Tagraxofusp and Azacitidine With Venetoclax in Newly Diagnosed Secondary AML After Hypomethylating Agents

Inclusion Criteria:

Subject must meet all of the following applicable inclusion criteria to participate in this study:

• Written informed consent and HIPAA authorization for release of personal healthinformation prior to registration. NOTE: HIPAA authorization may be included in theinformed consent or obtained separately.

• Subjects must have newly diagnosed, untreated AML, as defined by ≥ 20% blasts inperipheral blood or bone marrow by manual aspirate differential,immunohistochemistry staining, or flow cytometry, as defined by standard WHO 2016diagnostic criteria.

• Subjects must have documented CD123 positivity on leukemia cells by a centralizedflow cytometry assay (Hematologics).

• Documented diagnosis of prior MDS, CMML, MDS/MPN overlap syndromes, or MPN'saccording to WHO criteria. Subjects must have received at least 2 cycles ofhypomethylating agents (azacitidine or decitabine or oral decitabine/cedazuridine)for the management of MDS, CMML, MDS/MPN overlap syndromes, or MPN's. NOTE: Subjectswho have enrolled on clinical trials with investigational agents in combination withHMA's will still be eligible. Investigational agents must have been discontinued >14days prior to study treatment initiation. Subjects who have enrolled on clinicaltrials with investigational agents in combination with HMA's will still be eligible.Investigational agents must have been discontinued > 21 days prior to studytreatment initiation.

• WBC < 30 x 109 /µL- subjects with WBC ≥ 30 x 109 /µL may still be eligible afterreceiving cytoreduction measures such as hydroxyurea, and/or leukapheresis, if WBC < 30 x 109 /µL prior to study treatment initiation. Cytoreduction with hydroxyurea,leukapheresis and/or cyclophosphamide is allowed prior to treatment. Hydroxyureamust be discontinued ≥ 12 hours prior to study treatment initiation.Cyclophosphamide must be discontinued ≥ 5 days prior to study treatment initiation.

• Age ≥ 18 years at the time of consent.

• ECOG Performance Status of 0-2.

• Demonstrate adequate organ function within 28 days prior to registration.

• Left ventricular ejection fraction (LVEF) ≥ 45%.

• Females of childbearing potential must have a negative serum pregnancy test within 7days prior to registration. NOTE: Females are considered of childbearing potentialunless they are surgically sterile (have undergone a hysterectomy, bilateral tuballigation, or bilateral oophorectomy) or they are naturally postmenopausal for atleast 12 consecutive months.

• Females of childbearing potential and male participants must be willing to useeffective contraception as outlined in the protocol.

• Known HIV-infected patients on effective anti-retroviral therapy with undetectableviral load within 6 months of registration are eligible for this trial.

• Patients with known evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated. Patients witha history of hepatitis C virus (HCV) infection must have been treated and cured. Forpatients with HCV infection who are currently on treatment, the HCV viral load mustbe undetectable to be eligible for this trial.

• As determined by the enrolling physician or protocol designee, ability of thesubject to understand and comply with study procedures for the entire length of thestudy.

Exclusion Criteria:

Subjects meeting any of the criteria below may not participate in the study:

• Subjects who are suitable for and are willing to receive intensive chemotherapy.

• Diagnosis of acute promyelocytic leukemia.

• Known CNS involvement with AML.

• Previous receipt of tagraxofusp.

• Treatment with chemotherapy, wide-field radiation, or biologic therapy within 14days of registration. NOTE: hydroxyurea, leukapheresis and/or cyclophosphamide areallowed prior to study entry per the protocol.

• Treatment with investigational drug within 21 days of registration.

• Previous allogeneic stem cell transplant within 60 days prior to registration.

• Receiving immunosuppression therapy, with the exception of prednisone ≤ 10mg/d, forthe treatment or prophylaxis of GVHD. If the patient has been on immunosuppressanttreatment or prophylaxis for GVHD, the treatment must have been discontinued atleast 14 days prior to study treatment initiation and there must be no evidence ofGrade ≥ 2 GVHD.

• History of other malignancies (excluding MDS, CMML, MDS/MPN, MPN's) within 2 yearsprior to reigstration, with the exception of: adequately treated in situ carcinomaof the cervix, breast, prostate; basal cell carcinoma of the skin or localizedsquamous cell carcinoma of the skin; previous malignancy confined and surgicallyresected (or treated with other modalities) with curative intent. Subjects receivingmaintenance or adjuvant therapy for organ-confined malignancy such as breast orprostate cancer are eligible. Maintenance and/or adjuvant chemotherapy must bediscontinued >72 hours prior to study treatment initiation. Those with substantialpotential for recurrence and/or ongoing active malignancy must be discussed with thesponsor-investigator before registration.

• Clinically significant cardiovascular disease including:

• Uncontrolled CHF

• Cardiac insufficiency Grade III or IV per New York Heart Association (NYHA)classification

• Uncontrolled angina/hypertension/arrhythmia

• Clinically significant abnormalities on a 12-lead electrocardiogram

• History of myocardial infarction or stroke within 6 months of registration

• Uncontrolled significant pulmonary disease (e.g., COPD, pulmonary hypertension) thatin the opinion of the investigator would put the patient at significant risk forpulmonary complications during the study.

• Active uncontrolled or severe systemic infection. Enrollment is possible aftercontrol of infection, at discretion of the treating physician.

• Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use whilethe mother is being treated on study).

• Other severe medical or psychiatric condition or laboratory abnormality that mayincrease the risk associated with study participation or investigational productadministration, or may interfere with the interpretation of study results, and inthe judgement of the investigator would make the patient inappropriate forenrollment in this study. This may include psychological, familial, sociological, orgeographical condition that would preclude study compliance and follow-up.