New Double Epigenetic Regimen in the Treatment of Relapsed or Refractory Acute Myeloid Leukemia

Study Overview
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Brief Summary
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This study is to investigate the therapeutic efficacy and side effect of chidamide, azacitidine combined with priming HAG regimen for relapsed or refractroy acute myeloid leukemia

Official Title
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A Multi-center, Randomized Clinical Trial of Chidamide Combined With Azacytidine and the HAG Regimen in the Treatment of Relapsed/Refractory Acute Myeloid Leukemia Patients

Conditions
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Acute Myeloid Leukemia, Refractory Acute Leukemia, Relapsed Adult AML

Intervention / Treatment
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* Drug: CAHAG regimen
* Drug: Placebo regimen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults aged ≥ 18 and ≤ 70 years Patients diagnosed with AML according to 2016 WHO myeloid malignant disease diagnosis standard (Non-APL) Patients with AML must meet one of the following criteria, A or B: A: Refractory AML disease was defined as follows: (1) failure to attain CR following exposure to at least 2 courses of standard or intensive induction therapy; or (2) bone marrow leukemia cell decline index (BMCDI) < 50% and > 20% after 1 course of standard or intensive induction therapy. B: Relapsed AML disease was defined as follows: (1) reappearance of leukemic blasts in the peripheral blood after CR; or (2) detection of ≥ 5% blasts in the BM not attributable to another cause (e.g., BM regeneration after consolidation therapy); or (3) extramedullary relapse. ECOG performance status score less than 3 Expected survival time ˃ 3 months Patients without serious heart, lung, liver, or kidney disease Ability to understand and voluntarily provide informed consent Exclusion Criteria: 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 Surgery 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 69 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Chidamide+AZA+HHT+AraC+G-CSF group<br>The patients are randomized into the group. Patients whose last induction failure regimen is a demethylated agent combined with priming regimen enter the experimental group directly. | Drug: CAHAG regimen<br>* Chidamide 30mg orally twice every week for 2 weeks on days 1, 4, 8, 11, azacytidine 75mg/m2 intravenously daily for 7 days (d3-d9) and HAG regimen (cytarabine, 10 mg/m2 subcutaneously every 12 h on days 3-16; homoharringtonine, 1mg/m2 intravenously every day on days 3-16; and concurrent granulocyte colony-stimulating factor, 200mg/m2/day subcutaneously daily from days 2 to neutral granulocyte recovery. (when WBC > 20×10E9/L, G-CSF paused). One treatment cycle for 28 days, a total of 2 cycles. If the bone marrow assessment is MLFS on the 28th day in the first cycle, the second cycle of treatment will be started after NE<1.0×10E9/L; if the delay exceeds 2 weeks, the patient needs to withdraw from the trial.<br>|
| Placebo Comparator: Placebo+AZA+HHT+AraC+G-CSF group<br>The patients are randomized into the group. | Drug: Placebo regimen<br>* Chidamide 0mg orally twice every week for 2 weeks on days 1, 4, 8, 11, azacytidine 75mg/m2 intravenously daily for 7 days (d3-d9) and HAG regimen (cytarabine, 10 mg/m2 subcutaneously every 12 h on days 3-16; homoharringtonine, 1mg/m2 intravenously every day on days 3-16; and concurrent granulocyte colony-stimulating factor, 200mg/m2/day subcutaneously daily from days 2 to neutral granulocyte recovery. (when WBC > 20×10E9/L, G-CSF paused). One treatment cycle for 28 days, a total of 2 cycles. If the bone marrow assessment is MLFS on the 28th day in the first cycle, the second cycle of treatment will be started after NE<1.0×10E9/L; if the delay exceeds 2 weeks, the patient needs to withdraw from the trial.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) | The overall response (completed remission without minimal residual disease, completed remission with incomplete blood count recovery, morphologic leukemia-free state and partial remission) rate achieved after one or two courses(28 days) induction therapy by CAHAG regimen. | At the end of Cycle 1 (each cycle is 28 days) | 
| Complete remission without minimal residual disease (CR with MRD-) | If studied pretreatment, CR with negativity for a genetic marker by RT-qPCR, or CR with negativity by MFC | At the end of Cycle 1 (each cycle is 28 days) | 
| Complete remission with incomplete hematologic recovery (CRi) | All CR criteria except for residual neutropenia (,1.0*10E9/L [1000/uL]) or thrombocytopenia (<100*10E9/L [100 000/uL]) | At the end of Cycle 1 (each cycle is 28 days) | 
| Morphologic leukemia-free state (MLFS) | Bone marrow blasts ,5%; absence of blasts with Auer rods; absence of extramedullary disease; no hematologic recovery required | At the end of Cycle 1 (each cycle is 28 days) | 
| Partial remission (PR) | All hematologic criteria of CR; decrease of bone marrow blast percentage to 5% to 25%; and decrease of pretreatment bone marrow blast percentage by at least 50%. | At the end of Cycle 1 (each cycle is 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response (DOR) | It is measured the time from initial response to subsequent disease progression or relapse. | 1 year | 
| Overall Survival (OS) | It is measured from the time of entry into this trial to the date of death from any cause; patients not known to have died at last follow-up are censored on the date they were last known to be alive. | 1 year | 
| Progression-Free Survival (PFS) | It is measured from the time from randomization to progression or death. | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chidamide, Azacitidine, priming regimen