Phase II trial of 10-day ASTX727 (decitabine/cedazuridine) in combination with venetoclax for relapsed or refractory acute myeloid leukemia.

6551 Background: The disease outcomes in relapsed refractory acute myeloblastic leukemia (R/R AML) remain dismal. We previously demonstrated safety and encouraging activity of 10-day regimen of IV decitabine with venetoclax (VEN) in R/R AML. In this prospective clinical trial, we investigate the efficacy of a novel 10-day induction regimen with fully oral combination therapy for pts with R/R AML. Methods: We conducted a phase II trial in pts with R/R aged ≥18 y with ECOG performance status ≤2 was eligible for enrollment. Exclusion criteria included GI conditions affecting absorption of the drugs, active GvHD, and APL. For induction, pts received oral ASTX727 (100mg/35mg) D1-10 and VEN 400mg D1-28. In subsequent cycles, ASTX727 was reduced to D1-5 in pts achieving CR/Cri (NCT04975919). Results: Between December 2021 and March 2024, 20 were enrolled on this trial. The median age was 65 (39-76), 25% of pts (n=5) had therapy-related AML. 60% pts (n= 12) had prior VEN exposure. Eighty-five percent of the pts were either and/or harbored complex karyotype. Median duration of the treatment was 1.7 m (0.5-9.5) and median no of cycles was 1 (range 1-6). The composite CR/CRi/MLFS rate was 40% (n=8), with best response achieved at median 1.3 m. Duration of response in responders was 8.5 m (2.9-30.8). MRD was negative in 25% (2/8) of responding pts, and 3 pts (15%) proceeded to stem cell transplantation (SCT). Two transplanted patients (67%) were in CR before SCT, while 1 patient (33%) was in MLFS. The median OS was 8.6 m. VEN-naive pts showed longer OS (10.5m vs 4.4m with prior VEN, p=0.12). Responding pts who could be bridged to SCT had better OS benefit (not reached vs 6.6m, p=0.01). The median OS of pts with TP53 mut was 3.1 m vs 8.6 m in pts who were TP53 WT (p=0.60). The 4-week mortality rate was 6%, and the 8-week mortality rate was 17%. Treatment-emergent adverse events of Gr 3/4 were observed in 81% of pts (17), with infections and febrile neutropenia being the most frequent complications (35% each). After a median follow up of 8.7 m (0.5-30.8), 80% of pts (16) died. Among the deaths, 40% were attributed to disease progression, and 25% to bacterial infections. None of the deaths were associated with bacterial infections occurred in patients with CR. Conclusions: The 10-day ASTX727-VEN combination showed safety profile comparable to other HMA-VEN regimens in salvage setting. TP53 wild type, VEN-naïve pts and those who could be bridged to SCT had better outcomes. Novel therapies are needed to improve outcomes in R/R AML. Clinical trial information: NCT04975919 .