A Clinical Study of VA-CAG as Induction Therapy in Newly Diagnosed AML Patients

Study Overview
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Brief Summary
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This study aims to assess the therapeutic efficacy and safety of venetoclax in combination with azacitidine and CAG(VA-CAG) as induction regimen in newly diagnosed young patients with acute myeloid leukemia(AML).

Detailed Description
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This is an open-label, multicenter, phase II clinical trial to assess the therapeutic efficacy and safety of venetoclax in combination with azacitidine (VA) and CAG (G-CSF priming, low dose cytarabine, and aclarubicin) as induction regimen in newly diagnosed patients with acute myeloid leukemia (AML). The combination of venetoclax and azacitidine is the standard therapy for elderly (> 60 year old) patients with newly diagnosed AML who are not eligible for intensive chemotherapy. Previous studies have shown that venetoclax plus intense chemotherapy represent promising efficacy in de novo AML patients with high complete remission rates and good tolerance. The preliminary results suggest that venetoclax in combination with azacitidine and CAG are well tolerated and effective for newly diagnosed young patients with AML. Thus, this phase II clinical trial is going to further explore its efficacy and safety. It is expected that about 62 patients will take part in this trial.

Official Title
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A Phase II Study to Evaluate the Safety and Efficacy of Venetoclax in Combination With Azacitidine and CAG(VA-CAG) as Induction Therapy in Newly Diagnosed Patients With Acute Myeloid Leukemia(AML)

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Venetoclax in combination with azacitidine and CAG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients ≥ 18 years old and ≤ 65 years old Newly diagnosed as AML patients according to 2016 World Health Organization (WHO) classification; Patients without receiving prior therapy for AML; Eastern Cooperative Oncology Group (ECOG) Performance status score less than 3; Liver function: Total bilirubin ≦2 upper limit of normal (ULN); aspartate aminotransferase (AST) ≦3 ULN; alanine aminotransferase (ALT)≦3 ULN Renal function：Ccr（Creatinine Clearance Rate） ≧30 ml/min; Scr (serum creatinine) ≦2 ULN Heart function: left ventricular ejection fraction ≧45% Patients must participate in this clinical trial voluntarily and sign an informed consent form. Exclusion Criteria: Acute promyeloid leukemia； AML with central nervous system (CNS) infiltration； Patients have received prior hypomethylating agents (HMA) therapy for myelodysplastic syndrome (MDS) and progressed to AML； Patients with a life expectancy <3 months Patients with uncontrolled active infection; HIV infection; Evidence of other clinically significant uncontrolled condition(s) including, but not limited to: a) Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment; b) An active second cancer that requires treatment within 6 months of study entry. Female who are pregnant, breast feeding or childbearing potential. Patients deemed unsuitable for enrollment by the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment group<br>Induction: Subjects who meet the enrollment conditions will receive Venetoclax plus Azacitidine and CAG(VA-CAG) . Participants will receive this induction Therapy as azacitidine on days 1-7, venetoclax aily on days 1-28, cytarabine q12h on days 1-7, aclacinomycin on days 1,3,5,7, and granulocyte colony-stimulating factor on days 0-8. Participants will receive second induction if not reach complete remission. Consolidation: If patients are intermediate or poor risk and have plans for allogeneic hematopoietic stem-cell transplantation(allo-HSCT) , high dose cytarabine (3g/m2 q12h days 1-3) for 1-2 cycles and follow up with allo-HSCT. In other cases, high dose cytarabine for 4 cycles. | Drug: Venetoclax in combination with azacitidine and CAG<br>* Induction: VA regimen： Drug: Venetoclax orally once daily (100 mg d1, 200 mg d2, 400 mg d3-21); Drug: Azacitidine 75 mg/m2 subcutaneously once daily on days 1-7. CAG regimen： Drug: Cytarabine 10mg/m2 subcutaneously q12h on days 1-7; Drug: Aclacinomycin 12-14mg/m2 on days 1,3,5,7; Drug: Granulocyte colony-stimulating factor 5ug/kg on days 0-8, discontinue if WBC >20×10^9/L； Consolidation: Drug: Cytarabine 3g/m2 q12h on days 1-3.<br>* Other names: VA-CAG regimen;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) | The overall remission rate (ORR) was defined as the percentage of patients who achieved complete remission (CR), complete remission with incomplete count recovery (CRi), or morphologic leukemia free state (MLFS) per the International Working Group criteria for AML. | At the end of Cycle 1 and Cycle 2 of induction(each cycle is 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events (>=grade 3 ) | Safety and tolerability analysis will be assessed by the Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0. | Up to 2 years | 
| Duration of myelosuppression | The duration of absolute value of peripheral blood neutrophils <0.5×10^9/L and platelet count <50×10^9/L during myelosuppression. | Up to 2 years | 
| Leukaemia-free survival | Leukaemia-free survival will be defined as the time since date of CR until either relapse or death in remission. | Up to 2 years | 
| Overall survival | Overall Survival will be defined as the time from administration of the initial doses until death from any cause. | Up to 2 years | 
| Rate of Minimal Residual Disease (MRD) negativity | Percentage of participants who converted to MRD < 10^-3 by flow cytometry before initiation of consolidation therapy. | Up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Venetoclax, Azacitidine, Granulocyte colony-stimulating factor(G-CSF), Cytarabine, Aclarubicin