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 biasagainst gender identity, race, or ethnicity

• Ability to comprehend the investigational nature of the study and provide writteninformed consent

• Patients with previously untreated, morphologically documented AML based on WorldHealth Organization (WHO) 2008 definitions who are ineligible for standard of care (SOC) intensive chemotherapy induction and also meet the following criteria:

• Documented intermediate- or adverse-risk AML based on European Leukemia Network (ELN) 2022 criteria

• Note: Cases of AML/myelodysplastic syndrome (MDS) overlap with 10-19% bonemarrow (BM) or peripheral blood (PB) blasts will be considered

• Note: Cases of acute promyelocytic leukemia (PML) and AML with BCR::ABL1fusions 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, atthe time of consent)

• High total bilirubin values may require indirect and direct bilirubin testing.Individuals with known Gilbert's syndrome may be considered for enrollmentdespite high indirect (and total) bilirubin

• Creatinine clearance (CrCl) of ≥ 60 mL/min (estimated using the Cockcroft Gaultformula or measured by 24 hours urine collection) (Patients aged ≥ 75 years, at thetime of consent)

• Patients aged ≥ 18 to 74 years (ECOG performance status [PS] ≤ 3 is accepted) atconsent 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 mustmeet criteria of one of the following comorbidities.)

• Cardiac history of congestive heart failure (CHF) requiring treatment orejection fraction ≤ 50% or chronic stable angina

• Diffusing capacity of the lung for carbon monoxide (DLCO) ≤ 65% or forcedexpiratory 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 bilirubintesting. Individuals with known Gilbert's syndrome may be considered forenrollment despite high indirect (and total) bilirubin

• Other comorbidities that the physician judges to be incompatible with intensivechemotherapy (IC). In these cases, the comorbidity must be reviewed andapproved by the principal investigator (PI) before study enrollment

• Ability to swallow oral medications

• No ongoing anticoagulation or antiplatelet therapy within 14 days of start oftreatment with IADA (i.e., cycle 0 day 1 [C0D1])

• No history of severe bleeding disorder such as hemophilia A, hemophilia B, vonWillebrand disease, or history of spontaneous bleeding requiring blood transfusionor 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 andHemostasis (ISTH), within 12 weeks of start of IADA

• Uncorrected international normalized ratio (INR) or activated partial thromboplastintime (aPTT) of < 1.5 x ULN.

• If INR or aPTT > 1.5 x ULN has been corrected (prior to enrollment), thenhistory of disseminated intravascular coagulation (DIC) must be absent

• White blood cell (WBC) < 20 x 10^9/L prior to study start. Cytoreduction prior tostudy 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]) oralanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.0x institutional ULN

• Lower hepatic function may be considered if liver enzyme abnormalities aredetermined by the treating MD and principal investigator (PI) to be due toleukemic infiltration

• Willing and able to

• Adhere to study schedule of activities and life style restrictions while ontreatment;

• 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 childbearingpotential (PCBP)

• Willingness to comply with study requirements for contraception, as follows: PCBPand sperm-producing participants who are sexually active with a PCBP must use studyapproved contraception from start of investigational product (first dose of IADA)until 6 months after the last dose of IADA. Pregnancy is exclusionary because theagents used in this study have the potential for teratogenic or abortifacienteffects

Exclusion Criteria:

• Prior allergic response to iadademstat (IADA), venetoclax, azacitidine, or anyexcipients in the formulations

• Body weight < 50 kg

• Investigational therapy within 5 half-lives or, if unknown, within 28 days prior tostart of IADA

• Treatment for AML within 14 days prior to start of IADA. Cytoreduction for patientswith 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 daysprior to the start of IADA, or stem cell transplant within 100 days prior to thestart 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 theinvestigator's discretion

• Treatments targeting or inhibiting LSD1/KDM1A or BCL 2 within 12 months prior to thestart of IADA

• Documented dysphagia, short-gut syndrome, gastroparesis, or other conditions thatlimit the ingestion or gastrointestinal absorption of drugs administered orally

• Treatment with monoamine oxidase inhibitors (e.g., tranylcypromine), if treatment isnot 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 andhemodynamically stable for at least 72 hours prior to start of IADA and must beamenable to alternate treatment if current treatment will interact withinvestigational 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 atleast 3 months prior to the start of IADA. (Hepatitis B or C testing is not requiredfor eligibility assessment.)

• Individuals serology positive for human immunodeficiency virus (HIV) and underactive treatment with highly active antiretroviral therapy (HAART) (or anothertherapy that may interfere with metabolism of study agents). Otherwise, enrollmentmay be considered in cases of HIV that is controlled with another treatment type orin cases that that acceptable modification of the patient's HIV treatment exists

• Use a P-gp inhibitor within 23 days prior to treatment with venetoclax

• Use of strong or moderate CYP3A4 inducers or inhibitors within 2 days or 3 halflives whichever is longer, prior to start of treatment with venetoclax

• Unwillingness to stop breastfeeding. Because there is a potential risk for adverseevents in nursing infants secondary to treatment of the mother with the chemotherapyagents, 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, diastolicblood pressure > 95 mm Hg). Use of anti-hypertensive agents to control hypertensionbefore C1D1 is allowed

• Patients with poorly controlled diabetes. Poorly controlled diabetes mellitusdefined as glycosylated hemoglobin (HbA1c) ≥ 8%; patients with a history oftransient glucose intolerance due to corticosteroid administration may be enrolledin this study if all other inclusion/exclusion criteria are met

• Patients with mean of triplicate corrected QT interval (Fridericia's correctionformula [QTcF]) > 450 ms at Screening based on central reading

• Uncontrolled intercurrent illness including, but not limited to ongoing or activeuncontrolled infection, unstable cardiac or pulmonary function or acuteinsufficiency (e.g., symptomatic congestive heart failure, unstable angina pectoris,cardiac arrhythmia), or psychiatric illness or social situation that could limitcompliance with study requirements, at the discretion of the investigator