Comparing Cytarabine + Daunorubicin Therapy Versus Cytarabine + Daunorubicin + Venetoclax Versus Venetoclax + Azacitidine in Younger Patients With Intermediate Risk AML (A MyeloMATCH Treatment Trial)

Study Overview
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Brief Summary
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This phase II MyeloMATCH treatment trial compares cytarabine with daunorubicin versus cytarabine with daunorubicin and venetoclax versus venetoclax with azacitidine for the treatment of younger patients with intermediate risk acute myeloid leukemia (AML). Cytarabine is a drug that inhibits some of the enzymes needed for deoxyribonucleic acid (DNA) replication and repair and can slow or stop the growth of cancer cells. Daunorubicin is a drug that blocks a certain enzyme needed for cell division and DNA repair, and it may kill cancer 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. Azacitidine is a drug that interacts with DNA to activate tumor-suppressing genes, resulting in an anti-tumor effect. Adding venetoclax to cytarabine and daunorubicin, and adding venetoclax to azacitidine, may work better than the usual treatment of cytarabine with daunorubicin alone. To decide if they are better, the study doctors are looking to see if venetoclax increases the rate of elimination of AML in participants by 20% or more compared to the usual approach.

Detailed Description
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PRIMARY OBJECTIVE: I. To compare the rates of undetectable measurable residual disease (MRD) in patients who achieve a complete remission/complete remission with incomplete count recovery (CR/CRi) after induction therapy with 7 +3 (cytarabine + daunorubicin hydrochloride [daunorubicin]) versus (vs.) azacitidine + venetoclax vs. 7+3 + venetoclax. SECONDARY OBJECTIVES: I. To estimate the frequency and severity of toxicities with each of the regimens. II. To estimate complete remission (CR) rates (with and without MRD), complete remission with incomplete count recovery (CRi) (with and without MRD) rates, event-free survival (EFS), relapse-free survival (RFS), and overall survival (OS) with each of the regimens. TERTIARY OBJECTIVES: I. To evaluate response to therapy received according to genomic findings. II. To evaluate MRD kinetics by following patients with detectable MRD through Tier 2 and beyond. III. To evaluate longer term outcomes by treatment arm, genomics, MRD outcome, and other features as patients receive additional myeloMATCH therapies to generate testable hypotheses for more precise patient selection for these therapies. OUTLINE: Patients are randomized to 1 of 3 arms. ARM I: Patients receive daunorubicin intravenously (IV), cytarabine IV, and venetoclax orally (PO) on study and undergo bone marrow aspiration and collection of blood samples on study and as clinically indicated. ARM II: Patients receive azacitidine IV or subcutaneously (SC) and venetoclax PO on study and undergo bone marrow aspiration and collection of blood samples on study and as clinically indicated. ARM III: Patients receive daunorubicin IV and cytarabine IV on study and undergo bone marrow aspiration and collection of blood samples on study and as clinically indicated.

Official Title
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A Measurable Residual Disease (MRD) Driven, Phase II Study of Venetoclax Plus Chemotherapy for Newly Diagnosed Younger Patients With Intermediate Risk Acute Myeloid Leukemia: A Tier 1 MYELOMATCH Clinical Trial

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Azacitidine
* Procedure: Biospecimen Collection
* Procedure: Bone Marrow Aspirate
* Drug: Cytarabine
* Drug: Daunorubicin Hydrochloride
* Drug: Venetoclax


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must have enrolled onto MYELOMATCH and must have been given a treatment assignment to MyeloMATCH to MM1YA-CTG01 based on the presence of an actionable mutation as defined in MYELOMATCH Participants must have been registered to master screening and re-assessment protocol (myeloMATCH MSRP) prior to consenting to this study. Participants must have been assigned to this clinical trial, via MATCHBox, prior to registration to this study. Participants must have agreed to have specimens submitted for translational medicine (MRD) and must be offered the opportunity to submit biosamples for banking for future research as per the myeloMATCH MSRP Note: Pre-enrollment/diagnosis labs must have already been performed under the MSRP Previously untreated, de novo acute myeloid leukemia (AML) defined by > 20% myeloblasts in the peripheral blood or bone marrow (refer to the 2016 updated World Health Organization [WHO] classification of myeloid neoplasms and acute leukemia) excluding all the following categories of AML: Favorable cytogenetics: (t(8;21)q22;q22.1); RUNX1-RUNX1T1, inversion 16(p13.1;q22), t(16;16)(p13.1;q22); CBFB-MYH11 CEBPA biallelic mutations NPM1 mutation AML with PML-RARalpha AML with any adverse cytogenetics, TP53 mutation, RUNX1 mutation, ASXL1, 11q23/KMT2 rearrangements AML with FLT3-ITD or FLT3-TKD mutations Therapy related AML, or AML following a diagnosis of myelodysplasia or myeloproliferative neoplasm Participants with central nervous system (CNS) disease are eligible for this trial and will be treated according to institutional guidelines with intrathecal chemotherapy for this aspect of their disease Age 18-59 years at time of induction therapy Eastern Cooperative Oncology Group (ECOG) performance status =< 3 Total bilirubin =< 2 x institutional upper limit of normal (ULN) (must be done within 7 days of enrollment) Aspartate aminotransferase (AST) (serum glutamate pyruvate transaminase [SGPT]) +/or alanine aminotransferase (ALT) (serum glutamic-oxaloacetic transaminase [SGOT]) =< 3 × institutional ULN (must be done within 7 days of enrollment) Cardiac ejection fraction >= 50% (echocardiography or multigated acquisition scan [MUGA]) (must be done within 7 days of enrollment) Calculated creatinine clearance >= 30 mL/min/ 1.73m^2; Clearance to be calculated using Cockcroft formula (must be done within 7 days of enrollment) White blood cells (WBC) must be < 25 x 10^9/L. Hydroxyurea and leukapheresis are permitted to control the WBC prior to enrollment and initiation of protocol-defined therapy but must be stopped within 24 hours of initiation of protocol therapy Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better Women/men of childbearing potential must have agreed to use a highly effective contraceptive method while on treatment and for 6 months after stopping study drug. A woman is considered to be of childbearing potential if she has had menses at any time in the preceding 12 consecutive months. In addition to routine contraceptive methods, 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, or vasectomy/vasectomized partner. However, if at any point a previously celibate patient 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. Women of childbearing potential will have a pregnancy test to determine eligibility as part of the pre-study evaluation; this may include an ultrasound to rule-out pregnancy if a false-positive is suspected. Patient will be considered eligible if an ultrasound is negative for pregnancy Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrollment in the trial to document their willingness to participate Patients must be accessible for treatment, response assessment and follow up. Patients enrolled on this trial must be treated and followed at the participating centre. Investigators must assure themselves the patients enrolled on this trial will be available for complete documentation of the treatment, adverse events, and follow-up. Patients must agree to return to their primary care facility for any adverse events which may occur through the course of the trial In accordance with Canadian Cancer Trials Group (CCTG) policy, protocol treatment is to begin within 7 working days of patient enrollment Participants receiving strong or moderate CYP3A inhibitors must agree to discontinue use at least 48 hours prior to start of study treatment if assigned to arm 1 or 2 Patients with known human immunodeficiency virus (HIV) infection who are on effective anti-retroviral therapy and have undetectable viral load within 6 months of enrollment are eligible for this trial Participants with evidence of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load within 28 days of enrollment. Patients need to be on suppressive therapy, if indicated Patients with a history of hepatitis C virus (HCV) infection who have been treated and cured are eligible. Patients who with active HCV infection who are currently being treated must have an undetectable HCV viral load within 28 days of enrollment to be eligible Exclusion Criteria: Prior therapy for AML except for hydroxyurea and leukapheresis to control blood counts. The use of all-trans retinoic acid (ATRA) is permitted until a diagnosis of acute promyelocytic leukemia, if suspected, is ruled out Patients who are receiving any other investigational agents History of allergic reactions attributed to compounds of similar chemical or biologic composition to cytarabine, daunorubicin, azacitidine, venetoclax Pregnant women are excluded from this study because venetoclax, cytarabine and azacitidine have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with venetoclax, cytarabine and azacitidine breastfeeding should be discontinued if the mother is treated with venetoclax, cytarabine and azacitidine. These potential risks may also apply to other agents used in this study Patients with isolated myeloid sarcoma are not eligible Any other serious intercurrent illness, life threatening condition, organ system dysfunction, or medical condition judged by the local investigator to compromise the subject's safety (for example): Active, uncontrolled bacterial, fungal, or viral infection

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ARM I (daunorubicin, cytarabine, venetoclax)<br>Patients receive daunorubicin IV, cytarabine IV, and venetoclax PO on study and undergo bone marrow aspiration and collection of blood samples on study and as clinically indicated. | Procedure: Biospecimen Collection<br>* Undergo collection of blood samples<br>* Other names: Specimen Collection;Procedure: Bone Marrow Aspirate<br>* Undergo bone marrow aspiration<br>* Other names: Human Bone Marrow Aspirate;Drug: Cytarabine<br>* Given IV<br>* Other names: WR-28453;Drug: Daunorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubilem;Drug: Venetoclax<br>* Given PO<br>* Other names: Venclyxto;|
| Experimental: ARM II (azacitidine, venetoclax)<br>Patients receive azacitidine IV or SC and venetoclax PO on study and undergo bone marrow aspiration and collection of blood samples on study and as clinically indicated. | Drug: Azacitidine<br>* Given IV or SC<br>* Other names: Vidaza;Procedure: Biospecimen Collection<br>* Undergo collection of blood samples<br>* Other names: Specimen Collection;Procedure: Bone Marrow Aspirate<br>* Undergo bone marrow aspiration<br>* Other names: Human Bone Marrow Aspirate;Drug: Venetoclax<br>* Given PO<br>* Other names: Venclyxto;|
| Active Comparator: ARM III (daunorubicin, cytarabine)<br>Patients receive daunorubicin IV and cytarabine IV on study and undergo bone marrow aspiration and collection of blood samples on study and as clinically indicated. | Procedure: Biospecimen Collection<br>* Undergo collection of blood samples<br>* Other names: Specimen Collection;Procedure: Bone Marrow Aspirate<br>* Undergo bone marrow aspiration<br>* Other names: Human Bone Marrow Aspirate;Drug: Cytarabine<br>* Given IV<br>* Other names: WR-28453;Drug: Daunorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubilem;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurable residual disease (MRD) undetectable complete remission (CR) | Will assess after one induction cycle with or without the addition of venetoclax or two cycles of venetoclax and azacitidine. The MRD negative CR will be assessed using European LeukemiaNet (ELN) 2017 criteria [Döhner 2017]. The analysis population for the primary outcome will be all randomized patients with the intent to treat (ITT) population. The MRD undetectable CR rate will be the number of patients with MRD undetectable CR divided by the total number of patients. The differences of MRD undetectable CR rates between the experimental groups and the control group will be estimated and the corresponding one-sided 80% confidence limit will be calculated using Normal distribution approximation. MRD non-evaluable patients will be considered as MRD positive. | Up to 2 cycles (56 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency and severity of toxicities with each of the regimens | All patients who have received at least one dose of study treatment will be included in the safety analysis. Adverse events will be graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The incidence of adverse events will be summarized by type severity and relationship to the study drugs. A Fisher's exact test will be used to compare toxicities between the two arms, if needed. | Up to 10 years | 
| Complete remission (CR) rates | Will be assessed per 2017 ELN guidelines and will be tabulated. Exact 95% confidence intervals will be calculated. | Up to 2 cycles (56 days) | 
| Complete remission with incomplete count recovery (CRi) | Will be assessed with and without MRD. Will be assessed per 2017 ELN guidelines and will be tabulated. Exact 95% confidence intervals will be calculated. | Up to 2 cycles (56 days) | 
| Event-free survival (EFS) | Patients not known to have any of these events are censored on the date of last contact. Will be described by the Kaplan-Meier estimate, and log-rank tests will be used to test the difference between each experimental arms to the control arms. | From the date of randomization to the first: date of primary refractory disease; date of progressive disease; date off protocol therapy without CR or CRi; date of relapse from CR or CRi, or death from any cause, assessed up to 10 years | 
| Relapse-free survival (RFS) | Will be calculated for participants who have achieved a CR or CRi. For patients who have not relapsed or died, will be censored on the date of the last disease assessment. Will be described by the Kaplan-Meier estimate, and log-rank tests will be used to test the difference between each experimental arms to the control arms. | From the time of CR or CRi, until the relapse from CR or CRi, or death from any cause, assessed up to 10 years | 
| Overall survival (OS) | For patients who did not die, overall survival time will be censored at the time of last known alive (LKA) date. Will be described by the Kaplan-Meier estimate, and log-rank tests will be used to test the difference between each experimental arms to the control arms. | From randomization to the time of death from any cause, assessed up to 10 years | 
| Responses to therapy received relative to genomic findings | Will evaluate to gain insights toward more precise patient selection for optimal outcomes. | Up to 10 years |