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    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

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    Authors
    Salamero, O.
    Montesinos, P.
    Willekens, C.
    Pérez-Simón, J. A.
    Pigneux, A.
    Récher, C.
    Popat, R.
    Carpio, C.
    Molinero, C.
    Mascaró, C.
    Vila, J.
    Arévalo, M. I.
    Maes, T.
    Buesa, C.
    Bosch, F.
    Somervaille, Tim C P
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    Affiliation
    Hospital Vall d'Hebron, Vall D'Hebron Institute of Oncology, Departament de Medicina, Universitat Autònoma de Barcelona, UAB, Barcelona, Spain.
    Issue Date
    2020
    
    Metadata
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    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).
    Citation
    Salamero O, Montesinos P, Willekens C, Perez-Simon JA, Pigneux A, Recher C, et al. 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:JCO1903250.
    Journal
    Journal of Clinical Oncology
    URI
    http://hdl.handle.net/10541/623429
    DOI
    10.1200/jco.19.03250
    PubMed ID
    33052756
    Additional Links
    https://dx.doi.org/10.1200/jco.19.03250
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1200/jco.19.03250
    Scopus Count
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