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

Study Overview
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Brief Summary
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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. 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
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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 4 arms. ARM I: Patients receive cytarabine intravenously (IV) and daunorubicin IV per standard approach on study. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial. ARM II: Patients receive cytarabine IV and daunorubicin IV with venetoclax orally (PO) on study. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial. ARM III: Patients receive azacitidine subcutaneously (SC) or IV and venetoclax PO on study. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial. ARM IV: Patients receive daunorubicin and cytarabine liposome IV on study. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial.

Official Title
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A Randomized Phase II Study Comparing Cytarabine + Daunorubicin (7 + 3) to (Daunorubicin and Cytarabine) Liposome, Cytarabine + Daunorubicin + Venetoclax, and Azacitidine + Venetoclax in Patients Aged 59 or Younger With High-Risk (Adverse) Acute Myeloid Leukemia; A MYELOMATCH Clinical Trial

Conditions
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Acute Myeloid Leukemia, Acute Myeloid Leukemia Arising From Previous Myelodysplastic/Myeloproliferative Neoplasm, Acute Myeloid Leukemia Post Cytotoxic Therapy, Acute Myeloid Leukemia, Myelodysplasia-Related

Intervention / Treatment
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* Drug: Azacitidine
* Procedure: Biospecimen Collection
* Procedure: Bone Marrow Aspiration
* Drug: Cytarabine
* Drug: Daunorubicin Hydrochloride
* Drug: Liposome-encapsulated Daunorubicin-Cytarabine
* Drug: Venetoclax


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: STEP 1 REGISTRATION: 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. Note: Pre-enrollment/diagnosis labs must have already been performed under the MSRP 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 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. 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 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 multi-gated acquisition (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 must have agreed to have specimens submitted for translational medicine (MRD) under the myeloMATCH MSRP and specimens must be submitted Participants must be offered participation in banking for future research. With participant's consent, 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 STEP 2 REGISTRATION - POST-REMISSION THERAPY Participants must have achieved a CR or CRi on Step 1 induction/reinduction treatment and be in CR or CRi at the time of Step 2 registration Exclusion Criteria: STAGE 1 REGISTRATION: 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 also excluded Participants must not be receiving or planning to receive any other investigational agents before completing protocol 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

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 |
| --- | --- |
| Active Comparator: Arm I (cytarabine, daunorubicin)<br>Patients receive cytarabine IV and daunorubicin IV per standard approach on study. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial. | Procedure: Biospecimen Collection<br>* Undergo collection of blood<br>* Other names: Specimen Collection;Procedure: Bone Marrow Aspiration<br>* Undergo bone marrow aspiration<br>Drug: Cytarabine<br>* Given IV<br>* Other names: WR-28453;Drug: Daunorubicin Hydrochloride<br>* Given IV<br>* Other names: Rubilem;|
| Experimental: Arm II (cytarabine, daunorubicin, venetoclax)<br>Patients receive cytarabine IV and daunorubicin IV with venetoclax PO on study. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial. | Procedure: Biospecimen Collection<br>* Undergo collection of blood<br>* Other names: Specimen Collection;Procedure: Bone Marrow Aspiration<br>* Undergo bone marrow aspiration<br>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 III (azacitidine, venetoclax)<br>Patients receive azacitidine SC or IV and venetoclax PO on study. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial. | Drug: Azacitidine<br>* Given SC or IV<br>* Other names: Vidaza;Procedure: Biospecimen Collection<br>* Undergo collection of blood<br>* Other names: Specimen Collection;Drug: Venetoclax<br>* Given PO<br>* Other names: Venclyxto;|
| Experimental: Arm IV (daunorubicin and cytarabine liposome)<br>Patients receive daunorubicin and cytarabine liposome IV on study. Patients also undergo a bone marrow aspiration and collection of blood throughout the trial. | Procedure: Biospecimen Collection<br>* Undergo collection of blood<br>* Other names: Specimen Collection;Procedure: Bone Marrow Aspiration<br>* Undergo bone marrow aspiration<br>Drug: Liposome-encapsulated Daunorubicin-Cytarabine<br>* Given IV<br>* Other names: Vyxeos;|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free survival (EFS) | Will be estimated using the Kaplan-Meier method. | 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 | 
| Relapse-free survival (RFS) | Defined for only patients achieving complete remission (CR), or CR with incomplete hematologic recovery (CRi). Will be estimated using the Kaplan-Meier method. | From the date of achievement of a remission until the date of relapse or death from any cause, assessed up to 5 years | 
| Overall survival (OS) | Will be estimated using the Kaplan-Meier method. | From day of randomization on study until death from any cause, assessed up to 5 years | 
| Time to relapse | 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. | Up to 5 years | 
| MRD negative complete remission (MRDneg CR) | 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. | Up to 5 years | 
| Incidence of adverse events | Will be analyzed using National Cancer Institute Common Terminology Criteria for Adverse Events version (v) 5.0 | Up to 5 years |