VA vs DA for ND Hig-risk AML

Study Overview
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Brief Summary
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This is an open-label, multicenter, phase 2b, randomized study aiming to compare the efficacy and safety of venetoclax plus azacytidine Versus daunorubicin plus cytarabine (conventional 7+3 regimen) in adult acute myeloid leukemia (AML) patients with adverse risk featuress. Participants will be 1:1 randomly assigned to the VA and DA groups. Once remission was achieved, consolidated chemotherapy will be performed and allogeneic hematopoietic stem cell transplantation is strongly recommended. After completion of the study intervention, participants will be followed-up every 1 to 2 months for up to 2 years.

Detailed Description
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This is an open-label, multicenter, phase 2b, randomized study aiming to compare the efficacy and safety of venetoclax plus azacytidine Versus daunorubicin plus cytarabine (conventional 7+3 regimen) in adult acute myeloid leukemia (AML) patients with adverse risk featuress. Newly diagnosed AML patients with adverse risk features according to 2022 European Leukemia Net risk stratification will be enrolled. In the study, a novel second generation targeted sequencing panel for the fast screening of adverse mutations with 72-hours after the bone marrow samples will be utilized. Randomized participants will receive induction treatment . Participants will be 1:1 randomly assigned to the VA and DA groups. VA regimen comprises of azacytidine, 75mg/m2, subcutaneously, on days 1-7; venetoclax, orally, once a day, 100mg, d1; 200mg, d2; 400mg, days 3-28. DA regimen comprises of daunorubicin (60mg/m2) on days 1-3, intraveneously injection, and cytarabine (100mg/m2) on days 1-7, intraveneously injection, for 1 cycle. Once remission was achieved, consolidated chemotherapy will be performed and allogeneic hematopoietic stem cell transplantation is strongly recommended. After completion of the study intervention, participants will be followed-up every 1 to 2 months for up to 2 years.

Official Title
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Study of the Efficacy and Safety of Venetoclax Plus Azacytidine Versus Daunorubicin Plus Cytarabine in Adult Acute Myeloid Leukemia (AML) Patients With Adverse Risk Features

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Venetoclax Oral Tablet
* Drug: Daunorubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Gender: female or male. Age:18-64 years old. Patients with newly diagnosed AML according to the WHO 2022 classification. AML patients with adverse risk features according to the 2022 European Leukemia Net risk stratification. Untreated AML (hydroxyurea, and low dose cytarabine with cummulative dose <1.0g are permitted). ECOG: 0-2. Adequate liver function: Total bilirubin ≤ 1.5×upper limit of normal (ULN); aspartate aminotransferase (AST) ≤3×ULN (liver infiltration of leukemia: ≤5×ULN); alanine aminotransferase (ALT)≤3×ULN (liver infiltration of leukemia: ≤5×ULN) . Adequate Renal function: Ccr (Creatinine Clearance Rate) ≥30 ml/min. Be able to understand and be willing to participate in the study. Be able to provide written informed consent. Exclusion Criteria: Patients with acute promyeloid leukemia. AML with central nervous system infiltration. Patients diagnosed with myeloid sarcoma. Patients have AML secondary to MDS and previously been treated with hypomethylating agents. Patients with active infection, which is considered as uncontrollable by the investigator. Patients with active hepatitis B, hepatitis C and HIV infection. Patients with heart failure (grade 3-4); Patients who are pregnant or breastfeeding. Patients who refused to be enrolled in the study. Patients who are considered as ineligible for the enrollment by the investigators.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 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: VA regimen<br>VA regimen: azacytidine and venetoclax | Drug: Venetoclax Oral Tablet<br>* VA regimen: azacytidine, 75mg/m2, subcutaneously, on days 1-7; venetoclax, orally, once a day, 100mg, d1; 200mg, d2; 400mg, days 3-28.<br>* Other names: venetoclax plus azacytidine;|
| Active Comparator: DA regimen<br>DA regimen: daunorubicin and cytarabine | Drug: Daunorubicin<br>* DA regimen: daunorubicin (60mg/m2) on days 1-3, intraveneously injection, and cytarabine (100mg/m2) on days 1-7, intraveneously injection, for 1 cycle.<br>* Other names: daunorubicin plus cytarabine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) | Rates of complete remission/complete remission with incomplete count recovery/morphologic leukemia free state. | From randomization to the end of induction therapy (before consolidation therapy, within 60 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DOR: duration of remission | Time between the first remission and relapse | 2 years | 
| EFS：event-free survival | time from the date of enrollment to treatment failure, relapse, death from any cause or the last follow-up | 2 years | 
| OS: overall survival | time from the date of enrollment to death from any cause or the last follow-up | 2 years | 
| Volume of infused blood products | The volume of infused blood products during the induction treatment. | Within 60 days after randomization | 
| AE | Adverse events during the induction treatment. | Within 60 days after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adverse risk, newly diagnosed, induction therapy