Navitoclax, Venetoclax, and Decitabine for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia Previously Treated With Venetoclax

Inclusion Criteria:

• Documented informed consent of the participant and/or legally authorizedrepresentative

• For participants under the age of 18 years, documentation of adolescent assent bythe participant and consent of both parents or guardian

• Adults aged >= 18 years

• Adolescent patients aged >= 16 years and < 18 years weighing at least 45 kg who haveno other standard-of-care option for treatment

• Eastern Cooperative Oncology Group (ECOG) =< 2

• Patients with histologically confirmed AML, according to World Health Organization (WHO) criteria, with refractory/relapsed (R/R) disease following avenetoclax-containing regimen who are ineligible for therapies known to be effectivefor treatment of their AML.

• Patients with extramedullary disease may be included if they also have marrowinvolvement

• Patients with acute promyelocytic leukemia (APL) will not be eligible

• Fully recovered from the acute toxic effects (except alopecia) to =< grade 1 ofprior anti-cancer therapy

• Ability to swallow pills

• Absolute neutrophil count (ANC) >= 750/mm^3 (performed within 14 days prior to day 1of protocol therapy unless otherwise stated)

• NOTE: Growth factor is not permitted within 14 days of ANC assessment unlesscytopenia is secondary to disease involvement

• White blood cell (WBC) =< 25 x 10^9/L prior to initiation of study therapy.Cytoreduction with hydroxyurea prior to treatment and/or during cycle 1 may berequired (performed within 14 days prior to day 1 of protocol therapy unlessotherwise stated)

• Platelets >= 75,000/mm^3

• NOTE: Platelet transfusions are not permitted within 14 days of plateletassessment unless cytopenia is secondary to disease involvement

• Total bilirubin =< 1.5 X upper limit of normal (ULN) (performed within 14 days priorto day 1 of protocol therapy unless otherwise stated)

• Aspartate aminotransferase (AST) =< 3.0 x ULN (performed within 14 days prior to day 1 of protocol therapy unless otherwise stated)

• Alanine aminotransferase (ALT) =< 3.0 x ULN (performed within 14 days prior to day 1of protocol therapy unless otherwise stated)

• Creatinine clearance of >= 45 ml/min per 24-hour urine test or the Cockcroft-Gaultformula (performed within 14 days prior to day 1 of protocol therapy unlessotherwise stated)

• If in the absence of anticoagulants: International normalized ratio (INR) ORprothrombin (PT) =< 1.5 x ULN (performed within 14 days prior to day 1 of protocoltherapy unless otherwise stated)

• If in the absence of anticoagulants: Activated partial thromboplastin time (aPTT) =< 1.5 x ULN (performed within 14 days prior to day 1 of protocol therapy unlessotherwise stated)

• Left ventricular ejection fraction (LVEF) >= 50%

• Note: To be performed within 28 days prior to day 1 of protocol therapy

• Corrected QT interval (QTc) =< 480 ms

• Note: To be performed within 28 days prior to day 1 of protocol therapy

• Seronegative for human immunodeficiency virus (HIV) antigen (Ag)/antibody (Ab)combo, hepatitis C virus (HCV), active hepatitis B virus (HBV) (surface antigennegative), and syphilis (RPR) (performed within 14 days prior to day 1 of protocoltherapy unless otherwise stated)

• If positive, Hepatitis C RNA quantitation must be performed

• Meets other institutional and federal requirements for infectious disease titerrequirements

• Note Infectious disease testing to be performed within 28 days prior to day 1of protocol therapy

• Women of child-bearing potential (WOCBP): negative urine or serum pregnancy test. Ifthe urine test is positive or cannot be confirmed as negative, a serum pregnancytest will be required (performed within 14 days prior to day 1 of protocol therapyunless otherwise stated)

• Agreement by females and males of childbearing potential to use an effective methodof birth control or abstain from heterosexual activity for the course of the studythrough at least 3 months (males) and 6 months (females) after the last dose ofprotocol therapy

• Childbearing potential defined as not being surgically sterilized (men andwomen) or have not been free from menses for > 1 year (women only)

Exclusion Criteria:

• Hematopoietic stem cell transplant within 100 days prior to day 1 of protocoltherapy

• Chemotherapy, radiation therapy, biological therapy, or immunotherapy within 14 daysor 5 half-lives, whichever is shorter, prior to day 1 of protocol therapy with thefollowing exceptions:

• Subjects will be allowed to have been on venetoclax at screening and remain onit through treatment start.

• Hydroxyurea is allowed prior to treatment and through cycle 1 for control ofrapidly progressing leukemia

• Strong or moderate CYP3A4 inducers within 14 days prior to day 1 of protocol therapy

• Grapefruit, grapefruit products, Seville oranges (including marmalade containingSeville oranges) or star fruit consumed within 3 days prior to the first dose ofstudy drug

• Immunosuppressants (steroids =< 10 mg/day of oral prednisone or equivalent isallowed) within the last 28 days

• Hematopoietic growth factors in the last 14 days

• Must not have received or planning to receive live vaccine while being on study or 4weeks before and after completion of treatment

• Herbal medications known to affect platelet function within 14 days of therapyinitiation

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to study agent

• Active graft-versus-host-disease (GVHD)

• Active central nervous system (CNS) disease

• No measurable disease in the bone marrow

• Active diarrhea

• Gastrointestinal disorder that interferes with oral drug absorption such asmalabsorption syndrome

• Clinically significant cardiac morbidities (class III/IV cardiovascular disabilityaccording to the New York Heart Association classification, arrhythmia not stable onmedical management, acute cardiovascular ischemic event within 6 months ofenrollment, etc.)

• Clinically significant uncontrolled illness

• Active infection requiring antibiotics

• Active/uncontrolled HIV infection, acquired immunodeficiency syndrome (AIDS), orcurrently taking contraindicated medications for HIV control

• Diagnosis of Gilbert's disease

• Any other active malignancy at time of enrollment. Exceptions include basal/squamouscell carcinoma, in situ adequately treated breast and uterine cancer

• Females only: Pregnant or breastfeeding

• Any other condition that would, in the Investigator's judgment, contraindicate thepatient's participation in the clinical study due to safety concerns with clinicalstudy procedures

• Prospective participants who, in the opinion of the investigator, may not be able tocomply with all study procedures (including compliance issues related tofeasibility/logistics)