Abstract CT246: Tagraxofusp plus venetoclax and azacitidine in patients ineligible for intensive chemotherapy with previously untreated CD123+ acute myeloid leukemia: A phase 2 multicenter trial

Abstract Background and Significance: Some patients with acute myeloid leukemia (AML) cannot tolerate high-intensity treatments or have a high risk of relapse with standard therapies. The standard of care for patients with AML who are considered unfit for or refusing intensive chemotherapy (IC) is venetoclax + azacitidine (VEN/AZA; complete remission [CR] 36.7%; median overall survival [OS] 14.7 months; DiNardo et al 2020). Achieving prolonged remission and longer OS with VEN/AZA is challenging in AML patients with adverse prognostic factors, including TP53 mutations. AML patients with TP53 mutations have poor responses with VEN/AZA (22% CR rate, median OS 5.5 months; Döhner et al 2022). This difficult-to-treat population may benefit from the addition of an agent with a unique mechanism of action. CD123, present on the surface of most AML blasts, is enriched on leukemia stem cells. Tagraxofusp (TAG), a first-in-class CD123-targeted therapy, may overcome AZA resistance by targeting the CD123-high escape clone, and AZA overcomes TAG resistance by upregulating DPH1. In a phase 1b cohort of patients with untreated adverse-risk AML, TAG/VEN/AZA induced 39% CR, and 71% of responders had no flow measurable residual disease (MRD-); in patients with TP53 mutations, 54% achieved CR/CRi/MLFS, 57% were MRD- (Lane et al 2024). This phase 2 trial evaluates the ability of TAG plus VEN/AZA to reduce disease burden and contribute to the elimination of therapy-resistant leukemia cells. Study Design and Methods: This multicenter, open-label phase 2 trial (NCT06456463) evaluates the combination of TAG plus VEN/AZA in adults ineligible for IC with previously untreated CD123+ AML. Key eligibility includes histological confirmation of AML; any CD123 expression; ≥75 years old (ECOG PS 0-2) or between 18-74 years (ECOG PS 0-3) with at least one of the following comorbidities: ECOG PS 2 or 3, diffusing capacity of the lung for carbon monoxide ≤65% or forced expiratory volume in 1 second ≤65%, creatinine clearance ≥30-<45 mL/min, hepatic disorder with total bilirubin >1.5x ULN, or any other comorbidity incompatible with IC. Part 1 will evaluate 2 doses of intravenous (IV) TAG (9 μg/kg/day and 12 μg/kg/day) on days 4, 5 and 6 of a 28-day cycle, plus VEN 400 mg orally daily (cycle 1 ramp-up) and AZA 75 mg/m2 SC or IV days 1-7. Patients will be randomized 1:1 (n=24) and stratified by TP53 mutation status. The primary endpoint is to determine the part 2 dose based on safety, efficacy, and PK data after 4 cycles. Part 2 will investigate TAG at the selected dose combined with VEN/AZA; 48 additional patients will enroll in 2 cohorts by TP53 mutation status. An interim futility analysis will occur after 12 patients (including part 1 patients treated at selected dose) are enrolled in each cohort. Citation Format: Naval G. Daver, Naveen Pemmaraju, Mikkael A. Sekeres, Amir Fathi, Andrew A. Lane, Anna Compagnoni, Ira Gupta, Alessandra Tosolini, Jessica Garzon, Hagop M. Kantarjian. Tagraxofusp plus venetoclax and azacitidine in patients ineligible for intensive chemotherapy with previously untreated CD123+ acute myeloid leukemia: A phase 2 multicenter trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT246.