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

Primary Purpose

Acute Myeloid Leukemia

Status
Recruiting
Phase
Not Applicable
Locations
China
Study Type
Interventional
Intervention
Azacitidine
Dasatinib
Sponsored by
LanZhou University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia focused on measuring AML,Maintenance Therapy,Azacitidine,Dasatinib

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • The First Hospital of Lanzhou UniversityRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

experimental group

control group

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

overall survival
OS is defined as the time from the date of enrollment until the date of death from any cause.
disease-free survival
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.

Secondary Outcome Measures

mortality
The proportion of patients from enrollment to death was recorded.
recurrence rate
Record the proportion of patients with recurrence in the study.
adverse events
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0.
apoptotic protein and phosphorylated protein
The relative expression of apoptotic protein(caspase3, caspase8) and phosphorylated protein(pSTAT3, pSTAT5, pAKT) were detected by western blot with bone marrow aspirate.
DNA methyltransferase, tumor suppressor genes and differentiation genes
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.
methylation level in the promoter region of some tumor suppressor genes.
Detection of methylation level in the promoter region of the above tumor suppressor genes by pyrophosphate sequencing using patient bone marrow aspirate.
Percentage of bone marrow cell apoptosis population
The percentage of apoptotic population of bone marrow cells was determined by flow cytometry.

Full Information

First Posted
September 1, 2021
Last Updated
April 21, 2022
Sponsor
LanZhou University
Collaborators
Beijing Health Alliance Charitable Foundation
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1. Study Identification

Unique Protocol Identification Number
NCT05042531
Brief Title
Clinical Research for Azacitidine Combined With Low-dose Dasatinib in Maintenance Therapy of Acute Myeloid Leukemia
Official Title
Clinical Research for Azacitidine Combined With Low-dose Dasatinib in Maintenance Therapy of Acute Myeloid Leukemia
Study Type
Interventional

2. Study Status

Record Verification Date
April 2022
Overall Recruitment Status
Recruiting
Study Start Date
November 13, 2021 (Actual)
Primary Completion Date
September 1, 2023 (Anticipated)
Study Completion Date
December 15, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
LanZhou University
Collaborators
Beijing Health Alliance Charitable Foundation

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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.
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia
Keywords
AML,Maintenance Therapy,Azacitidine,Dasatinib

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
The patients were randomly divided into two groups among intermediate and high-risk AML, namely azacitidine group, azacitidine combined with low-dose dasatinib group, with overall survival and disease-free survival as the main research endpoints , taking mortality and recurrence rates as secondary research endpoints, assessing the incidence of adverse events, and studying its related mechanisms.
Masking
Investigator
Masking Description
According to the random number table
Allocation
Randomized
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
experimental group
Arm Type
Experimental
Arm Description
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.
Arm Title
control group
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Azacitidine
Intervention Description
Azacitidine, 75mg/m2,d1-7;Treatment cycles every 28 days
Intervention Type
Drug
Intervention Name(s)
Dasatinib
Intervention Description
dasatinib,20mg,po,qd,treatment cycles every 28 days
Primary Outcome Measure Information:
Title
overall survival
Description
OS is defined as the time from the date of enrollment until the date of death from any cause.
Time Frame
up to 30 months.
Title
disease-free survival
Description
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.
Time Frame
up to 30 months.
Secondary Outcome Measure Information:
Title
mortality
Description
The proportion of patients from enrollment to death was recorded.
Time Frame
mortality rate at 30 months.
Title
recurrence rate
Description
Record the proportion of patients with recurrence in the study.
Time Frame
recurrence rate at 30 months.
Title
adverse events
Description
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0.
Time Frame
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.
Title
apoptotic protein and phosphorylated protein
Description
The relative expression of apoptotic protein(caspase3, caspase8) and phosphorylated protein(pSTAT3, pSTAT5, pAKT) were detected by western blot with bone marrow aspirate.
Time Frame
once before enrollment and once after the completion of the study, up to 30 months.
Title
DNA methyltransferase, tumor suppressor genes and differentiation genes
Description
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.
Time Frame
once before enrollment and once after the completion of the study, up to 30 months.
Title
methylation level in the promoter region of some tumor suppressor genes.
Description
Detection of methylation level in the promoter region of the above tumor suppressor genes by pyrophosphate sequencing using patient bone marrow aspirate.
Time Frame
once before enrollment and once after the completion of the study, up to 30 months.
Title
Percentage of bone marrow cell apoptosis population
Description
The percentage of apoptotic population of bone marrow cells was determined by flow cytometry.
Time Frame
once before enrollment and once after the completion of the study, up to 30 months.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients with intermediate and high-risk AML who are diagnosed according to the 2016 WHO guidelines, aged ≥18 years; Detect minimal residual disease(-) after induction therapy and consolidation therapy; Eastern Cooperative Oncology Group (ECOG) performance status score 0-2; The heart, pulmonary, liver and kidneys have sufficient organ functions: Cardiac color doppler ultrasound shows cardiac ejection fraction> 50%, heart function classification NYHA III/IV, no heart block or arrhythmia; Patients without severe restrictive/obstructive pulmonary disease; 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; Renal function: serum creatinine (Cr) < 1.5 times the upper limit of normal. The patient and family members agree and sign an informed consent form. Exclusion Criteria: Patients with malignant tumors of other organs; HCV positive; or HIV positive; or one of the following HBV test results: HBsAg positive; HBsAg negative, HBcAb positive and HBV DNA titer positive; Pregnant and lactating women, and patients who have family planning during the enrollment period; Patients considered to be unsuitable for enrollment by the investigator.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Bei Liu, MD
Phone
+86 13809319379
Email
liubeiff@163.com
First Name & Middle Initial & Last Name or Official Title & Degree
Long Zhao
Phone
+18919128021
Email
dragonzhao@126.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bei Liu, MD
Organizational Affiliation
The First Hospital of Lanzhou University,Lanzhou,Gansu,China
Official's Role
Principal Investigator
Facility Information:
Facility Name
The First Hospital of Lanzhou University
City
Lanzhou
State/Province
Gansu
ZIP/Postal Code
730000
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Bei Liu, MD
Phone
+8613809319379
Email
liubeiff@163.com
First Name & Middle Initial & Last Name & Degree
Long Zhao
Phone
+18919128021
Email
zhaodragon@126.com
First Name & Middle Initial & Last Name & Degree
Bei Liu, MD
First Name & Middle Initial & Last Name & Degree
Long Zhao
First Name & Middle Initial & Last Name & Degree
Jinli Jian
First Name & Middle Initial & Last Name & Degree
Haizhen Ma
First Name & Middle Initial & Last Name & Degree
Juan Cheng, MD
First Name & Middle Initial & Last Name & Degree
Hao Zhang

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
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.
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Clinical Research for Azacitidine Combined With Low-dose Dasatinib in Maintenance Therapy of Acute Myeloid Leukemia

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