Iadademstat in combination with azacitidine in patients with newly diagnosed acute myeloid leukaemia (ALICE) : an open-label, phase 2a dose-finding study
Salamero, Olga (Universitat Autònoma de Barcelona. Departament de Medicina)
Molero, Antonieta (Hospital Universitari Vall d'Hebron)
Pérez-Simón, José Antonio (Hospital Universitario Virgen del Rocío (Sevilla, Andalusia))
Arnan, Montserrat (Hospital Duran i Reynals (Barcelona))
Coll, Rosa (Hospital Universitari de Girona Doctor Josep Trueta)
Garcia-Avila, Sara (Parc de Salut MAR de Barcelona)
Acuña-Cruz, Evelyn (Hospital Universitari i Politècnic La Fe (València))
Cano, Isabel (Hospital Universitari i Politècnic La Fe (València))
Somervaille, Tim C.P. (The Christie NHS Foundation Trust (Manchester, Regne Unit))
Gutierrez, Sonia (Oryzon Genomics. Cornellà de Llobregat)
Arévalo, María Isabel (Oryzon Genomics. Cornellà de Llobregat)
Xaus, Jordi (Oryzon Genomics. Cornellà de Llobregat)
Buesa, Carlos (Oryzon Genomics. Cornellà de Llobregat)
Limón, Ana (Oryzon Genomics, Boston)
Faller, Douglas V. (Oryzon Genomics, Boston)
Bosch Albareda, Francesc 1947- (Vall d'Hebron Institut d'Oncologia)
Montesinos, Pau (Instituto de Investigación Sanitaria La Fe)

Fecha:	2024
Resumen:	Background: 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 leukaemia cell lines. Therefore, we aimed to investigate the combination of iadademstat and azacitidine for the treatment of adult patients with newly diagnosed acute myeloid leukaemia. Methods: The open-label, phase 2a, dose-finding ALICE study was conducted at six hospitals in Spain and enrolled patients aged 18 years or older with newly diagnosed acute myeloid leukaemia not eligible for intensive chemotherapy and an ECOG performance status of 0-2. In the dose escalation portion of the trial, patients received a starting dose of iadademstat at 90 μg/m per day (with de-escalation to 60 μg/m per day and escalation up to 140 μg/m per day) orally, for 5 days on, 2 days off weekly, with azacitidine 75 mg/m subcutaneously, for seven of 28 days. The primary objectives were safety (analysed in the safety analysis set; all patients who received at least one dose of study treatment) and establishing the recommended phase 2 dose; secondary objectives included response rates in the efficacy analysis set (all patients who had at least one efficacy assessment). This study is registered on EudraCT (EudraCT 2018-000482-36) and has been completed. Findings: Between Nov 12, 2018, and Sept 30, 2021, 36 patients with newly diagnosed acute myeloid leukaemia were enrolled; the median age was 76 (IQR 74-79) years, all patients were White, 18 (50%) were male, and 18 (50%) were female, and all had intermediate-risk or adverse-risk acute myeloid leukaemia. The median follow-up was 22 (IQR 16-31) months. The most frequent (≥10%) adverse events considered to be related to treatment were decreases in platelet (25 [69%]) and neutrophil (22 [61%]) counts (all grade 3-4) and anaemia (15 [42%]; of which ten [28%] were grade 3-4). Three patients had treatment-related serious adverse events (one fatal grade 5 intracranial haemorrhage, one grade 3 differentiation syndrome, and one grade 3 febrile neutropenia). Based on safety, pharmacokinetic and pharmacodynamic data, and efficacy, the recommended phase 2 dose of iadademstat was 90 μg/m per day with azacitidine. 22 (82%; 95% CI 62-94) of 27 patients in the efficacy analysis set had an objective response. 14 (52%) of 27 patients had complete remission or complete remission with incomplete haematological recovery; of these, ten of 11 evaluable for measurable residual disease achieved negativity. In the safety analysis set, 22 (61%) of 36 patients had an objective response. Interpretation: The combination of iadademstat and azacitidine has a manageable safety profile and shows promising responses in patients with newly diagnosed acute myeloid leukaemia, including those with high-risk prognostic factors.
Ayudas:	Agencia Estatal de Investigación RTC-2017-6407-1
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Lengua:	Anglès
Documento:	Article ; recerca ; Versió acceptada per publicar
Materia:	Iadademstat ; Azacitidine ; Acute myeloid leukemia ; LSD1 ; Epigenetics
Publicado en:	The Lancet. Haematology, Vol. 11 Núm. 7 (July 2024) , p. e487-e498, ISSN 2352-3026

DOI: 10.1016/S2352-3026(24)00132-7

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