Iadademstat and Azacitidine Combination Therapy Demonstrates Manageable Safety, Promising Efficacy for Patients With Newly Diagnosed AML

According to results from the open-label, phase 2a, dose-finding ALICE study, the frontline combination of iadademstat and azacitidine demonstrates promising responses among patients with acute myeloid leukemia (AML), including patients with high-risk factors.

“Iadademstat is a potent, selective, oral inhibitor of both the enzymatic and scaffolding activities of the transcriptional repressor lysine-specific demethylase 1 (LSD1; also known as KDM1A) that showed promising early activity and safety in a phase 1 trial and strong preclinical synergy with azacitidine in acute myeloid [leukemia] cell lines,” explained lead study author Olga Salamero, MD, Universitat Autònoma de Barcelona, Barcelona, Spain, and colleagues.

This trial was conducted at 6 hospitals in Spain and enrolled 36 patients with newly diagnosed AML, aged 18 years or older, who were not eligible for intensive chemotherapy and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. It was noted that in the dose escalation portion of the study, patients received a starting dose of iadademstat at 90 μg/m² per day (with de-escalation to 60 μg/m² per day and escalation up to 140 μg/m² per day) orally, for 5 days on, 2 days off weekly, with azacitidine 75 mg/m² subcutaneously, for 7 of 28 days. 

The primary objectives were safety (analyzed in the safety analysis set; all patients who received at least 1 dose of study treatment) and establishing the recommended phase 2 dose. The median follow-up was 22 ([interquartile range] IQR 16 to 31) months. Based on safety, pharmacokinetic and pharmacodynamic data, and efficacy, the recommended phase 2 dose of iadademstat was 90 μg/m² per day with azacitidine.

Results demonstrated that 22 (82%; 95% [confidence interval] CI, 62 to 94) of 27 patients in the efficacy analysis set had an objective response (OR). Additionally, 14 (52%) of 27 patients had complete remission or complete remission with incomplete hematological recovery. Of these, 10 of 11 evaluable for measurable residual disease (MRD) achieved negativity. In the safety analysis set, 22 (61%) of 36 patients had an OR.

Study authors noted that the most frequent (≥10%) treatment-related adverse events were decreases in platelet (25 [69%]) and neutrophil (22 [61%]) counts (all grade 3 or 4) and anemia (15 [42%]; of which 10 [28%] were grade 3 or 4). Furthermore, 3 patients experienced serious treatment-related adverse events, including 1 fatal grade 5 intracranial hemorrhage, 1 grade 3 differentiation syndrome, and 1 grade 3 febrile neutropenia.

“The combination of iadademstat and azacitidine has a manageable safety profile and shows promising responses in patients with newly diagnosed acute myeloid [leukemia], including those with high-risk prognostic factors,” concluded Dr Salamero et al.

Source:

Salamero O, Molero A, Pérez-Simón JA, et al. Iadademstat in combination with azacitidine in patients with newly diagnosed acute myeloid leukemia (ALICE): an open-label, phase 2a dose-finding study. The Lancet Hem. Published online May 30, 2024. doi: 10.1016/S2352-3026(24)00132-7