Phase 2 Multicenter Trial of Tagraxofusp in Combination with Venetoclax and Azacitidine in Adults with Previously Untreated CD123+ Acute Myeloid Leukemia Ineligible for Intensive Chemotherapy

Background and Significance: Although complete remission (CR) rates after first-line therapy in acute myeloid leukemia (AML) are relatively high, some patients cannot tolerate high-intensity treatments or have a high risk of relapse with standard therapies. Venetoclax + azacitidine (VEN/AZA), a less intensive regimen, is the current standard of care for patients unfit for or declining intensive chemotherapy for AML (CR 36.7%; median OS 14.7 months; DiNardo et al 2020). Maintaining a prolonged duration of remission and long-term overall survival with VEN/AZA is challenging in AML patients with negative prognostic factors, including older age, comorbidities, unfavorable cytogenetics, and high-risk genetic aberrations (eg, TP53 mutations). AML patients with TP53 mutations often have very poor responses as evidenced by the poor outcomes observed in an exploratory post-hoc analysis of VEN/AZA in patients with TP53-mutated AML (22% CR rate, median OS 5.5 months; Döhner et al 2022). Adding an agent with a nonoverlapping mechanism of action and safety profile may improve outcomes in this difficult-to-treat population with high unmet medical need. CD123, present on the surface of most AML blasts, is enriched on leukemia stem cells. Tagraxofusp (TAG), a first-in-class CD123-directed therapy, is a recombinant fusion protein consisting of human interleukin-3 conjugated to a truncated diphtheria toxin payload. Preclinical studies show synergistic efficacy with TAG and AZA in patient-derived xenografts treated in vivo (Togami et al 2019). TAG may overcome AZA resistance by targeting the CD123-high escape clone, and AZA overcomes TAG resistance by upregulating DPH1 and thus re-sensitizing the cell to diphtheria toxin. In a phase 1b expansion 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% with MRD (Lane et al 2024). Based on promising early data and high unmet need, we have initiated a phase 2 trial to evaluate the addition of TAG to standard VEN/AZA to reduce overall disease burden and contribute to elimination of therapy-resistant leukemia cells. Study Design and Methods: This is a multicenter, open-label phase 2 study (NCT06456463) designed to evaluate the combination of TAG with VEN/AZA in adults with previously untreated CD123+ AML ineligible for intensive chemotherapy. Key eligibility criteria include previously untreated individuals with histological confirmation of AML by WHO criteria; any level of CD123 expression on blasts; ≥75 years old or between 18-74 years with at least one of the following comorbidities: ECOG Score 2 or 3, diffusing capacity of the lung for carbon monoxide ≤65% or forced expiratory volume in 1 second ≤65%, left ventricular ejection fraction ≤50%; creatinine clearance ≥30-<45 mL/min, hepatic disorder with total bilirubin >1.5x ULN, or any other comorbidity judged to be incompatible with intensive chemotherapy; and ECOG Score 0-2 if ≥75 years old or 0-3 if 18-74 years old. Part 1 will evaluate 2 doses of intravenous (IV) TAG (9 μg/kg/day and 12 μg/kg/day) in combination with VEN/AZA. VEN will be administered orally daily at 400 mg in a 28-day cycle with cycle 1 ramp-up days 1-3. AZA 75 mg/m2 IV or SC will be administered over 7 days per institutional guidelines/physician choice. TAG will be administered IV on days 4, 5, and 6 of each 28-day cycle. Patients will be randomized 1:1 (n=24) to one of the 2 parallel experimental arms; randomization will be stratified by TP53 mutation status (TP53 wild type and TP53 mutated). The primary endpoint of Part 1 is the determination of the Part 2 selected dose based on safety, efficacy (using central results), and PK data after completion of 4 cycles. Secondary endpoints for Part 1 include AEs, CR rate, DOR, EFS, OS, rate of hematopoietic stem cell transplant, and PK. Part 2 will investigate TAG at the selected dose in combination with VEN/AZA; 48 additional patients will enroll in 2 cohorts by TP53 mutation status. An interim futility analysis will be conducted after 12 patients (including Part 1 patients treated at selected dose) have been enrolled in each cohort. Genomic profiling and CD123 expression will be analyzed at baseline and during study treatment. Part 1 will enroll patients from North America, S Korea & Australia.