First-in-Human Phase I Study of Iadademstat (ORY-1001)

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 demet...

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Autores: Salamero, Olga|||0000-0003-3237-0025, Montesinos, Pau|||0000-0002-3275-5593, Willekens, Christophe|||0000-0001-9814-8537, Pérez-Simón, José Antonio|||0000-0003-3616-6101, Pigneux, Arnaud, Récher, Christian|||0000-0002-3332-4525, Popat, Rakesh|||0000-0001-6553-4618, Carpio Segura, Cecilia del Carmen|||0000-0001-9346-0134, Molinero, César|||0000-0003-0478-9152, Mascaró, Cristina, Vila, Joaquim, Arévalo, M. Isabel|||0000-0001-7347-9831, Maes, Tamara|||0000-0001-5104-6867, Buesa, Carlos|||0000-0001-6293-2514, Bosch Albareda, Francesc|||0000-0001-9241-2886, Somervaille, Tim|||0000-0002-9188-4379
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:252982
Acceso en línea:https://ddd.uab.cat/record/252982
https://dx.doi.org/urn:doi:10.1200/JCO.19.03250
Access Level:acceso abierto
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spelling 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 LeukemiaSalamero, Olga|||0000-0003-3237-0025Montesinos, Pau|||0000-0002-3275-5593Willekens, Christophe|||0000-0001-9814-8537Pérez-Simón, José Antonio|||0000-0003-3616-6101Pigneux, ArnaudRécher, Christian|||0000-0002-3332-4525Popat, Rakesh|||0000-0001-6553-4618Carpio Segura, Cecilia del Carmen|||0000-0001-9346-0134Molinero, César|||0000-0003-0478-9152Mascaró, CristinaVila, JoaquimArévalo, M. Isabel|||0000-0001-7347-9831Maes, Tamara|||0000-0001-5104-6867Buesa, Carlos|||0000-0001-6293-2514Bosch Albareda, Francesc|||0000-0001-9241-2886Somervaille, Tim|||0000-0002-9188-4379This 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).Universitat Autònoma de Barcelona 22020-01-0120202020-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/252982https://dx.doi.org/urn:doi:10.1200/JCO.19.03250reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengopen accesshttp://purl.org/coar/access_right/c_abf2Aquest 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.https://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2529822026-06-06T12:50:31Z
dc.title.none.fl_str_mv 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
title First-in-Human Phase I Study of Iadademstat (ORY-1001)
spellingShingle First-in-Human Phase I Study of Iadademstat (ORY-1001)
Salamero, Olga|||0000-0003-3237-0025
title_short First-in-Human Phase I Study of Iadademstat (ORY-1001)
title_full First-in-Human Phase I Study of Iadademstat (ORY-1001)
title_fullStr First-in-Human Phase I Study of Iadademstat (ORY-1001)
title_full_unstemmed First-in-Human Phase I Study of Iadademstat (ORY-1001)
title_sort First-in-Human Phase I Study of Iadademstat (ORY-1001)
dc.creator.none.fl_str_mv Salamero, Olga|||0000-0003-3237-0025
Montesinos, Pau|||0000-0002-3275-5593
Willekens, Christophe|||0000-0001-9814-8537
Pérez-Simón, José Antonio|||0000-0003-3616-6101
Pigneux, Arnaud
Récher, Christian|||0000-0002-3332-4525
Popat, Rakesh|||0000-0001-6553-4618
Carpio Segura, Cecilia del Carmen|||0000-0001-9346-0134
Molinero, César|||0000-0003-0478-9152
Mascaró, Cristina
Vila, Joaquim
Arévalo, M. Isabel|||0000-0001-7347-9831
Maes, Tamara|||0000-0001-5104-6867
Buesa, Carlos|||0000-0001-6293-2514
Bosch Albareda, Francesc|||0000-0001-9241-2886
Somervaille, Tim|||0000-0002-9188-4379
author Salamero, Olga|||0000-0003-3237-0025
author_facet Salamero, Olga|||0000-0003-3237-0025
Montesinos, Pau|||0000-0002-3275-5593
Willekens, Christophe|||0000-0001-9814-8537
Pérez-Simón, José Antonio|||0000-0003-3616-6101
Pigneux, Arnaud
Récher, Christian|||0000-0002-3332-4525
Popat, Rakesh|||0000-0001-6553-4618
Carpio Segura, Cecilia del Carmen|||0000-0001-9346-0134
Molinero, César|||0000-0003-0478-9152
Mascaró, Cristina
Vila, Joaquim
Arévalo, M. Isabel|||0000-0001-7347-9831
Maes, Tamara|||0000-0001-5104-6867
Buesa, Carlos|||0000-0001-6293-2514
Bosch Albareda, Francesc|||0000-0001-9241-2886
Somervaille, Tim|||0000-0002-9188-4379
author_role author
author2 Montesinos, Pau|||0000-0002-3275-5593
Willekens, Christophe|||0000-0001-9814-8537
Pérez-Simón, José Antonio|||0000-0003-3616-6101
Pigneux, Arnaud
Récher, Christian|||0000-0002-3332-4525
Popat, Rakesh|||0000-0001-6553-4618
Carpio Segura, Cecilia del Carmen|||0000-0001-9346-0134
Molinero, César|||0000-0003-0478-9152
Mascaró, Cristina
Vila, Joaquim
Arévalo, M. Isabel|||0000-0001-7347-9831
Maes, Tamara|||0000-0001-5104-6867
Buesa, Carlos|||0000-0001-6293-2514
Bosch Albareda, Francesc|||0000-0001-9241-2886
Somervaille, Tim|||0000-0002-9188-4379
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universitat Autònoma de Barcelona
description 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).
publishDate 2020
dc.date.none.fl_str_mv 2
2020-01-01
2020
2020-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
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dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/252982
https://dx.doi.org/urn:doi:10.1200/JCO.19.03250
url https://ddd.uab.cat/record/252982
https://dx.doi.org/urn:doi:10.1200/JCO.19.03250
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
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dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
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