Phase II Trial of 10-Day ASTX727 (Decitabine/Cedazuridine) with Venetoclax for Relapsed or Refractory Acute Myeloid Leukemia

Background: Patients with relapsed/refractory acute myeloid leukemia (R/R AML) have poor outcomes and limited therapeutic options. We previously conducted a phase II trial of 10-day IV decitabine and venetoclax with encouraging results in venetoclax-naïve R/R AML (DiNardo et al. Lancet Haematol 2020). We hypothesized that a total oral regimen with ASTX727 (decitabine/cedazuridine) and venetoclax may offer similar outcomes while offering convenience of an oral regimen.

Methods: This phase II trial enrolled adults with R/R AML with ECOG PS ≤2, WBC ≤10 x10³/uL, and adequate organ function (NCT04975919). Pts with prior BCL2 inhibitor therapy were eligible. Pts with t(15;17) or active graft-vs-host disease were excluded. Pts received ASTX727 containing decitabine/cedazuridine 100/35 mg for 10 days with venetoclax 400 mg (or equivalent based on CYP interactions) for 21-28 days for induction followed by ASTX727 for 5 days with venetoclax daily in subsequent cycles. The primary objective was to determine overall responses rate (ORR) and secondary objectives were to determine duration of response (DOR), overall survival (OS), and safety of the combination.

Results: Between December 2021 and April 2023 we enrolled 18 pts with R/R AML. The median age was 65 yrs (range 39-76), median bone marrow blasts was 40% (range 6-93), median no. of prior therapies was 2 (range 1-4) including 11 pts (61%) who had received prior venetoclax-based regimens. 94% pts had ELN2022 adverse risk AML, including 6 pts (33%) with TP53 mutations and 11 pts (61%) with complex cytogenetics.

The ORR was 28% (n=5/18) including CR in 2 pts and MLFS in 3 pts. Negative MRD by flow cytometry was achieved in 2/5 responding pts. After a median follow up of 15.3 months (mo), 5 pts are alive, and the median OS was 9.1 mos (Fig 1). 2 pts (11%) who achieved CR proceeded to allogeneic stem cell transplantation remain in remission for 15.3 and 2.4 mos. CR/MLFS response occurred in 4/7 pts who were venetoclax naïve vs 1/11 pts with prior venetoclax exposure (p=0.03). CR/MLFS response occurred in 1/6 pts who were TP53 mutated vs 4/12 pts who were TP53 wild type (p=0.45).

Pts received a median of 1 cycle of treatment (range 1-6). The 30-day and 60-day mortality were 17% and 28%. Most common treatment-related grade 3/4 adverse events included infections in 50% pts, febrile neutropenia in 29% pts, and respiratory failure in 17% pts. Trial continues to accrue and updated results will be presented.

Conclusion: An oral regimen of 10-day ASTX727 with venetoclax showed safety profile comparable to other venetoclax-based regimens in R/R AML and responses occurred in ELN adverse risk venetoclax-naïve pts. Novel therapies are needed for patients progressing on prior BCL2 inhibitor-based regimens.