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

Inclusion Criteria:

• Patient must have enrolled onto MYELOMATCH and must have been given a treatmentassignment to MyeloMATCH to MM1YA-CTG01 based on the presence of an actionablemutation as defined in MYELOMATCH

• Participants must have been registered to master screening and re-assessmentprotocol (myeloMATCH MSRP) prior to consenting to this study. Participants must havebeen assigned to this clinical trial, via MATCHBox Protocol Assignment Team, priorto registration to this study. Participants must have agreed to have specimenssubmitted for translational medicine (MRD) and must be offered the opportunity tosubmit biosamples for banking for future research as per the myeloMATCH MSRP

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

• Previously untreated, de novo acute myeloid leukemia (AML) defined by > 20%myeloblasts in the peripheral blood or bone marrow (refer to the 2016 updated WorldHealth 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 ormyeloproliferative neoplasm Participants with central nervous system (CNS)disease are eligible for this trial and will be treated according toinstitutional guidelines with intrathecal chemotherapy for this aspect of theirdisease

• 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 donewithin 7 days of enrollment)

• Aspartate aminotransferase (AST) (serum glutamate pyruvate transaminase [SGPT]) +/oralanine 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]) (if clinically indicated must be done within 14 days of enrollment)

• Calculated creatinine clearance >= 30 mL/min/ 1.73m^2; Clearance to be calculatedusing Cockcroft formula (must be done within 7 days of enrollment)

• White blood cells (WBC) must be < 25 x 10^9/L. Hydroxyurea and leukapheresis arepermitted to control the WBC prior to enrollment and initiation of protocol-definedtherapy but must be stopped at least 24 hours prior to the initiation of protocoltherapy. 1 dose of cytarabine at 1 mg/m^2 for urgent cytoreduction is also permitted

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial

• Patients with known history or current symptoms of cardiac disease, or history oftreatment with cardiotoxic agents, should have a clinical risk assessment of cardiacfunction using the New York Heart Association Functional Classification. To beeligible for this trial, patients should be class 2B or better

• Males and females of reproductive potential must have agreed to use a highlyeffective contraceptive method while on treatment and for 6 months after stoppingstudy drug. A woman is considered to be of "childbearing potential" if she has hadmenses at any time in the preceding 12 consecutive months. In addition to routinecontraceptive methods, "effective contraception" also includes heterosexual celibacyand surgery intended to prevent pregnancy (or with a side-effect of pregnancyprevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tuballigation, or vasectomy/vasectomized partner. However, if at any point a previouslycelibate patient chooses to become heterosexually active during the time period foruse of contraceptive measures outlined in the protocol, he/she is responsible forbeginning 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 localand regulatory requirements. Each patient must sign a consent form prior toenrollment 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 participatingcentre. Investigators must assure themselves the patients enrolled on this trialwill be available for complete documentation of the treatment, adverse events, andfollow-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 isto begin within 7 working days of patient enrollment

• Participants receiving strong or moderate CYP3A inhibitors must agree to discontinueuse 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 oneffective anti-retroviral therapy and have undetectable viral load within 6 monthsof enrollment are eligible for this trial

• Participants with evidence of chronic hepatitis B virus (HBV) infection must haveundetectable HBV viral load within 28 days of enrollment. Patients need to be onsuppressive therapy, if indicated

• Patients with a history of hepatitis C virus (HCV) infection who have been treatedand cured are eligible. Patients who with active HCV infection who are currentlybeing treated must have an undetectable HCV viral load within 28 days of enrollmentto be eligible

Exclusion Criteria:

• Prior therapy for AML except for hydroxyurea and leukapheresis to control bloodcounts. The use of all-trans retinoic acid (ATRA) is permitted until a diagnosis ofacute 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 orbiologic composition to cytarabine, daunorubicin, azacitidine, venetoclax

• Pregnant women are excluded from this study because venetoclax, cytarabine andazacitidine have the potential for teratogenic or abortifacient effects. Becausethere is an unknown but potential risk for adverse events in nursing infantssecondary to treatment of the mother with venetoclax, cytarabine and azacitidinebreastfeeding should be discontinued if the mother is treated with venetoclax,cytarabine and azacitidine. These potential risks may also apply to other agentsused in this study

• Patients with isolated myeloid sarcoma are not eligible

• Any other serious intercurrent illness, life threatening condition, organ systemdysfunction, or medical condition judged by the local investigator to compromise thesubject's safety (for example):

• Active, uncontrolled bacterial, fungal, or viral infection