A Multi-Site Break Through Cancer Trial: Targeting Measurable Residual Disease in Patients With Acute Myeloid Leukemia: A Phase 1/2 Study of Tagraxofusp, Azacitidine, and Venetoclax

Inclusion Criteria: * Age ≥ 18 years. * History of known diagnosis of Acute Myeloid Leukemia (including de novo, secondary or AML arising from MDS). * Subjects must be in CR, CRi, or CRh with \<5% morphologic blasts in bone marrow * Any evidence of CD123+ by central assessment. * Participants must have measurable disease, defined as ≥ 0.1% by multiparametric flow cytometric assay as assessed by central laboratory * ECOG performance status ≤2 (see Appendix A). * Subjects must have adequate organ and marrow function as defined below: * total bilirubin ≤ 1.5 x institutional upper limit of normal unless due to Gilbert or non-hepatic in origin * AST(SGOT) and ALT(SGPT) ≤ 3.0 × institutional upper limit of normal * Creatinine clearance ≥ 45 ml/min GFR by MDRD * Albumin ≥ 3.2 g/dL * Left ventricular ejection fraction ≥ institutional lower limit of normal by MUGA or echocardiogram within 30 days of first protocol treatment. This can be locally assessed. * Pregnancy potential: Female subjects of childbearing potential must have negative results for pregnancy test. Females with reproductive potential are advised to use effective contraception during study treatment and for at least 6 months after last dose. Similarly, males with female partners of reproductive potential are advised to use effective contraception during treatment and for at least 3 months after the last dose. Men must agree to abstain from donating sperm. * Subject is able and willing to adhere to the study visit schedule and other protocol requirements Exclusion Criteria: * Prior treatment with CD123-targeted therapy * Known diagnosis of acute promyelocytic leukemia. * Subjects who received intensive anti-leukemic chemotherapy within 2 weeks from first dose of study. If on venetoclax, subjects must be off venetoclax for at least 5 days * Subjects pre-arranged for SCT are only excluded if it is imminent. * History of prior allogeneic stem cell transplant * Subject has uncontrolled, clinically significant pulmonary disease (e.g. COPD, pulmonary hypertension, etc.) that in the opinion of the Investigator would put the subject at significant risk for pulmonary complications during the study. * Subject has experienced Grade 3 or Grade 4 capillary leak syndrome (CLS) in the past for any reason * Subjects with known HBV and/or HCV infection must have undetectable viral load during screening (HBV and HCV testing are not required.) Participants with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface (HBs) antigen negative-, anti-HBs antibody positive and anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate. * Subjects with known HIV positivity are permitted provided they have undetectable viral load at the time of screening (HIV testing is not required). * Subject has a concurrent malignancy or prior malignancy within the 6-month period before screening. To be eligible, subjects must be in remission from the prior malignancy at least 6 months prior to screening and all treatment-related toxicities must have resolved to ≤ Grade 1 except for alopecia. Exceptions include adequately treated basal or squamous cell skin cancer, superficial bladder cancer, adequately treated carcinoma in situ of the cervix or uterus, or carcinoma in situ of the breast, previous malignancy confined and surgically resected (or successfully treated with other modalities) with curative intent, which are permissible for inclusion. Maintenance therapy, hormonal therapy, or steroid therapy for a well-controlled concurrent malignancy is allowed. * Subject has uncontrolled systemic fungal, bacterial, or viral infection, defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antivirals, or antifungals, either IV or oral. However, subjects with controlled infection still requiring anti-infectives are eligible. * Subjects with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, that have New York Heart Association Functional Class III or IV symptoms. * Subject has evidence of ongoing alcohol or drug abuse * Subjects with known active/symptomatic CNS involvement. CNS prophylaxis allowed * Subjects receiving moderate or strong P450 3A (CYP3A) inducers within 7 days of start of study therapy. See Appendix B for examples * Subjects with uncontrolled intercurrent illness. * Administration or consumption of any of the following within 3 days prior to the first dose of study drug: * grapefruit or grapefruit products * Seville oranges (including marmalade containing Seville oranges) * star fruit * Pregnant women are excluded from this study because of the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with trial therapy, breastfeeding should be discontinued if the mother is treated on trial.