2. Academic Validation
  3. First-in-Human Phase I Study of Iadademstat (ORY-1001): A First-in-Class Lysine-Specific Histone Demethylase 1A Inhibitor, in Relapsed or Refractory Acute Myeloid Leukemia

First-in-Human Phase I Study of Iadademstat (ORY-1001): A First-in-Class Lysine-Specific Histone Demethylase 1A Inhibitor, in Relapsed or Refractory Acute Myeloid Leukemia

  • J Clin Oncol. 2020 Dec 20;38(36):4260-4273. doi: 10.1200/JCO.19.03250.
Olga Salamero 1,  Pau Montesinos 2 3,  Christophe Willekens 4,  José Antonio Pérez-Simón 5 6,  Arnaud Pigneux 7,  Christian Récher 8,  Rakesh Popat 9,  Cecilia Carpio 1,  César Molinero 10,  Cristina Mascaró 10,  Joaquim Vila 10,  M Isabel Arévalo 10,  Tamara Maes 10,  Carlos Buesa 10,  Francesc Bosch 1,  Tim C P Somervaille 11 12
Affiliations

Affiliations

  • 1 Hospital Vall d'Hebron, Vall D'Hebron Institute of Oncology, Departament de Medicina, Universitat Autònoma de Barcelona, UAB, Barcelona, Spain.
  • 2 Hospital Universitari I Politécnic La Fe, València, Spain.
  • 3 Centro de Investigación Biomédica en Red de Cáncer, Instituto Carlos III, Madrid, Spain.
  • 4 Institut Gustave Roussy, Villejuif Cedex, France.
  • 5 Hospital Universitario Virgen del Rocío, Sevilla, Spain.
  • 6 Instituto de Biomedicina de Sevilla (Insitituto de Biomedicina De Sevilla/Consejo Superior De Investigaciones Científicas/Centro de Investigación Biomédica en Red de Cáncer), Universidad de Sevilla, Sevilla, Spain.
  • 7 Centre Hospitalier Universitaire CHU Bordeaux, Hôpital du Haut Lévêque, Pessac, France.
  • 8 Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Université Toulouse III Paul Sabatier, Toulouse, France.
  • 9 National Institute for Health Research UCLH Clinical Research Facility, University College London Hospitals NHS Foundation Trust, London, United Kingdom.
  • 10 Oryzon Genomics, Barcelona, Spain.
  • 11 The Christie NHS Foundation Trust, Manchester, United Kingdom.
  • 12 Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom.
PMID: 33052756 DOI: 10.1200/JCO.19.03250
Abstract

Purpose: Iadademstat is a novel, highly potent, and selective inhibitor of LSD1 (KDM1A), with preclinical in vitro and in vivo antileukemic activity. This study aimed to determine safety and tolerability of iadademstat as monotherapy in patients with relapsed/refractory acute myeloid leukemia (R/R AML).

Methods: This phase I, nonrandomized, open-label, dose-escalation (DE), and extension-cohort (EC) trial included patients with R/R AML and evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antileukemic activity of this orally bioavailable first-in-class lysine-specific demethylase 1 inhibitor.

Results: Twenty-seven patients were treated with iadademstat on days 1 to 5 (5-220 µg/m2/d) of each week in 28-day cycles in a DE phase that resulted in a recommended dose of 140 µg/m2/d of iadademstat as a single agent. This dose was chosen to treat all patients (n = 14) in an EC enriched with patients with MLL/KMT2A-rearranged AML. Most adverse events (AEs) were as expected in R/R AML and included myelosuppression and nonhematologic AEs, such as infections, asthenia, mucositis, and diarrhea. PK data demonstrated a dose-dependent increase in plasma exposure, and PD data confirmed a potent time- and exposure-dependent induction of differentiation biomarkers. Reductions in blood and bone marrow blast percentages were observed, together with induction of blast cell differentiation, in particular, in patients with MLL translocations. One complete remission with incomplete count recovery was observed in the DE arm.

Conclusion: Iadademstat exhibits a good safety profile together with signs of clinical and biologic activity as a single agent in patients with R/R AML. A phase II trial of iadademstat in combination with azacitidine is ongoing (EudraCT No.: 2018-000482-36).

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