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Clinical Research for Azacitidine Combined With Low-dose Dasatinib in Maintenance Therapy of Acute Myeloid Leukemia

2022年4月21日 更新者：Bei Liu、LanZhou University
This project is a prospective, single-center study to evaluate the efficacy, safety and related mechanisms of azacitidine combined with low-dose dasatinib in maintenance therapy in patients with intermediate and high-risk acute myeloid leukemia(AML). The patients were randomly divided into azacitidine group and azacitidine combined with low-dose dasatinib group. The overall survival and disease-free survival were taken as the main end points, and the mortality and recurrence rate were taken as the secondary end points, meanwhile, the incidence of adverse events were evaluated. At the same time, the mRNA expressions of DNA methyltransferase (DNMT1, DNMT3a, DNMT3b), tumor suppressor genes (TP53, P15, P16, P21, CDH1, DOK6, SHP1, PTPN11) and differentiation genes (pu.1, C/EBP α, C/EBP β) were detected. Pyrophosphate sequencing was used to detect the methylation level of the promoter region of these tumor suppressor genes. Western Blot was used to detect apoptosis proteins (caspase3, caspase8) and phosphorylated proteins (pSTAT3, pSTAT5, pAKT). The proportion of apoptotic population of bone marrow cells was determined by flow cytometry. Therefore, the data in this study will reflect the efficacy and safety of azacitidine or azacitidine combined with low-dose dasatinib in real-world maintenance therapy in patients with medium and high-risk AML.

研究概览

地位

招聘中

条件

干预/治疗

详细说明

In addition to studying the overall survival, disease-free survival and recurrence rates, mortality and incidence of adverse events of patients treated with azacitidine or azacitidine combined with low-dose dasatinib, we will also study its related mechanisms. One of the pathogenesis of AML is that abnormal DNA methylation makes the cell cycle out of control and carcinogenesis by inhibiting the expression of tumor suppressor genes. In addition, the abnormal activation of tyrosine kinase signal pathway also promotes the development of leukemia. Azacitidine, the hypomethylating agents, can not only inhibit the DNA methyltransferase family, but also activate tumor suppressor genes to inhibit a variety of tyrosine kinase signaling pathways, including JAK-STAT. NaShen et al have directly demonstrated that tyrosine kinase inhibitors (TKIs) can not only inhibit the abnormal activation of tyrosine kinase pathway, but also reduce DNA methylation. This study found that the combination of the second generation TKIs and hypomethylating agents can reduce has a synergistic effect on promoting apoptosis and reducing DNA methylation. In addition, TKIs often produces drug resistance due to long exposure time, and the main mechanisms of drug resistance is due to DNA methylation and abnormal reactivation of tyrosine kinase signal pathway. The combination of TKI and azacitidine reduces DNA methylation and inhibits the reactivation of abnormal tyrosine kinase signal pathway, which is helpful to improve TKI drug resistance. Based on the above theory, we assume that patients treated with azacitidine and dasatinib may have more obvious demethylation effect, increased expression of tumor suppressive genes, more obvious apoptosis, and inhibition of phosphorylated protein expression.So we did the lab tests of these mechanisms.We innovatively used azacitidine and TKIs in the treatment of patients with AML maintenance, in order to reduce drug toxicity, enhance drug efficacy, improve patient prognosis and reduce the financial burden of patients.

研究类型

介入性

注册 (预期的)

30

阶段

  • 不适用

联系人和位置

本节提供了进行研究的人员的详细联系信息，以及有关进行该研究的地点的信息。

学习联系方式

学习地点

  • 中国
    • Gansu
      • Lanzhou、Gansu、中国、730000
        • 招聘中
        • The First Hospital of Lanzhou University
        • 副研究员：
          • Long Zhao
        • 副研究员：
          • Haizhen Ma
        • 副研究员：
          • Juan Cheng, MD
        • 接触：
        • 首席研究员：
          • Bei Liu, MD
        • 副研究员：
          • Jinli Jian
        • 副研究员：
          • Hao Zhang

参与标准

研究人员寻找符合特定描述的人，称为资格标准。这些标准的一些例子是一个人的一般健康状况或先前的治疗。

资格标准

适合学习的年龄

18年 及以上 (成人、年长者)

接受健康志愿者

不

有资格学习的性别

全部

描述

Inclusion Criteria:

  1. Patients with intermediate and high-risk AML who are diagnosed according to the 2016 WHO guidelines, aged ≥18 years;
  2. Detect minimal residual disease(-) after induction therapy and consolidation therapy;
  3. Eastern Cooperative Oncology Group (ECOG) performance status score 0-2;

  4. The heart, pulmonary, liver and kidneys have sufficient organ functions:

    1. Cardiac color doppler ultrasound shows cardiac ejection fraction> 50%, heart function classification NYHA III/IV, no heart block or arrhythmia;
    2. Patients without severe restrictive/obstructive pulmonary disease;
    3. Liver function: total bilirubin (TBIL) < 2 times the upper limit of normal, alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) <2.5 times the upper limit of normal;
    4. Renal function: serum creatinine (Cr) < 1.5 times the upper limit of normal.
  5. The patient and family members agree and sign an informed consent form.

Exclusion Criteria:

  1. Patients with malignant tumors of other organs;

  2. HCV positive; or HIV positive; or one of the following HBV test results:

    1. HBsAg positive;
    2. HBsAg negative, HBcAb positive and HBV DNA titer positive;
  3. Pregnant and lactating women, and patients who have family planning during the enrollment period;
  4. Patients considered to be unsuitable for enrollment by the investigator.

学习计划

本节提供研究计划的详细信息，包括研究的设计方式和研究的衡量标准。

研究是如何设计的？

设计细节

  • 主要用途：治疗
  • 分配：随机化
  • 介入模型：并行分配
  • 屏蔽：单身的

武器和干预

参与者组/臂
干预/治疗
实验性的：experimental group
Patients with intermediate and high risk AML were negative for minimal residual disease after intensive induction and consolidation chemotherapy,the patients were randomly divided into two groups, and one group was given azacitidine(75mg/m2, per day on day 1-7]. Dasatinib 100 mg p.o. qd was administered on days 1-28 of each consolidation cycle.
药品：Azacitidine
Azacitidine, 75mg/m2,d1-7;Treatment cycles every 28 days
药品：Dasatinib
dasatinib,20mg,po,qd,treatment cycles every 28 days
有源比较器：control group
Patients with intermediate and high risk AML were negative for minimal residual disease after intensive induction and consolidation chemotherapy,the patients were randomly divided into two groups, and the other group was given azacitidine(75mg/m2, per day on day 1-7)on days 1-28 of each consolidation cycle.
药品：Azacitidine
Azacitidine, 75mg/m2,d1-7;Treatment cycles every 28 days

研究衡量的是什么？

主要结果指标

结果测量
措施说明
大体时间
overall survival
大体时间：up to 30 months.
OS is defined as the time from the date of enrollment until the date of death from any cause.
up to 30 months.
disease-free survival
大体时间：up to 30 months.
Event-free survival is defined as the time from enrollment until documented refractory disease, relapse after complete remission(CR) or CR with incomplete recovery of blood counts(CRi), or death from any cause.
up to 30 months.

次要结果测量

结果测量
措施说明
大体时间
mortality
大体时间：mortality rate at 30 months.
The proportion of patients from enrollment to death was recorded.
mortality rate at 30 months.
recurrence rate
大体时间：recurrence rate at 30 months.
Record the proportion of patients with recurrence in the study.
recurrence rate at 30 months.
adverse events
大体时间：Adverse events were assessed weekly during the first and second cycles, and every two cycles thereafter (each cycle is 28 days), up to 30 months.
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0.
Adverse events were assessed weekly during the first and second cycles, and every two cycles thereafter (each cycle is 28 days), up to 30 months.
apoptotic protein and phosphorylated protein
大体时间：once before enrollment and once after the completion of the study, up to 30 months.
The relative expression of apoptotic protein(caspase3, caspase8) and phosphorylated protein(pSTAT3, pSTAT5, pAKT) were detected by western blot with bone marrow aspirate.
once before enrollment and once after the completion of the study, up to 30 months.
DNA methyltransferase, tumor suppressor genes and differentiation genes
大体时间：once before enrollment and once after the completion of the study, up to 30 months.
To detect the mRNA expression of DNA methyltransferase(DNMT1, DNMT3a, DNMT3b), tumor suppressor genes(TP53,P15, P16, P21, CDH1, DOK6, SHP1, PTPN11) and differentiation gene(pu.1, C/EBPα, C/EBPβ) with bone marrow aspirate by Q-PCR.
once before enrollment and once after the completion of the study, up to 30 months.
methylation level in the promoter region of some tumor suppressor genes.
大体时间：once before enrollment and once after the completion of the study, up to 30 months.
Detection of methylation level in the promoter region of the above tumor suppressor genes by pyrophosphate sequencing using patient bone marrow aspirate.
once before enrollment and once after the completion of the study, up to 30 months.
Percentage of bone marrow cell apoptosis population
大体时间：once before enrollment and once after the completion of the study, up to 30 months.
The percentage of apoptotic population of bone marrow cells was determined by flow cytometry.
once before enrollment and once after the completion of the study, up to 30 months.

合作者和调查者

在这里您可以找到参与这项研究的人员和组织。

赞助

LanZhou University

合作者

Beijing Health Alliance Charitable Foundation

出版物和有用的链接

负责输入研究信息的人员自愿提供这些出版物。这些可能与研究有关。

一般刊物

研究记录日期

这些日期跟踪向 ClinicalTrials.gov 提交研究记录和摘要结果的进度。研究记录和报告的结果由国家医学图书馆 (NLM) 审查，以确保它们在发布到公共网站之前符合特定的质量控制标准。

研究主要日期

学习开始 (实际的)

2021年11月13日

初级完成 (预期的)

2023年9月1日

研究完成 (预期的)

2023年12月15日

研究注册日期

首次提交

2021年9月1日

首先提交符合 QC 标准的

2021年9月6日

首次发布 (实际的)

2021年9月13日

研究记录更新

最后更新发布 (实际的)

2022年4月25日

上次提交的符合 QC 标准的更新

2022年4月21日

最后验证

2022年4月1日

更多信息

与本研究相关的术语

关键字

其他相关的 MeSH 术语

其他研究编号

  • AZALDDASA3
  • ChiCTR2100042418 (注册表标识符：Chinese Clinical Trial Registry)

计划个人参与者数据 (IPD)

计划共享个人参与者数据 (IPD)？

不

IPD 计划说明

After the completion of the clinical trial, we will choose whether to disclose the result according to the relevant regulations of the Chinese Genetic Office.

药物和器械信息、研究文件

研究美国 FDA 监管的药品

不

研究美国 FDA 监管的设备产品

不

此信息直接从 clinicaltrials.gov 网站检索，没有任何更改。如果您有任何更改、删除或更新研究详细信息的请求，请联系 register@clinicaltrials.gov. clinicaltrials.gov 上实施更改，我们的网站上也会自动更新.

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