Venetoclax + Decitabine vs. 7+3 Induction Chemotherapy in Young AML

Study Overview
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Brief Summary
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This research is being done to assess the therapeutic efficacy and safety of a promising (venetoclax and decitabine) versus conventional 7+3chemotherapy in induction young patients with acute myeloid leukemia. This study involves the following: Venetoclax and decitabine (investigational combination) Cytarabine and idarubicin (per standard of care)

Detailed Description
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This is an open-label, multicenter, phase Ⅲ randomized clinical trial to compare the therapeutic efficacy and safety of conventional induction chemotherapy (7+3 regimen) to the combination of venetoclax and decitabine among fit, young adults with newly diagnosed acute myeloid leukemia (AML). Conventional induction chemotherapy with idarubicin and cytarabine is the standard of induction chemotherapy for acute myeloid leukemia (AML). The FDA has approved the combination therapy of venetoclax and decitabine for elderly (> 60 year old) patients with newly diagnosed AML not eligible for intensive chemotherapy. Venetoclax is an inhibitor of BCL-2 (B-cell lymphoma 2, a protein that initiates tumor growth, disease progression, and drug resistance), which can lead to cancer cell death. Decitabine, a demethylation agent, has the potential to synergically target leukemia stem cell populations when combined with venetoclax as its homologous drug azacytidine. Participants will be randomly assigned to one of the different induction groups and followed with either consolidated chemotherapy or allogeneic hematopoietic stem cell transplantation after remission. After completion of study treatment, participants are followed up every 3 to 6 months for up to 2 years. It is expected that about 188 people will take part in this research study.

Official Title
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Comparing the Efficacy and Safety of Venetoclax Combined With Decitabine Versus Conventional 7+3 Induction Chemotherapy of Acute Myeloid Leukemia in Young Adults

Conditions
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AML, Adult, Chemotherapy Effect

Intervention / Treatment
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* Drug: Venetoclax
* Drug: Decitabine for Injection
* Drug: Cytarabine
* Drug: Idarubicin
* Drug: Gilteritinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, 59 > =Age (years) >= 18; Newly diagnosed as AML patients according to World Health Organization (WHO) classification; Patients have not received prior therapy for AML (except hydroxyurea and Ara-C<1.0g/d); Eastern Cooperative Oncology Group (ECOG) Performance status of 0,1, 2 ; Liver function: Total bilirubin ≦3 upper limit of normal (ULN); aspartate aminotransferase (AST) ≦3 ULN; alanine aminotransferase (ALT)≦3 ULN(except extramedullary infiltration of leukemia) Renal function：Ccr（Creatinine Clearance Rate） ≧30 ml/min; Patients who sign the informed consent must have the ability to understand and be willing to participate in the study and sign the informed consent. 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； HIV infection; Patients with severe heart failure (grade 3-4) ; Evidence of other clinically significant uncontrolled condition(s) including, but not limited to: a) Uncontrolled and/or active systemic infection (viral, bacterial or fungal); b) Chronic hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment. c) An active second cancer that requires treatment within 6 months of study entry Patients deemed unsuitable for enrolment by the investigator; Patients willing to receive intensive induction chemotherapy Female who are pregnant, breast feeding or childbearing potential without a negative urine pregnancy test at screen； Patients reject to participate in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 59 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
Interventional Model Description: De novo adult AML patients randomly assigned to two induction treatment groups: venetoclax+decitabine group and conventional idarubicin(12mg/m2)+cytarabine group.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Investigational ( venetoclax, decitabine)<br>Randomized participants will receive induction as decitabine on days 1-5 and venetoclax daily on days 1-28. Second Induction (if not reach complete remission, but the percentage of blaste cells in bone marrow decreased by more than 50%):Re-induction with pre-induction therapy. Consolidation: If patients with favorable risk and MRD (Minimal Residual Disease) negative or refuse to allo-HSCT (Hematopoietic stem-cell transplantation), intermediate-dose (2g/m2 q12h days 1-3) for 4 cycles. If patients with intermediate or poor risk or favorable risk but MRD positive, intermediate-dose cytarabine for 1-2 cycles and follow up with allo-HSCT. For patients with FLT3 mutation, gilteritinib can be combined with the follow-up treatment after the end of initial induction. | Drug: Venetoclax<br>* Orally by mouth<br>* Other names: Venclexta;Drug: Decitabine for Injection<br>* Intravenous infusion<br>Drug: Gilteritinib<br>* Orally by mouth<br>* Other names: XOSPATA;|
| Experimental: Standard of Care (Conventional Induction 7+3)<br>Randomized participants will receive cytarabine and idarubicin per standard of care as follows: Induction: cytarabine on days 1-7 and idarubicin (12mg/m2) on days 1-3 . Second Induction (if not reach complete remission, but the percentage of blaste cells in bone marrow decreased by more than 50%): Re-induction with pre-induction therapy. Consolidation: If patients with favorable risk and MRD negative or refuse to allo-HSCT, intermediate-dose cytarabine (2g/m2 q12h days 1-3) for 4 cycles. If patients with intermediate or poor risk or favorable risk but MRD positive, intermediate-dose cytarabine for 1-2 cycles and follow up with allo-HSCT. For patients with FLT3 mutation, gilteritinib can be combined with the follow-up treatment after the end of initial induction. | Drug: Cytarabine<br>* Intravenous infusion<br>* Other names: Ara-C;Drug: Idarubicin<br>* Intravenous infusion<br>* Other names: IDA;Drug: Gilteritinib<br>* Orally by mouth<br>* Other names: XOSPATA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) | Complete remission/complete remission with incomplete count recovery/Morphologic Leukemia Free State | From randomization to 2 cycles of induction before consolidation therapy（100 days） | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of severe infection (>=grade 3 ) | Assessed using CTCAE 5 | From randomization to 2 cycles of induction before consolidation therapy（100 days） | 
| 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. | From randomization to 2 cycles of induction before consolidation therapy（100 days） | 
| Event free survival | Events include progressive disease, relapse, changes in treatment regimens, fatal or intolerable side effects and any death. | From the time from randomization to time for up to 2 years | 
| Overall survival | Overall survival | From the time from randomization to time for up to 2 years | 
| Rate of Minimal Residual Disease (MRD) negativity | Percentage of participants who converted to MRD < 10^-3 before initiation of consolidation therapy. | From randomization to 2 cycles of induction before consolidation therapy（100 days） | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Venetoclax, AML, young, induction therapy