AML-328 Phase 2 Study of ASTX727 (Decitabine/Cedazuridine) Plus Venetoclax in Patients With Relapsed/Refractory Acute Myeloid Leukemia or Previously Untreated, Older Adult Patients Unfit for Chemotherapy

Context: ASTX727 is an oral formulation of the fixed-dose combination of decitabine and cedazuridine (100 mg/35 mg). Objective: To investigate whether a total oral regimen of ASTX727+venetoclax (ven) is feasible and safe. Methods: Pts ≥18 with relapsed/refractory AML (R/R) or pts with AML aged ≥75 or 18–74 unfit for intensive chemotherapy (frontline; FL) were eligible. Other eligibility criteria included adequate renal and hepatic function and ECOG performance status (PS) ≤2. ASTX727 is administered on days 1–5 of each cycle and ven on days 1–28 of the 1st cycle (21 days in subsequent cycles). Ven is held if blast <5% on day 21±3 bone marrow. Results: Between March 2021 and January 2022, 28 pts (15 FL,13 R/R) were treated. The median age is 75 years (range, 47–90); 81 in the FL cohort and 72 in the R/R cohort. Nine FL pts (60%) were ≥80 and 5 (30%) were 70–80 years. In the R/R cohort, 9 pts (69%) were 70–80 years. The median PS is 2. The R/R cohort had a median of 2 prior treatments (range, 1–4). In the FL cohort, 5 (33%) had normal and 6 (40%) a complex karyotype; 3 had other. In the R/R cohort, 15% had normal and 46% a complex karyotype and 31% had other. Mutations in the FL cohort were RUNX1 (33%), ASXL1 (33%), DNMT3A (7%), TET2 (40%), and TP53 (20%). Overall response in the FL cohort is 61% (4 complete response [CR], 4 CR with incomplete count recovery [Cri], 1 morphological leukemia-free state [MLFS], 3 non-responders) and 45% in the R/R cohort (2 CR, 2 CRi, 2 MLFS, 5 non-responders, 2 not-evaluable). Both cohorts received a median of 2 cycles (range, 1–5). With a median follow-up of 5 months, the median survival for the FL cohort has not been reached (range, 0.6–7.3) and is 7.2 (range, 0.8–7.3) months for the R/R cohort. Grade ≥3 adverse events were neutropenic infections in 3 (11%) and liver enzymes elevation in 1 (4%). Conclusions: ASTX727 and venetoclax combination is safe and feasible and demonstrates significant efficacy in pts unfit for chemotherapy. Research funding by Taiho.