Phase I/II study of the clinical activity and safety of GSK3326595 in patients with myeloid neoplasms

Sep 21, 2026

Uploaded by Levi

GSK3326595 is a selective, reversible PRMT5 inhibitor evaluated for treatment of myelodysplastic syndrome, chronic myelomonocytic leukemia, and acute myeloid leukemia. A phase I/II open-label, multicenter study assessed clinical activity, safety, tolerability, dosing, pharmacokinetics and pharmacodynamics in adults with relapsed/refractory disease receiving oral once-daily monotherapy. Clinical benefit was limited, with 5 of 30 patients meeting CBR criteria, including responses such as stable disease and complete marrow remission, alongside common AEs like thrombocytopenia, dysgeusia, fatigue, and nausea.

LanguageEnglish

CategoryResearch & Report

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Pages16

Reading Time40 min

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Background and objectives

Study design and methods

Results and conclusions

Phase I/II study of the clinical activity and safety of GSK3326595 in patients with myeloid neoplasms Justin Watts, Mark D. Minden, Kimo Bachiashvili, Andrew M. Brunner, SameemAbedin, Timothy Crossman, Magdalena Zajac, Veronica Moroz, Jacqueline L. Egger, Aarti Tarkar, Brandon E. Kremer, Olena Barbash and Gautam Borthakur Abstract Background: 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. Objectives: To determine the clinical activity, safety, tolerability, dosing, additional measures of clinical activity, pharmacokinetics, and pharmacodynamics of GSK3326595 . Design: 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 mg oral GSK3326595 once daily. Study termination occurred prior to part 2 enrollment. Methods: 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) >8 weeks, 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 . Results: Thirty patients with a median age of 73.5 years (range, 47–90) were enrolled; 13 (43%) and 17 (57%) received 400 and 300 mg of GSK3326595, respectively. Five (17%) patients met CBR criteria: 4 (13%) with SD >8 weeks and 1 (3%) achieving mCR. Of five patients with clinical benefit: three had SRSF2 mutation, one U2AF1, and one was splicing factor wildtype. Frequent GSK3326595-related AEs were decreased platelet count (27%), dysgeusia (23%), fatigue (20%), and nausea (20%) . GSK3326595 had rapid absorption, with a Tmax of approximately 2 h and a terminal half-life of 4–6 h. Conclusion: 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. Trial registration: [ClinicalTrials.gov:](ClinicalTrials.gov:) NCT03614728. Plain language summary A clinical study to determine the effectiveness and safety of a medication called GSK3326595 in patients with cancers that affect the blood and bone marrow What is this study about? This summary provides the results of a study performed to see how safe and effective treatment with a once daily, oral medication called GSK3326595 was in patients with blood and bone marrow cancers. TherAdv Hematol 2024, Vol. 15: 1–16 DOI: 10. 1177/ 20406207241275376 © The Author(s), 2024. Article reuse guidelines: [sagepub.com/journals](sagepub.com/journals)permissions Correspondence to: Timothy Crossman Oncology Clinical Development, GSK, Gunnels Wood Road, Stevenage, Herts SG1 2NY, UK timothy.r.crossman@ [gsk.com](gsk.com) Justin Watts Division of Hematology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA Mark D. Minden Department of Medical Oncology and Hematology, Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada Kimo Bachiashvili Division of Hematology and Oncology, O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA Andrew M. Brunner Leukemia Program, Massachusetts General Hospital Cancer Center, Boston, MA, USA Sameem Abedin Division of Hematology/ Oncology, Medical College of Wisconsin, Milwaukee, WI, USA Magdalena Zajac Jacqueline L. Egger Oncology Cl

FAQs

What is the purpose of the Phase I/II study of GSK3326595?

The study evaluates clinical activity, safety, tolerability, dosing, and pharmacokinetics/pharmacodynamics of GSK3326595 in relapsed/refractory myeloid neoplasms. It also explores how spliceosome mutation profiles relate to clinical response.

How was clinical activity measured in the study?

Clinical activity used the clinical benefit rate (CBR), defined by complete remission, complete marrow remission, partial remission, stable disease longer than 8 weeks, or hematologic improvement.

What were the main safety findings and common adverse events?

GSK3326595 showed a safety profile broadly consistent with other PRMT5 inhibitor studies. Frequent related adverse events included decreased platelet count, dysgeusia, fatigue, and nausea.

Sep 21, 2026

Uploaded by Levi