A Multicenter, Randomized, Controlled Clinical Trial of Venetoclax, Azacytidine Combined With Chidamide for the Treatment of Newly Diagnosed Acute Monocytic Leukemia Patients That Are Ineligible for Intensive Chemotherapy
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 92
- 试验地点
- 1
- 主要终点
- Composite Complete Remission Rate
研究概览
简要总结
This study is to investigate the therapeutic efficacy and side effect of venetoclax, azacytidine combined with chidamide for newly diagnosed acute monocytic leukemia patients that are ineligible for intensive chemotherapy
详细描述
Acute myeloid leukemia (AML) is one of the most aggressive blood cancers, with a very low survival rate and few options for patients who are unable to undergo intensive chemotherapy. Venetoclax in combination with hypomethylation agents or cytarabine has been approved by the Food and Drug Administration (FDA) for the treatment of patients with newly diagnosed AML unfit for intensive chemotherapy. However, resistance to venetoclax can be acquired through the upregulation of anti-apoptotic proteins in the BCL2 family, such as myeloid cell leukaemia 1 (MCL1). MCL1 plays a critical role in cell apoptosis regulation and high expression of MCL1 is observed in acute monocytic leukemia (AML-M5) . Chidamide, a newly designed selective histone deacetylase inhibitor, resulted in a decrease in the protein level of MCL1. This study is to investigate the therapeutic efficacy and side effect of venetoclax, azacytidine combined with chidamide for newly diagnosed AML-M5 patients that are ineligible for intensive chemotherapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 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
- •Confirmation of acute monocytic leukemia( AML-M5) diagnosis by the French-American-British (FAB) Classification and/or characterized for expression of monocytic and myeloid differentiation markers, have a projected life expectancy of at least 12 weeks, previously untreated, and ineligible for treatment with intensive chemotherapy.
- •Patients must be considered ineligible for induction therapy defined by the following:
- •>= 60 years of age
- •>=18 to 59years of age with at least one of the following comorbidities:
- •Any other comorbidity that the physician judges to be incompatible with intensive chemotherapy:
- •(A)Eastern Cooperative Oncology Group (ECOG) performance status of 2 or
- •(B)Cardiac history of congestive heart failure requiring treatment or ejection fraction <= 50% or chronic stable angina.
- •(C)Diffusing capacity of the lung for carbon monoxide (DLCO) <= 65% or forced expiratory volume during the first second (FEV1) <= 65%.
- •(D)Creatinine clearance >= 30 mL/min to < 45 mL/min. (E)Moderate hepatic impairment with total bilirubin > 1.5 to <= 3.0 × upper limit of normal (ULN).
- •Must meet the laboratory requirements per the protocol.
- •Female participant must not be pregnant or breastfeeding and is not considering becoming pregnant or donating eggs during the study or for approximately 90 days after the last dose of study drug.
- •Female participants of childbearing potential must agree to use at least 1 protocol-specified method of birth control and male participants, if sexually active with female partner(s) of childbearing potential, must agree to practice the protocol-specified contraception.
- •Did not receive radiotherapy, chemotherapy, targeted therapy or hematopoietic stem cell transplantation within 4 weeks before enrollment;
- •Other comorbidities that are not suitable for intensive chemotherapy;
- •The patient refused to receive intensive chemotherapy;
- •Ability to understand and willing to sign the informed consent for this trial.
排除标准
- •Patients who are allergic to the study drug or drugs with similar chemical structures
- •Pregnant or lactating women, and women of childbearing age who do not want to practice effective methods of contraception
- •Active infection
- •Active bleeding
- •Patients with new thrombosis, embolism, cerebral hemorrhage, or other diseases or a medical history within one year before enrollment
- •Patients with mental disorders or other conditions whereby informed consent cannot be obtained and where the requirements of the study treatment and procedures cannot be met
- •Liver function abnormalities (total bilirubin > 1.5 times the upper limit of the normal range, ALT/AST > 2.5 times the upper limit of the normal range or patients with liver involvement whose ALT/AST > 1.5 times the upper limit of the normal range), or renal anomalies (serum creatinine > 1.5 times the upper limit of the normal value)
- •Patients with a history of clinically significant QTc interval prolongation (male > 450 ms; female > 470 ms), ventricular heart tachycardia and atrial fibrillation, II-degree heart block, myocardial infarction attack within one year before enrollment, and congestive heart failure, and patients with coronary heart disease who have clinical symptoms and requiring drug treatment
- •Urgery on the main organs within the past six weeks
- •Drug abuse or long-term alcohol abuse that would affect the evaluation results
- •Patients who have received organ transplants (excepting bone marrow transplantation)
- •Patients not suitable for the study according to the investigator's assessment
研究组 & 干预措施
VAC group
Chidamide 10mg orally daily for 7 days (d1-d7), AZA 75mg/m2 daily for 7 days (d1-d7) and VEN orally once daily (100 mg d1, 200 mg d2, 400 mg d3-28); If the bone marrow assessment is CR/CRi/MLFS/PR/NR on the 21th-28th day in the first cycle, the second cycle of treatment will be started; If the bone marrow assessment is PR/NR, the patient needs to withdraw from the trial, If the bone marrow assessment is CR/CRi/MLFS, the patient will start post-remission therapy. For post-remission therapy, if the patients ineligible for intensive chemotherapy, continue with the same regimen until progression or recurrence of the disease, and the patients need to withdraw from the trial. If the patients were fit for intensive chemotherapy, patients will receive consolidation chemotherapy with other regimens or transplantation, and the patients needs to withdraw from the trial if progression or recurrence of the disease.
干预措施: Chidamide (Drug)
VAC group
Chidamide 10mg orally daily for 7 days (d1-d7), AZA 75mg/m2 daily for 7 days (d1-d7) and VEN orally once daily (100 mg d1, 200 mg d2, 400 mg d3-28); If the bone marrow assessment is CR/CRi/MLFS/PR/NR on the 21th-28th day in the first cycle, the second cycle of treatment will be started; If the bone marrow assessment is PR/NR, the patient needs to withdraw from the trial, If the bone marrow assessment is CR/CRi/MLFS, the patient will start post-remission therapy. For post-remission therapy, if the patients ineligible for intensive chemotherapy, continue with the same regimen until progression or recurrence of the disease, and the patients need to withdraw from the trial. If the patients were fit for intensive chemotherapy, patients will receive consolidation chemotherapy with other regimens or transplantation, and the patients needs to withdraw from the trial if progression or recurrence of the disease.
干预措施: Azacitidine (Drug)
VAC group
Chidamide 10mg orally daily for 7 days (d1-d7), AZA 75mg/m2 daily for 7 days (d1-d7) and VEN orally once daily (100 mg d1, 200 mg d2, 400 mg d3-28); If the bone marrow assessment is CR/CRi/MLFS/PR/NR on the 21th-28th day in the first cycle, the second cycle of treatment will be started; If the bone marrow assessment is PR/NR, the patient needs to withdraw from the trial, If the bone marrow assessment is CR/CRi/MLFS, the patient will start post-remission therapy. For post-remission therapy, if the patients ineligible for intensive chemotherapy, continue with the same regimen until progression or recurrence of the disease, and the patients need to withdraw from the trial. If the patients were fit for intensive chemotherapy, patients will receive consolidation chemotherapy with other regimens or transplantation, and the patients needs to withdraw from the trial if progression or recurrence of the disease.
干预措施: Venetoclax (Drug)
VA group
AZA 75mg/m2 daily for 7 days (d1-d7) and VEN orally once daily (100 mg d1, 200 mg d2, 400 mg d3-28); If the bone marrow assessment is CR/CRi/MLFS/PR/NR on the 21th-28th day in the first cycle, the second cycle of treatment will be started; If the bone marrow assessment is still PR/NR, the patient needs to enter VEN+AZA+Chidamide group. If the bone marrow assessment is CR/CRi/MLFS, the patient will start post-remission therapy. For post-remission therapy, if the patients ineligible for intensive chemotherapy, continue with the same regimen until progression or recurrence of the disease, and the patient needs to withdraw from the trial. If the patients fit for intensive chemotherapy, patients will receive consolidation chemotherapy with other regimens or transplantation, and the patient needs to withdraw from the trial if progression or recurrence of the disease.
干预措施: Azacitidine (Drug)
VA group
AZA 75mg/m2 daily for 7 days (d1-d7) and VEN orally once daily (100 mg d1, 200 mg d2, 400 mg d3-28); If the bone marrow assessment is CR/CRi/MLFS/PR/NR on the 21th-28th day in the first cycle, the second cycle of treatment will be started; If the bone marrow assessment is still PR/NR, the patient needs to enter VEN+AZA+Chidamide group. If the bone marrow assessment is CR/CRi/MLFS, the patient will start post-remission therapy. For post-remission therapy, if the patients ineligible for intensive chemotherapy, continue with the same regimen until progression or recurrence of the disease, and the patient needs to withdraw from the trial. If the patients fit for intensive chemotherapy, patients will receive consolidation chemotherapy with other regimens or transplantation, and the patient needs to withdraw from the trial if progression or recurrence of the disease.
干预措施: Venetoclax (Drug)
结局指标
主要结局
Composite Complete Remission Rate
时间窗: At the end of Cycle 1 or 2 (each cycle is 28 days)
The composite complete remission rate(complete remission plus complete remission with incomplete blood cell count recovery)
Overall response rate (ORR)
时间窗: At the end of Cycle 1 or 2 (each cycle is 28 days)
The overall response (completed remission without minimal residual disease, completed remission with incomplete blood count recovery, morphologic leukemia-free state and partial remission)
次要结局
- Overall Survival (OS)(1 year)
- Adverse reactions in hematology(At the end of Cycle 1 (each cycle is 28 days))
- Duration of Response (DOR)(1 year)
- Progression-Free Survival (PFS)(1 year)
- Nonhematological adverse reactions(At the end of Cycle 1 (each cycle is 28 days))
研究者
Sheng-Li Xue, MD
Principal Investigator
The First Affiliated Hospital of Soochow University