Iadademstat in Combination With Azacitidine and Venetoclax in Treating Newly Diagnosed Acute Myeloid Leukemia

Inclusion Criteria: * Patients at least 18 years of age will be considered for inclusion without bias against gender identity, race, or ethnicity * Ability to comprehend the investigational nature of the study and provide written informed consent * Patients with previously untreated, morphologically documented AML based on World Health Organization (WHO) 2008 definitions who are ineligible for standard of care (SOC) intensive chemotherapy (IC) induction OR documented unwillingness to undergo IC induction. Ineligible for IC is defined as: * Documented intermediate- or adverse-risk AML based on European Leukemia Network (ELN) 2022 criteria * Note: Cases of AML (MDS) overlap with 10-19% bone marrow (BM) or peripheral blood (PB) blasts will be considered * Note: Cases of acute promyelocytic leukemia (PML) and AML with BCR::ABL1 fusions will be excluded * Eastern Cooperative Oncology Group (ECOG) performance ≤ 2 (Patients aged ≥ 75 years, at the time of consent) * Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (Patients aged ≥ 75 years, at the time of consent) * High total bilirubin values may require indirect and direct bilirubin testing. Individuals with known Gilbert's syndrome may be considered for enrollment despite high indirect (and total) bilirubin * Creatinine clearance (CrCl) of ≥ 60 mL/min (estimated using the Cockcroft Gault formula or measured by 24 hours urine collection. If altered, CrCl is determined to be related to concomitant medication that alters renal function * Patients aged ≥ 18 to 74 years (ECOG performance status \[PS\] ≤ 3 is accepted) at consent must meet ≥ 1 of the following criteria defining a co morbidity: * ECOG PS of 2 or 3 (Note: Patients ≥ 18 to 74 years of age with PS of 0-1 must meet criteria of one of the following comorbidities.) * Cardiac history of congestive heart failure (CHF) requiring treatment or ejection fraction ≤ 50% or chronic stable angina * Diffusing capacity of the lung for carbon monoxide (DLCO) ≤ 65% or forced expiratory volume in 1 second (FEV1) ≤ 65% * CrCl ≥ 30 mL/min to \< 45 ml/min * Moderate hepatic impairment with total bilirubin \> 1.5 to ≤ 3.0 × ULN; * High total bilirubin values may require indirect and direct bilirubin testing. Individuals with known Gilbert's syndrome may be considered for enrollment despite high indirect (and total) bilirubin * Other comorbidities that the physician judges to be incompatible with intensive chemotherapy (IC). In these cases, the comorbidity must be reviewed and approved by the principal investigator (PI) before study enrollment * Ability to swallow oral medications * No ongoing anticoagulation or antiplatelet therapy within 14 days of start of treatment with IADA * No history of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention * No history of stroke or intracranial hemorrhage within 180 days of start of IADA * No major bleeding event, as defined by the International Society of Thrombosis and Hemostasis (ISTH), within 12 weeks of start of IADA * Uncorrected international normalized ratio (INR) or activated partial thromboplastin time (aPTT) of \< 1.5 x ULN. * If INR or aPTT \> 1.5 x ULN has been corrected (prior to enrollment), then history of disseminated intravascular coagulation (DIC) must be absent * White blood cell (WBC) \< 20 x 10\^9/L prior to study start. Cytoreduction prior to study treatment is allowed with * Hydroxyurea for up to 14 days and until 24 hours prior to start of IADA; or * Leukapheresis for up to 14 days prior to start of IADA * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) or alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) ≤ 2.0 x institutional ULN * Lower hepatic function may be considered if liver enzyme abnormalities are determined by the treating MD and principal investigator (PI) to be due to leukemic infiltration * Willing and able to * Adhere to study schedule of activities and life style restrictions while on treatment; * Provide bone marrow (BM) aspirate and core biopsy samples; and * Accept supportive and prophylactic care for hematologic toxicities, infection, and immediate sequelae, including transfusions * Negative pregnancy test within 72 hours of start of IADA for persons of childbearing potential (PCBP) * Willingness to comply with study requirements for contraception, as follows: PCBP and sperm-producing participants who are sexually active with a PCBP must use study approved contraception from start of investigational product (first dose of IADA) until 6 months after the last dose of IADA. Pregnancy is exclusionary because the agents used in this study have the potential for teratogenic or abortifacient effects Exclusion Criteria: * Prior allergic response to iadademstat (IADA), venetoclax, azacitidine, or any excipients in the formulations * Body weight \< 50 kg * Investigational therapy within 5 half-lives or, if unknown, within 28 days prior to start of IADA * Treatment for AML within 14 days prior to start of IADA. Cytoreduction for patients with proliferative disease must meet the criteria listed in inclusion criteria * Radiotherapy less than 14 days prior to start of IADA * Recent and significant medical interventions, such as major surgery within 28 days prior to the start of IADA, or stem cell transplant within 100 days prior to the start of IADA. Patients with active treatment for graft-versus-host disease (GVHD) are excluded * Another active malignancy within 5 years prior to the start of IADA, or at the investigator's discretion * Treatments targeting or inhibiting LSD1/KDM1A or BCL 2 within 12 months prior to the start of IADA * Documented dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally * Treatment with monoamine oxidase inhibitors (e.g., tranylcypromine), if treatment is not finalized at least 3 weeks prior to the start of IADA * Active central nervous system involvement with AML * Uncontrolled infection. Participants with controlled infection must be afebrile and hemodynamically stable for at least 72 hours prior to start of IADA and must be amenable to alternate treatment if current treatment will interact with investigational regimen * Active hepatic disorder or documented positive hepatitis B or C virus (HBV/HCV, respectively) status, except in cases of undetectable HBV/HCV viral load for at least 3 months prior to the start of IADA. (Hepatitis B or C testing is not required for eligibility assessment.) * Individuals serology positive for human immunodeficiency virus (HIV) and under active treatment with highly active antiretroviral therapy (HAART) (or another therapy that may interfere with metabolism of study agents). Otherwise, enrollment may be considered in cases of HIV that is controlled with another treatment type or in cases that that acceptable modification of the patient's HIV treatment exists * Use a P-gp inhibitor within 21 days or 3 half-lives whichever is longer prior to treatment with venetoclax * Use of strong or moderate CYP3A4 inducers or inhibitors within 2 days or 3 half lives whichever is longer, prior to start of treatment with venetoclax * Unwillingness to stop breastfeeding. Because there is a potential risk for adverse events in nursing infants secondary to treatment of the mother with the chemotherapy agents, breastfeeding should also be avoided throughout the study and until at least 60 days after last dose of IADA * Uncontrolled hypertension (i.e., systolic blood pressure \> 180 mm Hg, diastolic blood pressure \> 95 mm Hg). Use of anti-hypertensive agents to control hypertension before C1D1 is allowed * Patients with poorly controlled diabetes. Poorly controlled diabetes mellitus defined as glycosylated hemoglobin (HbA1c) ≥ 8%; patients with a history of transient glucose intolerance due to corticosteroid administration may be enrolled in this study if all other inclusion/exclusion criteria are met * Patients with mean of triplicate corrected QT interval (Fridericia's correction formula \[QTcF\]) \> 450 ms at Screening based on central reading * Uncontrolled intercurrent illness including, but not limited to ongoing or active uncontrolled infection, unstable cardiac or pulmonary function or acute insufficiency (e.g., symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia), or psychiatric illness or social situation that could limit compliance with study requirements, at the discretion of the investigator