학술논문
Phase 1 study of JNJ-64619178, a protein arginine methyltransferase 5 inhibitor, in patients with lower-risk myelodysplastic syndromes.
Document Type
Academic Journal
Author
Haque T; The Ohio State University, Columbus, OH, USA. Electronic address: haquet1@mskcc.org.; Cadenas FL; Hospital Clinico de Salamanca, Salamanca, Castile and León, Spain.; Xicoy B; Institut Català d'Oncologia, Hospital Germans Trias I Pujol, Badalona, Josep Carreras Leukemia Research Institute, Universitat Autònoma de Barcelona, Badalona, Spain.; Alfonso-Pierola A; Clinica Universidad de Navarra, Pamplona, Navarre, Spain.; Platzbecker U; Universitatsklinikum Leipzig, Leipzig, Germany.; Avivi I; Sourasky Medical Center, Tel Aviv, Israel.; Brunner AM; Massachusetts General Hospital, Boston, MA, USA.; Chromik J; Goethe Universitat Frankfurt, Frankfurt, Germany.; Morillo D; University Hospital Fundación Jiménez Díaz, START Madrid-FJD early phase unit, Spain.; Patel MR; Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, FL, USA.; Falantes J; Servicio de Hematologia, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS) / CSIC, Universidad de Sevilla, Spain.; Leitch HA; St. Paul's Hospital, University of British Columbia, Vancouver, BC, Canada.; Germing U; Universitätsklinikum Düsseldorf, Department of Hematology, Oncology and Clinical Immunology, Düsseldorf, Germany.; Preis M; Carmel Medical Center, Haifa, Israel.; Lenox L; Janssen Research & Development, USA.; Lauring J; Janssen Research & Development, USA.; Brown RJ; Janssen Research & Development, USA.; Kalota A; Janssen Research & Development, USA.; Mehta J; Janssen Research & Development, USA.; Pastore F; Janssen Research & Development, USA.; Gu J; Janssen Research & Development, USA.; Mistry P; Janssen Research & Development, UK.; Valcárcel D; Hematology Department, Vall d'Hebron Institute Oncology (VHIO), Hospital Universitari Vall d´Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
Source
Publisher: Pergamon Press Country of Publication: England NLM ID: 7706787 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-5835 (Electronic) Linking ISSN: 01452126 NLM ISO Abbreviation: Leuk Res Subsets: MEDLINE
Subject
Language
English
Abstract
Splicing factor (SF) gene mutations are frequent in myelodysplastic syndromes (MDS), and agents that modulate RNA splicing are hypothesized to provide clinical benefit. JNJ-64619178, a protein arginine methyltransferase 5 (PRMT5) inhibitor, was evaluated in patients with lower-risk (LR) MDS in a multi-part, Phase 1, multicenter study. The objectives were to determine a tolerable dose and to characterize safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity. JNJ-64619178 was administered on a 14 days on/7 days off schedule or every day on a 21-day cycle to patients with International Prognostic Scoring System (IPSS) Low or Intermediate-1 risk MDS who were red blood cell transfusion-dependent. Twenty-four patients were enrolled; 15 (62.5 %) patients had low IPSS risk score, while 18 (75.0 %) had an SF3B1 mutation. Median duration of treatment was 3.45 months (range: 0.03-6.93). No dose limiting toxicities were observed. The 0.5 mg once daily dose was considered better tolerated and chosen for dose expansion. Twenty-three (95.8 %) patients experienced treatment-emergent adverse events (TEAE). The most common TEAEs were neutropenia (15 [62.5 %]) and thrombocytopenia (14 [58.3 %]). JNJ-64619178 pharmacokinetics was dose-dependent. Target engagement as measured by plasma symmetric di-methylarginine was observed across all dose levels; however, variant allele frequency of clonal mutations in bone marrow or blood did not show sustained reductions from baseline. No patient achieved objective response or hematologic improvement per International Working Group 2006 criteria, or transfusion independence. A tolerable dose of JNJ-64619178 was identified in patients with LR MDS. However, no evidence of clinical benefit was observed.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)
(Copyright © 2023 Elsevier Ltd. All rights reserved.)