Uproleselan, Azacitidine, and Venetoclax for the Treatment of Treatment Naive Acute Myeloid Leukemia

Inclusion Criteria:

• Ability to understand and the willingness to sign a written informed consent

• Diagnosis of AML by World Health Organization (WHO) 2016 criteria (Arber 2016)

• Age >= 18 years

• Treatment naive and eligible for venetoclax plus hypomethylating agents (HMA)

• Age >= 75 OR

• Age 18-74 with at least one of the following co-morbidities:

• Eastern Cooperative Oncology Group (ECOG) performance status of 2 or 3

• Cardiac history of congestive heart failure (CHF) requiring treatment orleft ventricular ejection fraction (LVEF) =< 50% or chronic stable angina

• Carbon monoxide diffusing capability test (DLCO) =< 65% or forcedexpiratory volume in 1 second (FEV1) =< 65%

• Any other situation that the investigator judges to be incompatible withintensive chemotherapy must be reviewed with the study chair before studyenrollment

• ECOG performance status of:

• 0 to 2 for subjects >= 75 years of age OR

• 0 to 3 for subjects 18-74 years of age

• White blood cell (WBC) =< 25,000/mm^3 at the start of study therapy (leukapheresisand hydroxyurea are allowed to meet this criteria). No other hematologic parameters

• Total bilirubin =< 1.5 x institution's upper limit of normal (ULN) unless related toAML or Gilbert's syndrome

• Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) andalanine aminotransferase (ALT)/serum pyruvic glutamic transaminase (SPGT) =< 3 xinstitutional ULN unless related to AML

• Creatinine clearance >= 45 mL/min (calculated by the Cockcroft Gault formula ormeasured by 24-hour urine collection)

• Note, if >= 65 years of age, creatinine clearance or serum creatinine can beused for determining eligibility with creatinine clearance >= 45 mL/min (calculated by the Cockcroft Gault formula or measured by 24-hour urinecollection) or serum creatinine =< institution's ULN considered eligible

• Women of child-bearing potential and men with partners of child-bearing potentialmust agree to use adequate contraception (non-estrogen hormonal or barrier method ofbirth control; abstinence) prior to study entry, for the duration of studyparticipation, and for 90 days following completion of therapy. Should a woman orfemale partner of a male subject become pregnant or suspect she is pregnant whileparticipating in this study, she should inform her treating physician immediately

• A woman of child-bearing potential is any female (regardless of sexualorientation, having undergone a tubal ligation, or remaining celibate bychoice) who meets the following criteria:

• Has not undergone a hysterectomy or bilateral oophorectomy; or

• Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)

• Women of child-bearing potential has negative pregnancy test prior to initiatingstudy drug dosing

• Able to swallow and retain oral medication

Exclusion Criteria:

• Current or anticipated use of other investigational agents

• Diagnosis of acute promyelocytic leukemia

• Active central nervous system involvement by AML

• AML must be treatment naive. Prior treatment with hypomethylating agent (azacitidineor decitabine), venetoclax or uproleselan, including for antecedent hematologicdisorders. Prior allogeneic hematopoietic transplant for antecedent hematologicdisorder is allowed if done at least 3 months prior to enrollment and there is noevidence of active graft versus host disease (GVHD) or requirement for systemicimmune suppression

• Anticancer therapies, including investigational therapy, chemotherapy, targetedsmall molecule agents, or radiotherapy within 14 days or 5 half-lives (whichever isshorter) prior to the first dose and throughout venetoclax administration. Biologicagents (e.g. monoclonal antibodies) given for anti-neoplastic intent within 30 daysprior to the first dose and throughout venetoclax administration

• Known diagnosis of human immunodeficiency virus (HIV) infection or known activehepatitis A, B or C infection with the exception of those with an undetectable viralload within 3 months of starting study treatment

• Known strong and/or moderate CYP3A inducers within 7 days prior to the initiation ofstudy treatment

• Subject has consumed grapefruit, grapefruit products, Seville oranges or Starfruitwithin 3 days prior to the initiation of study treatment

• Severe or uncontrolled medical disorder that would, in the investigator's opinion,impair ability to receive study treatment (i.e., uncontrolled diabetes, chronicrenal disease, chronic pulmonary disease or active, uncontrolled infection,psychiatric illness/social situations that would limit compliance with studyrequirements)

• History of other malignancies, except for malignancy treated with curative intentwith no known active disease present for >= 1 year; treated non-melanoma skincancer; and localized, cured prostate and cervical cancer

• Evidence of uncontrolled active systemic infection requiring therapy (viral,bacterial, or fungal). Fever of unknown origin is not an exclusion criterion, asthis may be disease related

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to agents used in study

• Subject has a malabsorption syndrome of other condition that precludes enteral routeof administration

• Subjects with a cardiovascular disability status of New York Heart Association classgreater than 2

• Pregnant or nursing. There is a potential for congenital abnormalities and for thisregimen to harm nursing infants.