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
Salamero, Olga (Vall d'Hebron Institut d'Oncologia)
Montesinos, Pau (Centro de Investigación Biomédica en Red de Cáncer)
Willekens, Christophe (Institut Gustave Roussy (Villejuif, França))
Pérez-Simón, José Antonio (Universidad de Sevilla)
Pigneux, Arnaud (Centre Hospitalier Universitaire CHU Bordeaux)
Récher, Christian (Hospitalier Universitaire de Toulouse)
Popat, Rakesh (University College London)
Carpio Segura, Cecilia del Carmen (Vall d'Hebron Institut d'Oncologia)
Molinero, César (Parc Científic de Barcelona. Oryzon Genomics)
Mascaró, Cristina (Parc Científic de Barcelona. Oryzon Genomics)
Vila, Joaquim (Parc Científic de Barcelona. Oryzon Genomics)
Arévalo, M. Isabel (Parc Científic de Barcelona. Oryzon Genomics)
Maes, Tamara (Parc Científic de Barcelona. Oryzon Genomics)
Buesa, Carlos (Parc Científic de Barcelona. Oryzon Genomics)
Bosch José, Francesc Xavier 1947- (Vall d'Hebron Institut d'Oncologia)
Somervaille, Tim (The University of Manchester)
Universitat Autònoma de Barcelona

Data:	2020
Resum:	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. Twenty-seven patients were treated with iadademstat on days 1 to 5 (5-220 µg/m 2 /d) of each week in 28-day cycles in a DE phase that resulted in a recommended dose of 140 µg/m 2 /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. 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).
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Journal of Clinical Oncology, Vol. 38 (october 2020) , p. 4260-4273, ISSN 1527-7755

DOI: 10.1200/JCO.19.03250
PMID: 33052756

15 p, 1.2 MB

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