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

NCT ID: NCT05042531

Last Updated: 2022-04-25

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: NA
• Total Enrollment: 30 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-11-13
• Study Completion Date: 2023-12-15

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.

Conditions

Acute Myeloid Leukemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

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.

Group Type: EXPERIMENTAL

Azacitidine

Intervention Type: DRUG

Azacitidine, 75mg/m2,d1-7;Treatment cycles every 28 days

Dasatinib

Intervention Type: DRUG

dasatinib,20mg,po,qd,treatment cycles every 28 days

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.

Group Type: ACTIVE_COMPARATOR

Azacitidine

Intervention Type: DRUG

Azacitidine, 75mg/m2,d1-7;Treatment cycles every 28 days

Interventions

Azacitidine

Azacitidine, 75mg/m2,d1-7;Treatment cycles every 28 days

Intervention Type: DRUG

Dasatinib

dasatinib,20mg,po,qd,treatment cycles every 28 days

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Beijing Health Alliance Charitable Foundation

UNKNOWN

Sponsor Role: collaborator

LanZhou University

OTHER

Sponsor Role: lead

Responsible Party

Bei Liu

Chief Physician, Clinical Associate Professor，Deputy Director of Hematology Department

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Bei Liu, MD

Role: PRINCIPAL_INVESTIGATOR

The First Hospital of Lanzhou University,Lanzhou,Gansu,China

Locations

The First Hospital of Lanzhou University

Lanzhou, Gansu, China

Site Status: RECRUITING

Countries

China

Central Contacts

Bei Liu, MD

Role: CONTACT

liubeiff@163.com

+86 13809319379

Long Zhao

Role: CONTACT

dragonzhao@126.com

+18919128021

Facility Contacts

Bei Liu, MD

Role: primary

liubeiff@163.com

+8613809319379

Long Zhao

Role: backup

zhaodragon@126.com

+18919128021

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Other Identifiers

ChiCTR2100042418

Identifier Type: REGISTRY

Identifier Source: secondary_id

AZALDDASA3

Identifier Type: -

Identifier Source: org_study_id