AI Article Synopsis
- GSK3326595 is a selective inhibitor of PRMT5 being tested for treating blood cancers like MDS, CMML, and AML, showing promise in preclinical studies by decreasing cancer cell growth and increasing cell death.
- The study aimed to evaluate the drug's clinical activity, safety, and pharmacokinetics in adults with relapsed myeloid neoplasms, focusing on those who received either 400 or 300 mg daily doses.
- Out of 30 enrolled patients, 17% achieved clinical benefits, primarily those with specific genetic mutations; common side effects included low platelet counts and fatigue, while the drug demonstrated quick absorption characteristics.
Article 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 wild-type. Frequent GSK3326595-related AEs were decreased platelet count (27%), dysgeusia (23%), fatigue (20%), and nausea (20%). GSK3326595 had rapid absorption, with a 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: NCT03614728.
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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11406655 | PMC |
| http://dx.doi.org/10.1177/20406207241275376 | DOI Listing |
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