Testing the Use of Combination Therapy in Patients With Persistent Low Level Acute Myeloid Leukemia (AML) Following Initial Treatment

Study Overview
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Brief Summary
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ERASE is part of the MyeloMATCH initiative, Young Adult Basket and is a Tier 2 study. The study is comparing the use of Cytarabine to Cytarabine and Venetoclax, Daunorubicin/Cytarabine Liposome and Venetoclax, and Azacitidine and Venetoclax.

Detailed Description
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MM2YA-EA01 is a randomized Phase 2 study. Patients will be randomized to 1 of 4 treatment arms in a 1:1:1:1 ratio. The 4 treatment arms will compare: Cytarabine 3000 mg/m2 for CBD patients/1500 mg/m2 for non-CBD patients to cytarabine 3000 mg/m2 for CBD patients/1500 mg/m2 for non-CBD patients plus venetoclax 100 mg, daunorubicin 29 mg/m2/Cytarabine 65 mg/m2 liposome plus venetoclax 400 mg, and Azacitidine 75 mg/m2 plus venetoclax 400 mg.

Official Title
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Eradicating Measurable Residual Disease in Patients With Acute Myeloid Leukemia (AML) Prior to StEm Cell Transplantation (ERASE): A MyeloMATCH Treatment Trial

Conditions
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Leukemia, Myeloid, Acute

Intervention / Treatment
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* Drug: Cytarabine
* Drug: Venetoclax
* Drug: CPX-351
* Drug: Azacitidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient must be ≥ 18 and ≤ 59 years of age. Patient must have ECOG performance status 0-2 Patient must have morphologically documented AML or secondary AML [from prior conditions such as myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN)] or therapy related AML (t-AML), as defined by World Health Organization (WHO) criteria Patient must have completed induction chemotherapy in a myeloMATCH Young Adult Tier-1 protocol. Patient may have received prior hypomethylating agents (HMAs). Patient may have received prior azacitidine + venetoclax. Patient must have been assigned to this protocol by myeloMATCH MSRP/MATCHBOX/. Patients thereby assigned will have attained complete remission (CR) or CR with partial hematologic recovery (CRh) (defined as CR with (ANC) ≥ 500/mcL and/or platelets > 50/mcL) with detectable MRD at time of assignment. MRD is defined as >0.1% flow cytometry on bone marrow (BM) biopsy as assessed by MDNet. The definition of CR or CRh may be made ± 2 weeks from BM biopsy Patient must have the ability to understand and the willingness to sign a written informed consent document. Patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible. Patient must have recovered (i.e.: resolved to < grade 2) from adverse events related to prior anti-cancer therapy at the time of randomization with the exception of alopecia Patient must have adequate organ and marrow function as defined below (these labs must be obtained ≤ 7 days prior to protocol randomization): Absolute neutrophil count (ANC) ≥ 500/mcL ANC:__________ Date of Test:__________ Platelets ≥ 50,000/mcL Platelets:__________ Date of Test:__________ Total bilirubin ≤ 2 x institutional upper limit of normal (ULN) Total Bilirubin:__________ Institutional ULN:_________ Date of Test:__________ AST(SGOT)/ALT(SGPT) ≤ 3.0 × institutional ULN AST:_______ Institutional ULN:_________ Date of Test:_______ ALT: _______Institutional ULN:_________ Creatinine ≤ 1.5 x institutional ULN Creatinine ______________Date of Test:________ OR ≥ 50 mL/min/1.73 m2 Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of randomization are eligible for this trial. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load 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 must be able to swallow oral tablets and be free of GI absorption issues. Exclusion Criteria: Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. All patients of childbearing potential must have a blood test or urine study within 14 days prior to randomization to rule out pregnancy. A patient of childbearing potential is defined as anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). Patient of child bearing potential? ______ (Yes or No) Date of blood test or urine study: ___________ Patients of childbearing potential and/or sexually active patients must not expect to conceive or father children by using an accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study and continue for 6 months after the last dose of daunorubicin + cytrarabine liposome, 6 months after the last dose of azacitidine for patients of childbearing potential, 3 months after the last dose of azacitidine for male patients, and for 30 days after the last dose of venetoclax. Patient must also abstain from nursing an infant for 2 weeks after the last dose of daunorubicin + cytrarabine liposome and for 1 week after the last dose of azacitidine. Patients must not have FLT3 TKD or ITD mutation. Patients with this mutation, will be excluded from this study because myeloMATCH plans separate studies in tier-2 for those patients Patient must not be receiving any other investigational agents at the time of randomization. Patient must not have history of allergic reactions attributed to compounds of similar chemical or biologic composition to cytarabine, azacitidine, venetoclax or Daunorubicin and Cytarabine liposome Patients must not have uncontrolled intercurrent illness including but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or serious chronic gastrointestinal conditions associated with diarrhea

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: Participants will be randomized to 1 of 4 arms in a 1:1:1:1 ratio.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A: Cytarabine<br>Patients will participate for 2 cycles. Each cycle is 28 days. For Core Binding Factor (CBF) leukemia patients: Cytarabine 3000 mg/m2 IV twice daily (BID), 12 hours apart x 6 doses either on Days 1, 3, and 5 OR Days 1, 2, and 3 (per institutional preference) For non-Core Binding Factor (CBF) leukemia patients: Cytarabine 1500 mg/m2 IV twice daily (BID), 12 hours apart x 6 either on Days 1, 3, and 5 OR Days 1, 2, and 3 (per institutional preference) | Drug: Cytarabine<br>* Arm A: CBF-Cytarabine 3000 mg/m2 or 1500 mg/m2 IV twice daily (BID), 12 hours apart x 6 doses either on Days 1, 3, and 5 OR Days 1, 2, and 3<br>* Other names: 63878;|
| Experimental: Arm B: Cytarabine + Venetoclax<br>Patients will participate for 2 cycles. Each cycle is 28 days. For Core Binding Factor (CBF) leukemia patients: Cytarabine 3000 mg/m2 IV twice daily (BID), 12 hours apart x 6 doses either on Days 1, 3, and 5 OR Days 1, 2, and 3 (per institutional preference) followed by Venetoclax 100 mg daily Day 1 through Day 8 For non-Core Binding Factor (CBF) leukemia patients: Cytarabine 1500 mg/m2 IV twice daily (BID), 12 hours apart x 6 either on Days 1, 3, and 5 OR Days 1, 2, and 3 (per institutional preference) followed by Venetoclax 100 mg daily Day 1 through Day 8 | Drug: Cytarabine<br>* Arm A: CBF-Cytarabine 3000 mg/m2 or 1500 mg/m2 IV twice daily (BID), 12 hours apart x 6 doses either on Days 1, 3, and 5 OR Days 1, 2, and 3<br>* Other names: 63878;Drug: Venetoclax<br>* Venetoclax 100 mg daily Day 1 through Day 8 Venetoclax 400 mg orally once daily on Days 1-14 Venetoclax 400 mg orally once daily on Days 1-28<br>* Other names: 766270;|
| Experimental: Arm C: Daunorubicin + Cytarabine Liposome+ Venetoclax<br>Patients will participate for 2 cycles. Each cycle is 28 days. Daunorubicin 29 mg/m2/Cytarabine 65 mg/m2 liposome IV on Days 1 and 3 with Venetoclax 400 mg orally once daily on Days 1-14 | Drug: Venetoclax<br>* Venetoclax 100 mg daily Day 1 through Day 8 Venetoclax 400 mg orally once daily on Days 1-14 Venetoclax 400 mg orally once daily on Days 1-28<br>* Other names: 766270;Drug: CPX-351<br>* Daunorubicin 29 mg/m2/Cytarabine 65 mg/m2 liposome IV on Days 1 and 3<br>* Other names: 775341;|
| Experimental: Arm D: Azacitidine + Venetoclax<br>Patients will participate for 2 cycles. Each cycle is 28 days. Azacitidine 75 mg/m2 IV/SC on Days 1-7 OR Days 1-5 and Days 8-9 (per institutional preference) with Venetoclax 400 mg orally once daily on Days 1-28 | Drug: Venetoclax<br>* Venetoclax 100 mg daily Day 1 through Day 8 Venetoclax 400 mg orally once daily on Days 1-14 Venetoclax 400 mg orally once daily on Days 1-28<br>* Other names: 766270;Drug: Azacitidine<br>* Azacitidine 75 mg/m2 IV/SC on Days 1-7 OR Days 1-5 and Days 8-9 (per institutional preference)<br>* Other names: 102816;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Achieving Minimal residual disease (MRD) | Rate of Achieving MRD Negative CR | Day 56 |