Venetoclax + Azacitidine vs. Induction Chemotherapy in AML

Inclusion Criteria:

• Age ≥ 18 years

• Participants must have pathologically confirmed, newly diagnosed acute myeloidleukemia (AML), and characterized by 20% or more blasts in the peripheral blood orbone marrow. The AML may be either:

• De Novo: AML in patients with no clinical history of prior myelodysplasticsyndrome (MDS), myeloproliferative disorder, or exposure to potentiallyleukemogenic therapies or agents

• Secondary AML (sAML): refers to an acute leukemic process (1) evolving fromknown prior myelodysplasia, myeloproliferative disorder, or aplastic anemiawith or without treatment or; (2) as a product of previous exposure to a provenleukemogenic chemotherapeutic agent

• Eligible for intensive induction chemotherapy, according to their treating physician

• ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)

• Left ventricular ejection fraction > 50% as measured by echocardiogram or MUGA scan

• Must not have received systemic prior antineoplastic therapy for treatment for thenewly diagnosed AML, including radiation therapy, except hydroxyurea for thepurposes of cytoreduction. Patients may also have received all-trans retinoic acid (ATRA) if there is an early suspicion of acute promyelocytic leukemia (APL, M3-AML),although if confirmed to have APL these patients will be excluded from the study.

• Adequate renal function as defined by calculated creatinine clearance ≥ 30 mL/min (Cockcroft-Gault formula or measured by 24 hours urine collection).

• Adequate hepatic function per local laboratory reference ranges as follows:

• Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3.0X ULN (unlesssecondary to leukemia, in which case patient may be eligible afterconsideration and approval by the Overall PI)

• Total bilirubin ≤ 2.0 x ULN (unless bilirubin rise is known to be due toGilbert's syndrome or of non-hepatic origin)

• The effects of venetoclax on the developing human fetus are unknown. For this reasonand because other chemotherapeutic agents are known to be teratogenic, women ofchildbearing potential and men must agree to use adequate contraception (hormonal orbarrier method of birth control; abstinence) prior to study entry and for theduration of study participation. Should a woman become pregnant or suspect she ispregnant while she or her partner is participating in this study, she should informher treating physician immediately. Women should use contraceptives for at least 30days following the last dose of venetoclax. Men treated or enrolled on this protocolmust also agree to use adequate contraception prior to the study, for the durationof study participation, and 4 months after completion of therapy.

• Ability to understand and the willingness to sign a written informed consentdocument.

Exclusion Criteria:

• Diagnosis of Acute promyelocytic leukemia (APL) or AML with favorable cytogenetics [t(8;21), inv(16), t(16;16)]

• Patients < 60 years old with NPM1-mutated AML:

• Patients with FLT3-mutated AML (TKD or ITD) - see notes below.

• Institutional FLT3 mutational assays can be used to assess for detection of themutation.

• A patient with a FLT3 mutation detected at a level of 5% VAF or less, belowthat typically detectable on the companion diagnostics approved for use by theFDA (http://www.fda.gov/CompanionDiagnostics), would be deemed eligible toenroll.

• A negative FLT3 mutation result using an outside laboratory assay that isequivalent or similar to that approved as a companion diagnostic by the FDA (http://www.fda.gov/CompanionDiagnostics) is sufficient to rule out FLT3mutated disease.

• Patients with a known diagnosis of CML or known presence of BCR-Abl alteration

• Patients with acute leukemia with ambiguous lineage or mixed phenotype

• Patients that have received strong and/or moderate CYP3A inducers within 7 daysprior to the initiation of study treatment.

• Subject has consumed grapefruit, grapefruit products, Seville oranges (includingmarmalade containing Seville oranges) or Starfruit within 3 days prior to theinitiation of study treatment.

• Patients who have had prior systemic cytotoxic chemotherapy or radiotherapy for AML (excluding patients with therapy-related AML), except for hydroxyurea or 6-MP asnoted. Empiric intrathecal chemotherapy during a diagnostic lumbar puncture isallowed, as long as CNS disease is not suspected.

• Patients treated with prior hypomethylating therapy (such as azacitidine ordecitabine).

• Patients who will exceed a lifetime anthracycline exposure of >550 mg/m2daunorubicin or equivalent (or >400 mg/m2 daunorubicin or equivalent in the event ofprior mediastinal radiation) if they receive the maximum potential exposure toanthracyclines per protocol (including both induction and consolidation cycles).

• Individuals with a history of a different malignancy are ineligible except for thefollowing circumstances. Individuals with a history of other malignancies areeligible if they have been disease-free for at least 3 years and are deemed by theinvestigator to be at low risk for recurrence of that malignancy. Individuals with ahistory of other malignancies within 3 years and without any evidence of diseaseprogression may be considered, but only after consideration and approval by theOverall PI. Individuals with the following cancers are eligible if diagnosed andtreated within the past 3 years: cervical cancer in situ, breast DCIS, and basalcell or squamous cell carcinoma of the skin.

• Current clinical central nervous system (CNS) symptoms deemed by the investigator tobe related to leukemic CNS involvement (no lumbar puncture required, clinicalassessment per investigator's judgment is sufficient).

• Prior bone marrow transplantation for a myeloid malignancy

• Participants who are receiving any other investigational agents within the prior 14days.

• Currently clinically active hepatitis C or hepatitis B infection, as suggested byserology or viral load.

• Human immunodeficiency virus (HIV)-infected participants. Patients with detectableviral load on a stable anti-viral regimen may be eligible, after discussion with thestudy overall PI.

• Current or history of congestive heart failure New York Heart Association (NYHA)class 3 or 4, or any known history of an LVEF <50%, as measured by MUGA scan orechocardiogram. Prior to study entry, any ECG abnormality at screening has to bedocumented by the investigator as not medically relevant.

• Known hypersensitivity to the trial drugs or other contraindication to standard "7+3" induction chemotherapy.

• WBC > 25 x 109/L. Note: hydroxyurea is permitted to meet this criterion. If WBCcannot be controlled to <25 x 109/L at the time of enrollment, the WBC managementplan must be discussed and approved by the Overall PI.

• Patients who might refuse to receive blood products and/or have a hypersensitivityto blood products

• Patients with clinically significant persistent electrolyte abnormalities such ashypokalemia, hyperkalemia, hypocalcemia, hypercalcemia, hypomagnesemia, andhypermagnesemia of Grade > 1 per NCI CTCAE, v5.0. Treatment for correction of aboveelectrolyte imbalances is permitted during screening to meet eligibility.

• Uncontrolled intercurrent illness including, but not limited to, clinically ongoingor active infection requiring intravenous antibiotics (IV antibiotics are allowed ifinfection is deemed to be controlled), symptomatic congestive heart failure,unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/socialsituations that would limit compliance with study requirements.

• Known GI disease or GI procedures that could interfere with the oral absorption ortolerance of the study drugs. Examples include, but are not limited to partialgastrectomy, history of small intestine surgery, and celiac disease.

• Pregnant women are excluded from this study because venetoclax and azacitidine,along with standard induction chemotherapy, carries the potential for teratogenic orabortifacient effects. Because there is potential risk for adverse events in nursinginfants secondary to treatment of the mother with venetoclax as well as azacitidine,cytarabine, daunorubicin and idarubicin, breastfeeding should be avoided.Confirmation that the subject is not pregnant must be established by a negativeserum β-human chorionic gonadotropin (β-hCG) pregnancy test result obtained duringscreening. Pregnancy testing is not required for post-menopausal or surgicallysterilized women.

• Patients with psychological, familial, social, or geographic factors that otherwisepreclude them from giving informed consent, following the protocol, or potentiallyhamper compliance with study treatment and follow-up.

• Patients who are otherwise felt unable to comply with the protocol, in the opinionof the investigator.