Tagraxofusp-erzs, Azacitidine and Venetoclax for the Treatment of Untreated, Relapsed, or Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

Inclusion Criteria

• Histologically confirmed diagnosis of acute myeloid leukemia (AML) (Cohort B) or myelodysplastic syndrome (MDS) (Cohort A) or BPDCN (Cohort C) per 2016 World Health Organization (WHO) criteria
• CD123/IL3RA expression on the subject’s AML or MDS blasts or BPDCN cells determined locally within 3 months of first protocol treatment
• Age >= 18 years with relapsed or refractory AML (hydroxyurea is not considered a prior treatment regimen) [Cohort B] OR Age >= 18 years with treatment-naïve AML who decline intensive induction chemotherapy or who are unfit due to co-morbidity or other factors (hydroxyurea is not considered a prior treatment regimen) [Cohort B] OR Age >= 18 years with MDS and > 10% myeloblasts in the bone marrow [Cohort A] OR Age >= 18 years with relapsed or refractory blastic plasmacytoid dendritic cell neoplasm (BPDCN) (hydroxyurea is not considered a prior treatment regimen) [Cohort C] OR Age >= 18 years with previously untreated BPDCN (hydroxyurea is not considered a prior treatment regimen) [Cohort D]
• Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
• Albumin >= 3.2 g/dL (in the absence of receipt of intravenous albumin in the previous 72 hours)
• Serum creatinine =< 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x ULN
• Total bilirubin < 1.5 x ULN (if thought to be > 1.5 x ULN due to Gilbert’s disease or the patient’s AML, must discuss with the principal investigator [PI])
• Creatine phosphokinase (CPK) =< 2.5 x ULN
• Left ventricular ejection fraction >= institutional lower limit of normal by multi-gated acquisition (MUGA) scan or echocardiogram within 30 days of first protocol treatment
• COHORTS B, C, AND D: White blood cell (WBC) < 20,000/uL on day of first therapy, cytoreduction may be achieved using hydroxyurea
• Ability to understand and the willingness to sign a written informed consent document
• Able to adhere to study visit schedule and other protocol requirements including follow-up for survival assessment
• Women of child-bearing potential must agree to use adequate contraception for the duration of study participation and for 2 months after completion of protocol treatment; men treated or enrolled on this protocol must also agree to use adequate contraception for the duration of study participation and 2 months after completion of protocol treatment

Exclusion Criteria

• Diagnosis of acute promyelocytic leukemia
• Received treatment with chemotherapy, radiation, or biologic cancer therapy within 14 days of first protocol treatment; prior and concurrent hydroxyurea is permitted
• Hematopoietic stem cell transplantation (HSCT) within 60 days of screening, or active graft-versus-host-disease
• Symptomatic CNS involvement by AML or BPDCN; screening lumbar puncture (LP) required for patients with BPDCN. History of CNS involvement is not an exclusion.
• Known positive status for human immunodeficiency virus (HIV) infection; known active hepatitis B or hepatitis C infection
• Clinically significant cardiopulmonary disease including uncontrolled or New York Heart Association (NYHA) class 3 or 4 congestive heart failure, uncontrolled angina, uncontrolled hypertension, uncontrolled arrhythmia, myocardial infarction or stroke within 6 months of first protocol treatment, or corrected QT (QTc) > 480 ms
• Patients with known active advanced malignant solid tumors are excluded (except for basal or squamous skin cancers, or carcinomas in situ); patients with additional hematologic malignancies that require treatment are excluded
• Pregnant women are excluded from this study because there is an unknown but potential risk for adverse events in the developing fetus with SL-401, azacitidine, and venetoclax (negative urine or serum pregnancy test required within 14 days of Cycle 1, Day 1); because nursing infants have unknown potential for adverse events secondary to treatment of the mother, breastfeeding should be discontinued if the mother is treated with SL-401, azacitidine, and venetoclax
• Patients with uncontrolled infection shall not be enrolled until infection is treated and brought under control; patients with active infection are permitted to enroll provided that the infection is controlled
• COHORTS B, C, AND D: Patients with gastrointestinal (GI) tract disease causing the inability to take oral medication, malabsorption syndrome, a requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease (e.g., Crohn’s disease, ulcerative colitis)
• COHORTS B, C, AND D: Patients on strong CYP3A inducers within 7 days of first dose of study treatment