Phase II Study of TAGraxofusp and Azacitidine With or Without Venetoclax in Newly Diagnosed Secondary AML After Previous Exposure to HypOmethylatiNG Agents
A treatment cycle is 28 days for Cycle 1 and Cycle 2. Tagraxofusp will be administered at 12 mcg/kg IV over 15 minutes (-5 or +15 minutes) daily for 5 consecutive days (or 5 doses over a period not to exceed 10 days if postponement is required to allow for toxicity resolution). Subjects with a marrow CR (See the protocol) after Cycle 2 will continue Tagraxofusp for Cycles 3 to 12 (up to 1 year of treatment) at 12 mcg/kg IV for 5 consecutive days every 28 days. In subjects without a marrow CR after 2 cycles of treatment, azacitidine 75 mg/m2 SQ or IV will be added on Days 1-7 every 28 days for up to 4 additional cycles of treatment. A treatment cycle is 28 days for Cycle 3 to Cycle 12. Subjects who achieve a marrow CR receiving tagraxofusp only after Cycle 4, will continue tagraxofusp at 12 mcg/kg IV for 5 consecutive days every 28 days until Cycle 12. Subjects who continue to achieve an overall response (CR, CRi, PR, MLFS, marrow CR) receiving tagraxofusp and azacitidine will continue tagraxofusp at 12 mcg/kg IV for 3 consecutive days and azacitidine 75 mg/m2 SQ or IV on Days 1-7 every 28 days until Cycle 12. Please see the protocol. Patients without an overall response to tagraxofusp + azacitidine after completion of 4 cycles of this combination will be discontinued from study treatment.
⁃ Subject must meet all of the following applicable inclusion criteria to participate in this study:
• 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 \>21 days prior to day 1 of Tagraxofusp.
• WBC \< 30 x 109 /mL- subjects with WBC ≥ 30 x 109 /mL may still be eligible after receiving cytoreduction measures such as hydroxyurea, and/or leukapheresis, if WBC \< 30 x 109 /mL prior to treatment initiation. Cytoreduction with hydroxyurea, leukapheresis and/or cyclophosphamide is allowed prior to treatment. Hydroxyurea must be discontinued ≥ 12 hours prior to treatment initiation. Cyclophosphamide must be discontinued ≥ 5 days prior to 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.
• Written informed consent and HIPAA authorization for release of personal health information.
• 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.