PMID- 33052756 OWN - NLM STAT- MEDLINE DCOM- 20210315 LR - 20240210 IS - 1527-7755 (Electronic) IS - 0732-183X (Print) IS - 0732-183X (Linking) VI - 38 IP - 36 DP - 2020 Dec 20 TI - 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. PG - 4260-4273 LID - 10.1200/JCO.19.03250 [doi] AB - 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 microg/m(2)/d) of each week in 28-day cycles in a DE phase that resulted in a recommended dose of 140 microg/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. 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). FAU - Salamero, Olga AU - Salamero O AUID- ORCID: 0000-0003-3237-0025 AD - Hospital Vall d'Hebron, Vall D'Hebron Institute of Oncology, Departament de Medicina, Universitat Autonoma de Barcelona, UAB, Barcelona, Spain. FAU - Montesinos, Pau AU - Montesinos P AUID- ORCID: 0000-0002-3275-5593 AD - Hospital Universitari I Politecnic La Fe, Valencia, Spain. AD - Centro de Investigacion Biomedica en Red de Cancer, Instituto Carlos III, Madrid, Spain. FAU - Willekens, Christophe AU - Willekens C AUID- ORCID: 0000-0001-9814-8537 AD - Institut Gustave Roussy, Villejuif Cedex, France. FAU - Perez-Simon, Jose Antonio AU - Perez-Simon JA AUID- ORCID: 0000-0003-3616-6101 AD - Hospital Universitario Virgen del Rocio, Sevilla, Spain. AD - Instituto de Biomedicina de Sevilla (Insitituto de Biomedicina De Sevilla/Consejo Superior De Investigaciones Cientificas/Centro de Investigacion Biomedica en Red de Cancer), Universidad de Sevilla, Sevilla, Spain. FAU - Pigneux, Arnaud AU - Pigneux A AD - Centre Hospitalier Universitaire CHU Bordeaux, Hopital du Haut Leveque, Pessac, France. FAU - Recher, Christian AU - Recher C AD - Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Universite Toulouse III Paul Sabatier, Toulouse, France. FAU - Popat, Rakesh AU - Popat R AUID- ORCID: 0000-0001-6553-4618 AD - National Institute for Health Research UCLH Clinical Research Facility, University College London Hospitals NHS Foundation Trust, London, United Kingdom. FAU - Carpio, Cecilia AU - Carpio C AD - Hospital Vall d'Hebron, Vall D'Hebron Institute of Oncology, Departament de Medicina, Universitat Autonoma de Barcelona, UAB, Barcelona, Spain. FAU - Molinero, Cesar AU - Molinero C AUID- ORCID: 0000-0003-0478-9152 AD - Oryzon Genomics, Barcelona, Spain. FAU - Mascaro, Cristina AU - Mascaro C AD - Oryzon Genomics, Barcelona, Spain. FAU - Vila, Joaquim AU - Vila J AD - Oryzon Genomics, Barcelona, Spain. FAU - Arevalo, M Isabel AU - Arevalo MI AUID- ORCID: 0000-0001-7347-9831 AD - Oryzon Genomics, Barcelona, Spain. FAU - Maes, Tamara AU - Maes T AUID- ORCID: 0000-0001-5104-6867 AD - Oryzon Genomics, Barcelona, Spain. FAU - Buesa, Carlos AU - Buesa C AD - Oryzon Genomics, Barcelona, Spain. FAU - Bosch, Francesc AU - Bosch F AUID- ORCID: 0000-0001-9241-2886 AD - Hospital Vall d'Hebron, Vall D'Hebron Institute of Oncology, Departament de Medicina, Universitat Autonoma de Barcelona, UAB, Barcelona, Spain. FAU - Somervaille, Tim C P AU - Somervaille TCP AUID- ORCID: 0000-0002-9188-4379 AD - The Christie NHS Foundation Trust, Manchester, United Kingdom. AD - Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom. LA - eng SI - EudraCT/2013-002447-29 GR - 29389/CRUK_/Cancer Research UK/United Kingdom GR - C5759/A20971/CRUK_/Cancer Research UK/United Kingdom GR - DH_/Department of Health/United Kingdom PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20201014 PL - United States TA - J Clin Oncol JT - Journal of clinical oncology : official journal of the American Society of Clinical Oncology JID - 8309333 RN - 0 (Enzyme Inhibitors) RN - EC 1.14.11.- (Histone Demethylases) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Enzyme Inhibitors/pharmacology/*therapeutic use MH - Female MH - Histone Demethylases/*antagonists & inhibitors MH - Humans MH - Leukemia, Myeloid, Acute/*drug therapy MH - Male MH - Middle Aged MH - Recurrence PMC - PMC7768337 EDAT- 2020/10/15 06:00 MHDA- 2021/03/16 06:00 PMCR- 2021/12/20 CRDT- 2020/10/14 17:58 PHST- 2020/10/15 06:00 [pubmed] PHST- 2021/03/16 06:00 [medline] PHST- 2020/10/14 17:58 [entrez] PHST- 2021/12/20 00:00 [pmc-release] AID - 1903250 [pii] AID - 10.1200/JCO.19.03250 [doi] PST - ppublish SO - J Clin Oncol. 2020 Dec 20;38(36):4260-4273. doi: 10.1200/JCO.19.03250. Epub 2020 Oct 14.