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: A First-in-Class Lysine-Specific Histone Demethylase 1A Inhibitor, in Relapsed or Refractory Acute Myeloid Leukemia
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| Titel: | 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: A First-in-Class Lysine-Specific Histone Demethylase 1A Inhibitor, in Relapsed or Refractory Acute Myeloid Leukemia |
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| Autoren: | Olga Salamero, Pau Montesinos, Christophe Willekens, José Antonio Pérez-Simón, Arnaud Pigneux, Christian Récher, Rakesh Popat, Cecilia Carpio, César Molinero, Cristina Mascaró, Joaquim Vila, M. Isabel Arévalo, Tamara Maes, Carlos Buesa, Francesc Bosch, Tim C. P. Somervaille |
| Weitere Verfasser: | Ministerio de Economía y Competitividad (España), European Commission, Cancer Research UK, Centro para el Desarrollo Tecnológico Industrial (España), National Institute for Health Research (UK), University College London, NIHR Biomedical Research Centre (UK), Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72], Institut Català de la Salut, [Salamero O, Carpio C, Bosch F] Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain. [Montesinos P] Hospital Universitari I Politécnic La Fe, València, Spain. Centro de Investigación Biomédica en Red de Cáncer, Instituto Carlos III, Madrid, Spain. [Willekens C] Institut Gustave Roussy, Villejuif Cedex, France. [Pérez-Simón JA] Hospital Universitario Virgen del Rocío, Sevilla, Spain. 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. [Pigneux A] Centre Hospitalier Universitaire CHU Bordeaux, Hôpital du Haut Lévêque, Pessac, France. [Récher C] Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Université Toulouse III Paul Sabatier, Toulouse, France, Vall d'Hebron Barcelona Hospital Campus |
| Quelle: | J Clin Oncol Digital.CSIC. Repositorio Institucional del CSIC Consejo Superior de Investigaciones Científicas (CSIC) instname JOURNAL OF CLINICAL ONCOLOGY r-IIS La Fe. Repositorio Institucional de Producción Científica del Instituto de Investigación Sanitaria La Fe RISalud-ANDALUCIA. Repositorio Institucional de Salud de Andalucía Instituto de Investigación Sanitaria La Fe (IIS La Fe) Scientia Scientia. Dipòsit d'Informació Digital del Departament de Salut 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, T C P 2020, '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', Journal of Clinical Oncology, vol. 38, no. 36, pp. 4260-4273. https://doi.org/10.1200/JCO.19.03250 |
| Verlagsinformationen: | American Society of Clinical Oncology (ASCO), 2020. |
| Publikationsjahr: | 2020 |
| Schlagwörter: | Myeloid, Mucositis, Adult, Male, 0301 basic medicine, Other subheadings::Other subheadings::/therapeutic use, Leukemia, Myeloid, Acute/drug therapy, Otros calificadores::Otros calificadores::/uso terapéutico, Histone Demethylases/antagonists & inhibitors, 03 medical and health sciences, Recurrence, COMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos, 80 and over, Acute/drug therapy, Humans, Diferenciación celular, Enzyme Inhibitors, Aged, Enzyme Inhibitors/pharmacology, Aged, 80 and over, Histone Demethylases, Leukemia, Infecciones, Leucèmia mieloide aguda, Sangre, ORIGINAL REPORTS, Middle Aged, CHEMICALS AND DRUGS::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors, 3. Good health, Leukemia, Myeloid, Acute, ENFERMEDADES::neoplasias::neoplasias por tipo histológico::leucemia::leucemia mieloide::leucemia mieloide aguda, Azacitidina, Farmacocinética, Female, DISEASES::Neoplasms::Neoplasms by Histologic Type::Leukemia::Leukemia, Myeloid::Leukemia, Myeloid, Acute, Diarrea, Inhibidors enzimàtics - Ús terapèutic |
| Beschreibung: | 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). |
| Publikationsart: | Article Other literature type |
| Dateibeschreibung: | application/pdf |
| Sprache: | English |
| ISSN: | 1527-7755 0732-183X |
| DOI: | 10.1200/jco.19.03250 |
| DOI: | 10.13039/501100000272 |
| DOI: | 10.13039/501100000780 |
| DOI: | 10.13039/501100003329 |
| DOI: | 10.13039/501100000765 |
| DOI: | 10.13039/501100000289 |
| DOI: | 10.13039/501100001872 |
| Zugangs-URL: | https://pubmed.ncbi.nlm.nih.gov/33052756 http://hdl.handle.net/10261/237089 https://fundanet.iislafe.san.gva.es/publicaciones/ProdCientif/PublicacionFrw.aspx?id=13287 https://hdl.handle.net/10668/27814 https://hdl.handle.net/11351/6309 https://pubmed.ncbi.nlm.nih.gov/33052756/ https://digital.csic.es/bitstream/10261/237089/1/Myeloid_Leukemia.pdf http://www.ncbi.nlm.nih.gov/pubmed/33052756 https://ascopubs.org/doi/10.1200/JCO.19.03250 https://digital.csic.es/handle/10261/237089 https://christie.openrepository.com/handle/10541/623429 |
| Rights: | CC BY NC ND URL: http://creativecommons.org/licenses/by-nc-nd/4.0/Creative Commons Attribution Non-Commercial No Derivatives 4.0 License: http://creativecommons.org/licenses/by-nc-nd/4.0/ |
| Dokumentencode: | edsair.doi.dedup.....aef4e440cd2f7ff566f31eee883fc8ef |
| Datenbank: | OpenAIRE |
Nájsť tento článok vo Web of Science | 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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| ISSN: | 15277755 0732183X |
| DOI: | 10.1200/jco.19.03250 |