Testing the Effects of Novel Therapeutics for Newly Diagnosed, Untreated Patients With High-Risk Acute Myeloid Leukemia (A MyeloMATCH Treatment Trial)

Phase 2

Recruiting

• Conditions: Acute Myeloid Leukemia Arising From Previous Myelodysplastic/Myeloproliferative Neoplasm; Acute Myeloid Leukemia Post Cytotoxic Therapy; Acute Myeloid Leukemia; Acute Myeloid Leukemia, Myelodysplasia-Related
• Interventions: Procedure: Biospecimen Collection; Drug: Azacitidine; Procedure: Bone Marrow Aspiration; Drug: Cytarabine; Drug: Daunorubicin Hydrochloride; Drug: Liposome-encapsulated Daunorubicin-Cytarabine; Procedure: Echocardiography; Procedure: Multigated Acquisition Scan; Drug: Venetoclax

• Registration Number: NCT05554406
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

This phase II MyeloMATCH treatment trial tests whether the standard approach of cytarabine and daunorubicin in comparison to the following experimental regimens works to shrink cancer in patients with high risk acute myeloid leukemia (AML): 1) daunorubicin and cytarabine liposome alone; 2) cytarabine and daunorubicin with venetoclax; 3) azacitidine and venetoclax; 4) daunorubicin and cytarabine liposome and venetoclax. "High-risk" refers to traits that have been known to make the AML harder to treat. Cytarabine is in a class of medications called antimetabolites. It works by slowing or stopping the growth of cancer cells in the body. Daunorubicin is in a class of medications called anthracyclines. It also works by slowing or stopping the growth of cancer cells in the body. Azacitidine is in a class of medications called demethylation agents. It works by helping the bone marrow to produce normal blood cells and by killing abnormal cells. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. There is evidence that these newer experimental treatment regimens may work better in getting rid of more AML compared to the standard approach of cytarabine and daunorubicin.

Detailed Description

PRIMARY OBJECTIVE:

I. To compare measurable residual disease (MRD) negative complete remission (CR) rates between each of the experimental regimens and cytarabine + daunorubicin (7+3).

SECONDARY OBJECTIVES:

I. To estimate the frequency and severity of toxicities with each of the regimens.

II. To estimate complete remission (CR) rates, complete remission with incomplete count recovery (CRi, with and without MRD) rates, event-free survival (EFS), time to relapse, relapse-free survival (RFS), and overall survival (OS) with each of the regimens.

III. To describe and compare MRD negative CR rates by genomic subgroups within and across randomized arms.

BAKING OBJECTIVE:

I. To bank specimens for future correlative studies.

OUTLINE: Patients are randomized to 1 of 5 arms.

ARM I: Patients receive cytarabine intravenously (IV) continuously on days 1-7 and daunorubicin IV on days 1-3 per standard approach of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of cytarabine IV continuously on days 1-5 and daunorubicin IV on days 1-2. Patients undergo echocardiography (ECHO) or multigated acquisition (MUGA) scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.

ARM II: Patients receive cytarabine IV continuously on days 2-8 and daunorubicin IV on days 2-4 with venetoclax orally (PO) on days 1-11 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of cytarabine IV continuously on days 2-6 and daunorubicin IV on days 2-3 with venetoclax PO on days 1-8. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.

ARM III: Patients receive azacitidine subcutaneously (SC) or IV on days 1-7 and venetoclax PO on days 1-28 of each cycle. Cycles repeat every 28 days for 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.

ARM IV: Patients receive daunorubicin and cytarabine liposome IV over 90 minutes on days 1, 3, and 5 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of daunorubicin and cytarabine liposome IV over 90 minutes on days 1 and 3. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.

ARM V: Patients receive daunorubicin and cytarabine liposome IV over 90 minutes on days 1, 3, and 5 and venetoclax PO on days 1-14 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of daunorubicin and cytarabine liposome IV over 90 minutes on days 1 and 3 and venetoclax PO on days 1-7. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.

After completion of study treatment, patients follow up every month for first year, every 2 months for the second year, every 3 months for the third year and every 6 months to year 5.

Study Timeline

• Study First Submitted: 2022-09-22
• Study First Submitted QC: 2022-09-22
• Study First Posted: 2022-09-26
• Status Verified: 2024-09
• Study Start: 2024-09-25
• Last Update Submitted: 2025-01-09
• Last Update Posted: 2025-01-10
• Primary Completion: 2027-03-31
• Study Completion: 2027-03-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 335

Inclusion Criteria

• STEP 1 REGISTRATION:

• Participants must have been registered to Master Screening and Re-Assessment Protocol, MYELOMATCH, prior to consenting to this study. Participants must have been assigned to this clinical trial, via MATCHBox, prior to registration to this study.

  • Note: Pre-enrollment/diagnosis labs must have already been performed under the MYELOMATCH

• Participants must have newly diagnosed, untreated acute myeloid leukemia (AML) per World Health Organization (WHO) criteria

• Participants must have high-risk (adverse) AML per European LeukemiaNet (ELN) 2017 criteria

• Participants with therapy-related AML (t-AML), or with AML evolving from an antecedent hematologic disorder (such as myeloproliferative neoplasm), or AML with myelodysplasia-related changes (AML-MRC) are eligible

• Acute promyelocytic leukemia is excluded

• Participants with favorable or intermediate risk disease are excluded

• Participants with FLT3 mutations (ITD or TKD) are excluded

• Participants with t(9;22) translocation are excluded

• A single dose of intrathecal chemotherapy is allowed prior to study entry

• Prior anthracycline therapy is allowed but must not exceed a cumulative lifetime dose of 200 mg/m^2 daunorubicin or equivalent. Prior hypomethylating agent (HMA) exposure is allowed, as long as not for AML diagnosis

• Participants must not have received or be currently receiving any prior therapy for acute myeloid leukemia. Hydroxyurea to control the white blood cells (WBC) is allowed prior to registration and initiation of protocol-defined therapy. All trans retinoic acid (ATRA) given until a diagnosis of acute promyelocytic leukemia is ruled out is also allowed.

• Participants must not be receiving or planning to receive any other investigational agents before completing protocol therapy

• Participants must be between 18 and 59 years of age

• Participants must have Zubrod performance status =< 3 as determined by a history and physical (H&P) completed within 14 days prior to registration

• Participants must have a complete medical history and physical exam within 7 days prior to registration

• Participants must be able to swallow and retain oral medications and have no known gastrointestinal disorders likely to interfere with absorption of oral medications

• Participants with known human immunodeficiency virus (HIV)-infection must be on effective anti-retroviral therapy at time of registration and have undetectable HIV viral load within 6 months prior to registration

• Participants with evidence of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load within 28 days prior to registration and be on suppressive therapy, if indicated

• Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants with active HCV infection who are currently on treatment must have an undetectable HCV viral load within 28 days prior to registration

• The following tests must be performed within 14 days prior to registration to establish baseline values:

  • Complete blood count (CBC)/differential/platelets
  • Total bilirubin
  • Lactate dehydrogenase (LDH)
  • Albumin
  • Glucose
  • Fibrinogen

• Participants must have adequate kidney function as evidenced by creatinine clearance >= 30mL/min (by Cockcroft Gault) within 28 days prior to registration

• Participants must have adequate liver function as evidenced by aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3.0 x upper limit of normal (ULN), and total bilirubin =< 2.0 x ULN (or 5.0 x ULN if the participant has a history of Gilbert's disease) within 28 days prior to registration

• Total bilirubin =< 2.0 x ULN (or 5.0 x ULN if the participant has a history of Gilbert's disease) within 28 days prior to registration

• Participants must have adequate cardiac function as determined by echocardiography or MUGA scan with an ejection fraction >= 50% within 28 days prior to registration

• Participants with a prior or concurrent malignancy whose natural history (in the opinion of the treating physician) does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. No concurrent therapies for such malignancy are allowed with the exception of hormonal therapy

• Participants with known history of Wilson's disease or other known copper-metabolism disorder are excluded

• Participants must not be pregnant or nursing. Women/men of reproductive potential must have agreed to use 2 contraception methods. A woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods (e.g., hormonal contraceptives [examples include birth control pills, vaginal rings, or patches] associated with inhibition of ovulation for at least 1 month prior to taking study drug), "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation. However, if at any point a previously celibate participant chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures. A barrier method should be used during this study along with hormonal contraceptives from initial study drug administration to 30 days after the last dose of study drug as drug-drug interaction with venetoclax is unknown

• Participants must have agreed to have specimens submitted for translational medicine (MRD) under the myeloMATCH MSRP and specimens must be submitted

• Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines

• As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm I (cytarabine, daunorubicin)	Biospecimen Collection	Patients receive cytarabine IV continuously on days 1-7 and daunorubicin IV on days 1-3 per standard approach of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of cytarabine IV continuously on days 1-5 and daunorubicin IV on days 1-2. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.
Arm I (cytarabine, daunorubicin)	Bone Marrow Aspiration	Patients receive cytarabine IV continuously on days 1-7 and daunorubicin IV on days 1-3 per standard approach of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of cytarabine IV continuously on days 1-5 and daunorubicin IV on days 1-2. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.
Arm I (cytarabine, daunorubicin)	Cytarabine	Patients receive cytarabine IV continuously on days 1-7 and daunorubicin IV on days 1-3 per standard approach of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of cytarabine IV continuously on days 1-5 and daunorubicin IV on days 1-2. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.
Arm I (cytarabine, daunorubicin)	Daunorubicin Hydrochloride	Patients receive cytarabine IV continuously on days 1-7 and daunorubicin IV on days 1-3 per standard approach of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of cytarabine IV continuously on days 1-5 and daunorubicin IV on days 1-2. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.
Arm I (cytarabine, daunorubicin)	Echocardiography	Patients receive cytarabine IV continuously on days 1-7 and daunorubicin IV on days 1-3 per standard approach of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of cytarabine IV continuously on days 1-5 and daunorubicin IV on days 1-2. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.
Arm I (cytarabine, daunorubicin)	Multigated Acquisition Scan	Patients receive cytarabine IV continuously on days 1-7 and daunorubicin IV on days 1-3 per standard approach of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of cytarabine IV continuously on days 1-5 and daunorubicin IV on days 1-2. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.
Arm II (cytarabine, daunorubicin, venetoclax)	Biospecimen Collection	Patients receive cytarabine IV continuously on days 2-8 and daunorubicin IV on days 2-4 with venetoclax PO on days 1-11 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of cytarabine IV continuously on days 2-6 and daunorubicin IV on days 2-3 with venetoclax PO on days 1-8. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.
Arm II (cytarabine, daunorubicin, venetoclax)	Bone Marrow Aspiration	Patients receive cytarabine IV continuously on days 2-8 and daunorubicin IV on days 2-4 with venetoclax PO on days 1-11 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of cytarabine IV continuously on days 2-6 and daunorubicin IV on days 2-3 with venetoclax PO on days 1-8. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.
Arm V (daunorubicin and cytarabine liposome, venetoclax)	Bone Marrow Aspiration	Patients receive daunorubicin and cytarabine liposome IV over 90 minutes on days 1, 3, and 5 and venetoclax PO on days 1-14 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of daunorubicin and cytarabine liposome IV over 90 minutes on days 1 and 3 and venetoclax PO on days 1-7. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.
Arm II (cytarabine, daunorubicin, venetoclax)	Daunorubicin Hydrochloride	Patients receive cytarabine IV continuously on days 2-8 and daunorubicin IV on days 2-4 with venetoclax PO on days 1-11 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of cytarabine IV continuously on days 2-6 and daunorubicin IV on days 2-3 with venetoclax PO on days 1-8. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.
Arm II (cytarabine, daunorubicin, venetoclax)	Echocardiography	Patients receive cytarabine IV continuously on days 2-8 and daunorubicin IV on days 2-4 with venetoclax PO on days 1-11 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of cytarabine IV continuously on days 2-6 and daunorubicin IV on days 2-3 with venetoclax PO on days 1-8. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.
Arm II (cytarabine, daunorubicin, venetoclax)	Multigated Acquisition Scan	Patients receive cytarabine IV continuously on days 2-8 and daunorubicin IV on days 2-4 with venetoclax PO on days 1-11 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of cytarabine IV continuously on days 2-6 and daunorubicin IV on days 2-3 with venetoclax PO on days 1-8. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.
Arm III (azacitidine, venetoclax)	Biospecimen Collection	Patients receive azacitidine SC or IV on days 1-7 and venetoclax PO on days 1-28 of each cycle. Cycles repeat every 28 days for 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.
Arm III (azacitidine, venetoclax)	Echocardiography	Patients receive azacitidine SC or IV on days 1-7 and venetoclax PO on days 1-28 of each cycle. Cycles repeat every 28 days for 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.
Arm III (azacitidine, venetoclax)	Multigated Acquisition Scan	Patients receive azacitidine SC or IV on days 1-7 and venetoclax PO on days 1-28 of each cycle. Cycles repeat every 28 days for 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.
Arm IV (daunorubicin and cytarabine liposome)	Biospecimen Collection	Patients receive daunorubicin and cytarabine liposome IV over 90 minutes on days 1, 3, and 5 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of daunorubicin and cytarabine liposome IV over 90 minutes on days 1 and 3. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.
Arm IV (daunorubicin and cytarabine liposome)	Bone Marrow Aspiration	Patients receive daunorubicin and cytarabine liposome IV over 90 minutes on days 1, 3, and 5 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of daunorubicin and cytarabine liposome IV over 90 minutes on days 1 and 3. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.
Arm IV (daunorubicin and cytarabine liposome)	Echocardiography	Patients receive daunorubicin and cytarabine liposome IV over 90 minutes on days 1, 3, and 5 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of daunorubicin and cytarabine liposome IV over 90 minutes on days 1 and 3. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.
Arm IV (daunorubicin and cytarabine liposome)	Liposome-encapsulated Daunorubicin-Cytarabine	Patients receive daunorubicin and cytarabine liposome IV over 90 minutes on days 1, 3, and 5 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of daunorubicin and cytarabine liposome IV over 90 minutes on days 1 and 3. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.
Arm IV (daunorubicin and cytarabine liposome)	Multigated Acquisition Scan	Patients receive daunorubicin and cytarabine liposome IV over 90 minutes on days 1, 3, and 5 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of daunorubicin and cytarabine liposome IV over 90 minutes on days 1 and 3. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.
Arm V (daunorubicin and cytarabine liposome, venetoclax)	Biospecimen Collection	Patients receive daunorubicin and cytarabine liposome IV over 90 minutes on days 1, 3, and 5 and venetoclax PO on days 1-14 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of daunorubicin and cytarabine liposome IV over 90 minutes on days 1 and 3 and venetoclax PO on days 1-7. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.
Arm V (daunorubicin and cytarabine liposome, venetoclax)	Echocardiography	Patients receive daunorubicin and cytarabine liposome IV over 90 minutes on days 1, 3, and 5 and venetoclax PO on days 1-14 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of daunorubicin and cytarabine liposome IV over 90 minutes on days 1 and 3 and venetoclax PO on days 1-7. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.
Arm V (daunorubicin and cytarabine liposome, venetoclax)	Liposome-encapsulated Daunorubicin-Cytarabine	Patients receive daunorubicin and cytarabine liposome IV over 90 minutes on days 1, 3, and 5 and venetoclax PO on days 1-14 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of daunorubicin and cytarabine liposome IV over 90 minutes on days 1 and 3 and venetoclax PO on days 1-7. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.
Arm V (daunorubicin and cytarabine liposome, venetoclax)	Multigated Acquisition Scan	Patients receive daunorubicin and cytarabine liposome IV over 90 minutes on days 1, 3, and 5 and venetoclax PO on days 1-14 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of daunorubicin and cytarabine liposome IV over 90 minutes on days 1 and 3 and venetoclax PO on days 1-7. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.
Arm II (cytarabine, daunorubicin, venetoclax)	Cytarabine	Patients receive cytarabine IV continuously on days 2-8 and daunorubicin IV on days 2-4 with venetoclax PO on days 1-11 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of cytarabine IV continuously on days 2-6 and daunorubicin IV on days 2-3 with venetoclax PO on days 1-8. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.
Arm II (cytarabine, daunorubicin, venetoclax)	Venetoclax	Patients receive cytarabine IV continuously on days 2-8 and daunorubicin IV on days 2-4 with venetoclax PO on days 1-11 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of cytarabine IV continuously on days 2-6 and daunorubicin IV on days 2-3 with venetoclax PO on days 1-8. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.
Arm III (azacitidine, venetoclax)	Azacitidine	Patients receive azacitidine SC or IV on days 1-7 and venetoclax PO on days 1-28 of each cycle. Cycles repeat every 28 days for 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.
Arm III (azacitidine, venetoclax)	Venetoclax	Patients receive azacitidine SC or IV on days 1-7 and venetoclax PO on days 1-28 of each cycle. Cycles repeat every 28 days for 2 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.
Arm V (daunorubicin and cytarabine liposome, venetoclax)	Venetoclax	Patients receive daunorubicin and cytarabine liposome IV over 90 minutes on days 1, 3, and 5 and venetoclax PO on days 1-14 of each cycle. Cycles repeat every 28 days for 1 cycle in the absence of disease progression or unacceptable toxicity. Patients may receive an additional cycle of daunorubicin and cytarabine liposome IV over 90 minutes on days 1 and 3 and venetoclax PO on days 1-7. Patients undergo ECHO or MUGA scan during screening. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.

Primary Outcome Measures

Name	Time	Method
Minimal residual disease (MRD) response (Arm 1, 2, 4 and 5)	After induction (28 days) or re-induction (56 days)	Will be analyzed using intent-to-treat (ITT) principles.
Minimal residual disease (MRD) response (Arm 3)	After two cycles of therapy (56 days)	Will be analyzed using intent-to-treat (ITT) principles.

Secondary Outcome Measures

Name	Time	Method
Overall survival (OS)	From day of randomization on study until death from any cause, assessed up to 5 years	Will be estimated using the Kaplan-Meier method.
Time to relapse	Up to 5 years	Will be estimated with cumulative incidence curves with death without relapse analyzed a competing event. Response per 2017 European LeukemiaNet (ELN) guidelines will be tabulated and exact 95% confidence intervals will be calculated.
Relapse-free survival (RFS)	From the date of achievement of a remission until the date of relapse or death from any cause, assessed up to 5 years	Defined for only patients achieving complete remission (CR), or CR with incomplete hematologic recovery (CRi). Will be estimated using the Kaplan-Meier method.
Time to count recovery	After cycle 1 and cycle 2	Will be reported every DSMC cycle for the 7+3+venetoclax, (daunorubicin and cytarabine) liposome+venetoclax, and 7+3 arms. Median time to count recovery more than 7 days longer on either of the 7+3+venetoclax and (daunorubicin and cytarabine liposome+venetoclax arms compared to the 7+3 arm will be used a threshold to terminate accrual to an arm due to increased toxicity.
Event-free survival (EFS)	From randomization to the first of: primary refractory disease; progressive disease; off protocol therapy without complete remission (CR) or CR with incomplete count recovery (CRi); relapse from CR or CRi, or death from any cause, assessed up to 5 years	Will be estimated using the Kaplan-Meier method.
Incidence of adverse events	Up to 5 years	Will be analyzed using National Cancer Institute Common Terminology Criteria for Adverse Events version (v) 5.0
Early mortality	On or before day 28	Will be assessed by death due to any cause between experimental arms and the 7+3 arm will be reported for each arm every DSMC cycle. Fisher's exact will be used to compare observed rates. A one-sided p-value \< 0.05 indicating increased early mortality rates in an experimental arm will be a threshold for termination of accrual to an arm due to increased early mortality.
MRD negative complete remission (MRDneg CR)	Up to 5 years	MRDneg CR rates will be tabulated by genomic subgroups within randomized arms and pooling arms. Rates across arms will be compared using Fisher's exact test. All p-values reported will be nominal.

Trial Locations

Locations (122)

Tufts Medical Center; 🇺🇸 Boston, Massachusetts, United States

Banner University Medical Center - Tucson; 🇺🇸 Tucson, Arizona, United States

University of Arizona Cancer Center-North Campus; 🇺🇸 Tucson, Arizona, United States

University of Arkansas for Medical Sciences; 🇺🇸 Little Rock, Arkansas, United States

Cedars Sinai Medical Center; 🇺🇸 Los Angeles, California, United States

Augusta University Medical Center; 🇺🇸 Augusta, Georgia, United States

Saint Alphonsus Cancer Care Center-Boise; 🇺🇸 Boise, Idaho, United States

Saint Luke's Cancer Institute - Boise; 🇺🇸 Boise, Idaho, United States

Saint Alphonsus Cancer Care Center-Caldwell; 🇺🇸 Caldwell, Idaho, United States

Kootenai Health - Coeur d'Alene; 🇺🇸 Coeur d'Alene, Idaho, United States

Saint Luke's Cancer Institute - Fruitland; 🇺🇸 Fruitland, Idaho, United States

Saint Luke's Cancer Institute - Meridian; 🇺🇸 Meridian, Idaho, United States

Saint Alphonsus Cancer Care Center-Nampa; 🇺🇸 Nampa, Idaho, United States

Saint Luke's Cancer Institute - Nampa; 🇺🇸 Nampa, Idaho, United States

Kootenai Clinic Cancer Services - Post Falls; 🇺🇸 Post Falls, Idaho, United States

Kootenai Clinic Cancer Services - Sandpoint; 🇺🇸 Sandpoint, Idaho, United States

OSF Saint Joseph Medical Center; 🇺🇸 Bloomington, Illinois, United States

Illinois CancerCare-Bloomington; 🇺🇸 Bloomington, Illinois, United States

Illinois CancerCare-Canton; 🇺🇸 Canton, Illinois, United States

Illinois CancerCare-Carthage; 🇺🇸 Carthage, Illinois, United States

Northwestern University; 🇺🇸 Chicago, Illinois, United States

University of Chicago Comprehensive Cancer Center; 🇺🇸 Chicago, Illinois, United States

Cancer Care Specialists of Illinois - Decatur; 🇺🇸 Decatur, Illinois, United States

Decatur Memorial Hospital; 🇺🇸 Decatur, Illinois, United States

Illinois CancerCare-Dixon; 🇺🇸 Dixon, Illinois, United States

Crossroads Cancer Center; 🇺🇸 Effingham, Illinois, United States

Illinois CancerCare-Eureka; 🇺🇸 Eureka, Illinois, United States

Illinois CancerCare-Galesburg; 🇺🇸 Galesburg, Illinois, United States

Illinois CancerCare-Kewanee Clinic; 🇺🇸 Kewanee, Illinois, United States

Illinois CancerCare-Macomb; 🇺🇸 Macomb, Illinois, United States

Illinois CancerCare-Ottawa Clinic; 🇺🇸 Ottawa, Illinois, United States

Illinois CancerCare-Pekin; 🇺🇸 Pekin, Illinois, United States

Illinois CancerCare-Peoria; 🇺🇸 Peoria, Illinois, United States

Methodist Medical Center of Illinois; 🇺🇸 Peoria, Illinois, United States

OSF Saint Francis Medical Center; 🇺🇸 Peoria, Illinois, United States

Illinois CancerCare-Peru; 🇺🇸 Peru, Illinois, United States

Illinois CancerCare-Princeton; 🇺🇸 Princeton, Illinois, United States

Southern Illinois University School of Medicine; 🇺🇸 Springfield, Illinois, United States

Springfield Clinic; 🇺🇸 Springfield, Illinois, United States

Springfield Memorial Hospital; 🇺🇸 Springfield, Illinois, United States

Illinois CancerCare - Washington; 🇺🇸 Washington, Illinois, United States

Indiana University/Melvin and Bren Simon Cancer Center; 🇺🇸 Indianapolis, Indiana, United States

University of Kansas Clinical Research Center; 🇺🇸 Fairway, Kansas, United States

University of Kansas Cancer Center; 🇺🇸 Kansas City, Kansas, United States

University of Kansas Hospital-Indian Creek Campus; 🇺🇸 Overland Park, Kansas, United States

University of Kansas Hospital-Westwood Cancer Center; 🇺🇸 Westwood, Kansas, United States

University of Kentucky/Markey Cancer Center; 🇺🇸 Lexington, Kentucky, United States

The James Graham Brown Cancer Center at University of Louisville; 🇺🇸 Louisville, Kentucky, United States

UofL Health Medical Center Northeast; 🇺🇸 Louisville, Kentucky, United States

Trinity Health Saint Joseph Mercy Hospital Ann Arbor; 🇺🇸 Ann Arbor, Michigan, United States

Trinity Health IHA Medical Group Hematology Oncology - Brighton; 🇺🇸 Brighton, Michigan, United States

Trinity Health IHA Medical Group Hematology Oncology - Canton; 🇺🇸 Canton, Michigan, United States

Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital; 🇺🇸 Chelsea, Michigan, United States

Wayne State University/Karmanos Cancer Institute; 🇺🇸 Detroit, Michigan, United States

Weisberg Cancer Treatment Center; 🇺🇸 Farmington Hills, Michigan, United States

Cancer Hematology Centers - Flint; 🇺🇸 Flint, Michigan, United States

Genesee Hematology Oncology PC; 🇺🇸 Flint, Michigan, United States

Genesys Hurley Cancer Institute; 🇺🇸 Flint, Michigan, United States

Hurley Medical Center; 🇺🇸 Flint, Michigan, United States

Trinity Health Saint Mary Mercy Livonia Hospital; 🇺🇸 Livonia, Michigan, United States

Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus; 🇺🇸 Ypsilanti, Michigan, United States

Essentia Health - Deer River Clinic; 🇺🇸 Deer River, Minnesota, United States

Essentia Health Cancer Center; 🇺🇸 Duluth, Minnesota, United States

Essentia Health Hibbing Clinic; 🇺🇸 Hibbing, Minnesota, United States

Essentia Health Sandstone; 🇺🇸 Sandstone, Minnesota, United States

Essentia Health Virginia Clinic; 🇺🇸 Virginia, Minnesota, United States

Baptist Memorial Hospital and Cancer Center-Golden Triangle; 🇺🇸 Columbus, Mississippi, United States

Baptist Cancer Center-Grenada; 🇺🇸 Grenada, Mississippi, United States

Baptist Memorial Hospital and Cancer Center-Union County; 🇺🇸 New Albany, Mississippi, United States

Baptist Memorial Hospital and Cancer Center-Oxford; 🇺🇸 Oxford, Mississippi, United States

Baptist Memorial Hospital and Cancer Center-Desoto; 🇺🇸 Southhaven, Mississippi, United States

Siteman Cancer Center at West County Hospital; 🇺🇸 Creve Coeur, Missouri, United States

Washington University School of Medicine; 🇺🇸 Saint Louis, Missouri, United States

Siteman Cancer Center-South County; 🇺🇸 Saint Louis, Missouri, United States

Siteman Cancer Center at Christian Hospital; 🇺🇸 Saint Louis, Missouri, United States

Siteman Cancer Center at Saint Peters Hospital; 🇺🇸 Saint Peters, Missouri, United States

Billings Clinic Cancer Center; 🇺🇸 Billings, Montana, United States

Bozeman Health Deaconess Hospital; 🇺🇸 Bozeman, Montana, United States

Benefis Sletten Cancer Institute; 🇺🇸 Great Falls, Montana, United States

Logan Health Medical Center; 🇺🇸 Kalispell, Montana, United States

Community Medical Center; 🇺🇸 Missoula, Montana, United States

Nebraska Medicine-Bellevue; 🇺🇸 Bellevue, Nebraska, United States

Nebraska Medicine-Village Pointe; 🇺🇸 Omaha, Nebraska, United States

University of Nebraska Medical Center; 🇺🇸 Omaha, Nebraska, United States

OptumCare Cancer Care at Seven Hills; 🇺🇸 Henderson, Nevada, United States

OptumCare Cancer Care at Charleston; 🇺🇸 Las Vegas, Nevada, United States

OptumCare Cancer Care at Fort Apache; 🇺🇸 Las Vegas, Nevada, United States

Monmouth Medical Center; 🇺🇸 Long Branch, New Jersey, United States

Rutgers Cancer Institute of New Jersey; 🇺🇸 New Brunswick, New Jersey, United States

University of New Mexico Cancer Center; 🇺🇸 Albuquerque, New Mexico, United States

Montefiore Medical Center - Moses Campus; 🇺🇸 Bronx, New York, United States

University of Rochester; 🇺🇸 Rochester, New York, United States

State University of New York Upstate Medical University; 🇺🇸 Syracuse, New York, United States

Duke University Medical Center; 🇺🇸 Durham, North Carolina, United States

University of Oklahoma Health Sciences Center; 🇺🇸 Oklahoma City, Oklahoma, United States

Saint Alphonsus Cancer Care Center-Ontario; 🇺🇸 Ontario, Oregon, United States

Providence Portland Medical Center; 🇺🇸 Portland, Oregon, United States

Providence Saint Vincent Medical Center; 🇺🇸 Portland, Oregon, United States

Oregon Health and Science University; 🇺🇸 Portland, Oregon, United States

Geisinger Medical Center; 🇺🇸 Danville, Pennsylvania, United States

University of Pennsylvania/Abramson Cancer Center; 🇺🇸 Philadelphia, Pennsylvania, United States

Thomas Jefferson University Hospital; 🇺🇸 Philadelphia, Pennsylvania, United States

Reading Hospital; 🇺🇸 West Reading, Pennsylvania, United States

Prisma Health Cancer Institute - Spartanburg; 🇺🇸 Boiling Springs, South Carolina, United States

Prisma Health Cancer Institute - Easley; 🇺🇸 Easley, South Carolina, United States

Prisma Health Cancer Institute - Butternut; 🇺🇸 Greenville, South Carolina, United States

Prisma Health Cancer Institute - Faris; 🇺🇸 Greenville, South Carolina, United States

Prisma Health Cancer Institute - Eastside; 🇺🇸 Greenville, South Carolina, United States

Prisma Health Cancer Institute - Greer; 🇺🇸 Greer, South Carolina, United States

Prisma Health Cancer Institute - Seneca; 🇺🇸 Seneca, South Carolina, United States

Baptist Memorial Hospital and Cancer Center-Collierville; 🇺🇸 Collierville, Tennessee, United States

Baptist Memorial Hospital and Cancer Center-Memphis; 🇺🇸 Memphis, Tennessee, United States

Huntsman Cancer Institute/University of Utah; 🇺🇸 Salt Lake City, Utah, United States

University of Virginia Cancer Center; 🇺🇸 Charlottesville, Virginia, United States

ThedaCare Regional Cancer Center; 🇺🇸 Appleton, Wisconsin, United States

Duluth Clinic Ashland; 🇺🇸 Ashland, Wisconsin, United States

Saint Vincent Hospital Cancer Center Green Bay; 🇺🇸 Green Bay, Wisconsin, United States

Saint Vincent Hospital Cancer Center at Saint Mary's; 🇺🇸 Green Bay, Wisconsin, United States

Gundersen Lutheran Medical Center; 🇺🇸 La Crosse, Wisconsin, United States

Medical College of Wisconsin; 🇺🇸 Milwaukee, Wisconsin, United States

Centro Comprensivo de Cancer de UPR; 🇵🇷 San Juan, Puerto Rico

San Juan City Hospital; 🇵🇷 San Juan, Puerto Rico