
II. To determine the overall activity of this combination in patients newly diagnosed or relapsed/refractory (AML) (Phase 2).
SECONDARY OBJECTIVES:
I. Determine the preliminary assessment of efficacy by response to revised International Working Group (IWG) criteria and time to response variables including overall survival (OS), event-free survival (EFS) and duration of response (DOR).
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
- •Diagnosis of AML by World Health Organization (WHO) criteria. Patients with high risk myelodysplastic syndrome (MDS) as defined by the presence of >= 10% blasts are also eligible at the discretion of the principal investigator
- •Patients older than 65 who are deemed fit to receive intensive chemotherapy by the treating physician will be eligible after discussion with the principal investigator (PI).
- •Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
- •Creatinine clearance >= 30 mL/min based on the Cockcroft-Gault equation
- •Total bilirubin < 1.5 x upper limit of normal (ULN) unless increase is due to Gilbert's disease or leukemic involvement
- •Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) < 3 x ULN unless considered due to leukemic involvement
- •Ability to understand and provide signed informed consent
- •Male subjects must agree to refrain from unprotected sex and sperm donation from initial study drug administration until 90 days after the last dose of study drug
- •Only patients who are relapsed, refractory, or intolerant of standard AML therapy will be eligible for Part 1 (minimum of 1 prior line of AML-directed therapy)
排除标准
- •Patients with t(15;17) karyotypic abnormality or acute promyelocytic leukemia (French-American-British [FAB] class M3-AML)
- •Patients having received any prior BCL2 inhibitor therapy
- •Subject has known active central nervous system (CNS) involvement with AML
- •Patients with New York Heart Association (NYHA) class III or IV congestive heart failure or left ventricular ejection fraction (LVEF) < 40% by echocardiogram or multi-gated acquisition (MUGA) scan
- •Patients with a history of myocardial infarction within the last 6 months or unstable / uncontrolled angina pectoris or history of severe and/or uncontrolled ventricular arrhythmias
- •Patients with known infection with human immunodeficiency virus (HIV) or active hepatitis B or C
- •Patients with known dysphagia, short-gut syndrome, or other conditions that would affect the ingestion or gastrointestinal absorption of drugs administered orally
- •Subject has any other significant medical or psychiatric history that in the opinion of the investigator would adversely affect participation in this study
- •Subject has a white blood cell count > 25 x 10{9}/L. (Note: hydroxyurea is permitted to meet this criterion)
- •Nursing women, women of childbearing potential (WOCBP) with positive urine pregnancy test, or women of childbearing potential who are not willing to maintain adequate contraception (a) appropriate method(s) of contraception include oral or injectable hormonal birth control, intrauterine device (IUD), and double barrier methods (for example a condom in combination with a spermicide)
研究组 & 干预措施
Treatment (venetoclax, FLAG-IDA)
See detailed description.
干预措施: Filgrastim (Biological)
Treatment (venetoclax, FLAG-IDA)
See detailed description.
干预措施: Fludarabine (Drug)
Treatment (venetoclax, FLAG-IDA)
See detailed description.
干预措施: Idarubicin (Drug)
Treatment (venetoclax, FLAG-IDA)
See detailed description.
干预措施: Pegfilgrastim (Biological)
Treatment (venetoclax, FLAG-IDA)
See detailed description.
干预措施: Cytarabine (Drug)
Treatment (venetoclax, FLAG-IDA)
See detailed description.
干预措施: Venetoclax (Drug)
结局指标
主要结局
Overall response rate (ORR)
时间窗: Up to 6 years
Defined as complete response (CR) + CR with incomplete blood count recovery (CRi) + partial response (PR). Will be estimated along with the 95% credible interval.
CR/CRi rate
时间窗: Up to 6 years
Will be estimated along with the 95% credible interval.
Hematologic response
时间窗: Up to 6 years
Will be estimated along with the 95% credible interval.
Duration of response
时间窗: From the date of initial response, assessed up to 6 years
Defined as the number of days from the date of initial response (PR or better) to the date of first documented disease progression/relapse or death, whichever occurs first. Will be calculated for all patients.
Event-free survival
时间窗: From the date of treatment initiation, assessed up to 6 years
Defined as the number of days from the date of treatment initiation (i.e., course 1 day 1) to the date of documented treatment failure, relapses from CR, or death from any cause, whichever occurs first. Will be calculated for all patients. Estimated using Kaplan-Meier method. Log-rank tests will be used to compare among subgroups of patients.
Overall survival
时间窗: Up to 6 years
Estimated using Kaplan-Meier method. Log-rank tests will be used to compare among subgroups of patients.
Anti-tumor activity
时间窗: Up to 6 years
Will be summarized graphically and with descriptive statistics.
Pharmacodynamic markers
时间窗: Up to 6 years
Two samples t-test /Wilcoxon rank sum tests will be used to compare pharmacodynamics/pharmacokinetics (PD/PK) parameters between responder and non-responders, and logistic regression analysis will also be used to evaluate the association of PD/PK parameters with response.
Drug exposure levels
时间窗: Up to 6 years
Will be summarized graphically and with descriptive statistics.
Overall incidence and severity of all adverse events
时间窗: Up to 6 years
Graded using Common Toxicity Criteria version 4.0. Safety data will be summarized using frequency and percentage, by category and severity.
次要结局
- Morphologic leukemia-free state(Up to 6 years)