{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T05:59:55Z","timestamp":1793771995047,"version":"4.6.1"},"reference-count":38,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2024,1,1]],"date-time":"2024-01-01T00:00:00Z","timestamp":1704067200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004330","name":"GlaxoSmithKline","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004330","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Therapeutic Advances in Hematology"],"published-print":{"date-parts":[[2024,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>GSK3326595 is a potent, selective, reversible protein arginine methyltransferase 5 (PRMT5) inhibitor under investigation for treatment of myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML). In preclinical models of AML, PRMT5 inhibition decreased proliferation and increased cell death, supporting additional clinical research in myeloid neoplasms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives:<\/jats:title>\n                    <jats:p>To determine the clinical activity, safety, tolerability, dosing, additional measures of clinical activity, pharmacokinetics, and pharmacodynamics of GSK3326595.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Design:<\/jats:title>\n                    <jats:p>In part 1 of this open-label, multicenter, multipart, phase I\/II study, adults with relapsed\/refractory myeloid neoplasms (e.g., MDS, CMML, and AML) received monotherapy with 400 or 300\u2009mg oral GSK3326595 once daily. Study termination occurred prior to part 2 enrollment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>Clinical activity was determined by the clinical benefit rate (CBR; proportion of patients achieving complete remission (CR), complete marrow remission (mCR), partial remission, stable disease (SD) &gt;8\u2009weeks, or hematologic improvement). Adverse events (AEs) were assessed by incidence and severity. Exploratory examination of spliceosome mutations was performed to determine the relationship between genomic profiles and clinical response to GSK3326595.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Thirty patients with a median age of 73.5\u2009years (range, 47\u201390) were enrolled; 13 (43%) and 17 (57%) received 400 and 300\u2009mg of GSK3326595, respectively. Five (17%) patients met CBR criteria: 4 (13%) with SD &gt;8\u2009weeks and 1 (3%) achieving mCR. Of five patients with clinical benefit: three had SRSF2 mutation, one U2AF1, and one was splicing factor wild-type. Frequent GSK3326595-related AEs were decreased platelet count (27%), dysgeusia (23%), fatigue (20%), and nausea (20%). GSK3326595 had rapid absorption, with a T\n                      <jats:sub>max<\/jats:sub>\n                      of approximately 2\u2009h and a terminal half-life of 4\u20136\u2009h.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion:<\/jats:title>\n                    <jats:p>GSK3326595 monotherapy had limited clinical activity in heavily pretreated patients despite robust target engagement. The safety profile was broadly consistent with other published PRMT5 inhibitor studies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration:<\/jats:title>\n                    <jats:p>ClinicalTrials.gov: NCT03614728.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/20406207241275376","type":"journal-article","created":{"date-parts":[[2024,9,14]],"date-time":"2024-09-14T06:04:47Z","timestamp":1726293887000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":43,"title":["Phase I\/II study of the clinical activity and safety of GSK3326595 in patients with myeloid neoplasms"],"prefix":"10.1177","volume":"15","author":[{"given":"Justin","family":"Watts","sequence":"first","affiliation":[{"name":"Division of Hematology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark D.","family":"Minden","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology and Hematology, Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimo","family":"Bachiashvili","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, O\u2019Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew M.","family":"Brunner","sequence":"additional","affiliation":[{"name":"Leukemia Program, Massachusetts General Hospital Cancer Center, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sameem","family":"Abedin","sequence":"additional","affiliation":[{"name":"Division of Hematology\/Oncology, Medical College of Wisconsin, Milwaukee, WI, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5643-6408","authenticated-orcid":false,"given":"Timothy","family":"Crossman","sequence":"additional","affiliation":[{"name":"Oncology Clinical Development, GSK, Gunnels Wood Road, Stevenage, Herts SG1 2NY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Zajac","sequence":"additional","affiliation":[{"name":"Oncology Clinical Development, GSK, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"Moroz","sequence":"additional","affiliation":[{"name":"Biostatistics, GSK, Stevenage, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline L.","family":"Egger","sequence":"additional","affiliation":[{"name":"Oncology Clinical Development, GSK, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aarti","family":"Tarkar","sequence":"additional","affiliation":[{"name":"Oncology Clinical Development, GSK, Collegeville, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon E.","family":"Kremer","sequence":"additional","affiliation":[{"name":"Oncology Clinical Development, GSK, Collegeville, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olena","family":"Barbash","sequence":"additional","affiliation":[{"name":"Oncology Clinical Development, GSK, Collegeville, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gautam","family":"Borthakur","sequence":"additional","affiliation":[{"name":"Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2024,9,14]]},"reference":[{"key":"bibr1-20406207241275376","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-03-643544"},{"key":"bibr2-20406207241275376","doi-asserted-by":"publisher","DOI":"10.1080\/10428194.2016.1228927"},{"key":"bibr3-20406207241275376","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2016-05-714030"},{"key":"bibr4-20406207241275376","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.11051"},{"key":"bibr5-20406207241275376","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2019.222059"},{"key":"bibr6-20406207241275376","doi-asserted-by":"publisher","DOI":"10.2147\/IJGM.S371766"},{"key":"bibr7-20406207241275376","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2017009829"},{"key":"bibr8-20406207241275376","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13071610"},{"key":"bibr9-20406207241275376","unstructured":"National Cancer Institute. 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