Phase II Study of TAGraxofusp and Azacitidine With Venetoclax in Newly Diagnosed Secondary AML After Previous Exposure to HypOmethylatiNG Agents
A treatment cycle is 28 days. Tagraxofusp will be administered at 9 mcg/kg IV over 15 minutes (-5 or +15 minutes) daily for 3 consecutive days (or 3 doses over a period not to exceed 10 days if postponement is required to allow for toxicity resolution), followed by azacitidine administered at 75 mg/m2 SQ or IV daily on Day 4 through Day 10. Venetoclax will begin on Day 4 and continue through Day 24 (21 consecutive days). A bone marrow biopsy (BM Bx) will be performed on Day 24 (+3 days) of Cycle 1. Subjects who do not achieve a CRm will proceed with the next cycle of Induction Phase study treatment, irrespective of hematologic laboratory values. Cycle 2+ will consist of tagraxofusp 9 mcg/kg IV over 15 minutes daily for 3 consecutive days (Day 1-3 or 3 doses over a period not to exceed 10 days if postponement is required to allow for toxicity resolution), azacitidine 75 mg/m2 SQ or IV on Day 1 through Day 7 or Days 1-7 or 1-5, 8-9 and venetoclax 400 mg daily Day 1 through Day 21. A bone marrow biopsy (BM Bx) will be performed on Day 21 (+3 days) of Cycle 2. If a CRm is obtained or maintained, the subject will move to or remain on the Continuation Phase. Subjects who do not achieve a marrow CR (CRm) after Cycle 2 will proceed with the next cycle of Induction Phase study treatment as described above, irrespective of hematologic laboratory values. If a CRm is obtained after Cycle 3 or 4, the subject will move to the Continuation Phase . If a CRm is not obtained after Cycle 4, study treatment will be discontinued and the subject will move to follow up. If per the investigator, the subject is receiving clinical benefit, study treatment may continue until toxicity or completion of 12 total cycles. A BM Bx will be performed at least every 3 cycles for these subjects.
⁃ 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 health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
• Subjects must have newly diagnosed, untreated AML, as defined by ≥ 20% blasts in peripheral blood or bone marrow by manual aspirate differential, immunohistochemistry staining, or flow cytometry, as defined by standard WHO 2016 diagnostic criteria.
• Subjects must have documented CD123 positivity on leukemia cells by a centralized flow cytometry assay (Hematologics).
• Documented diagnosis of prior MDS, CMML, MDS/MPN overlap syndromes, or MPN's according to WHO criteria. Subjects must have received at least 2 cycles of hypomethylating agents (azacitidine or decitabine or oral decitabine/cedazuridine) for the management of MDS, CMML, MDS/MPN overlap syndromes, or MPN's. NOTE: Subjects who have enrolled on clinical trials with investigational agents in combination with HMA's will still be eligible. Investigational agents must have been discontinued \>14 days prior to study treatment initiation. Subjects who have enrolled on clinical trials with investigational agents in combination with HMA's will still be eligible. Investigational agents must have been discontinued \> 21 days prior to study treatment initiation.
• WBC \< 30 x 109 /µL- subjects with WBC ≥ 30 x 109 /µL may still be eligible after receiving 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. Hydroxyurea must 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 7 days prior to registration. NOTE: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months.
• Females of childbearing potential and male participants must be willing to use effective contraception as outlined in the protocol.
• Known HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial.
• Patients with known evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, the HCV viral load must be undetectable to be eligible for this trial.
• As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study.