Phase 1 Study of GSK3368715, a Type I PRMT Inhibitor, in Patients with Advanced Solid Tumors

Overview

Journal Br J Cancer

Specialty Oncology

Date 2023 May 26

PMID 37237172

Authors

Anthony B El-Khoueiry

James Clarke

Tobias Neff

Tim Crossman

Nirav Ratia

Chetan Rathi

Paul Noto

Aarti Tarkar

Ignacio Garrido-Laguna

Emiliano Calvo

Jordi Rodon

Ben Tran

Peter J ODwyer

Adam Cuker

Albiruni R Abdul Razak

Affiliations

Soon will be listed here.

Abstract

Background: GSK3368715, a first-in-class, reversible inhibitor of type I protein methyltransferases (PRMTs) demonstrated anticancer activity in preclinical studies. This Phase 1 study (NCT03666988) evaluated safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of GSK3368715 in adults with advanced-stage solid tumors.

Methods: In part 1, escalating doses of oral once-daily GSK3368715 (50, 100, and 200 mg) were evaluated. Enrollment was paused at 200 mg following a higher-than-expected incidence of thromboembolic events (TEEs) among the first 19 participants, resuming under a protocol amendment starting at 100 mg. Part 2 (to evaluate preliminary efficacy) was not initiated.

Results: Dose-limiting toxicities were reported in 3/12 (25%) patients at 200 mg. Nine of 31 (29%) patients across dose groups experienced 12 TEEs (8 grade 3 events and 1 grade 5 pulmonary embolism). Best response achieved was stable disease, occurring in 9/31 (29%) patients. Following single and repeat dosing, GSK3368715 maximum plasma concentration was reached within 1 h post dosing. Target engagement was observed in the blood, but was modest and variable in tumor biopsies at 100 mg.

Conclusion: Based on higher-than-expected incidence of TEEs, limited target engagement at lower doses, and lack of observed clinical efficacy, a risk/benefit analysis led to early study termination.

Trial Registration Number: NCT03666988.

Citing Articles

Protein Arginine Methyltransferase 1: A Multi-Purpose Player in the Development of Cancer and Metabolic Disease.

de Korte D, Hoekstra M Biomolecules. 2025; 15(2).

PMID: 40001488 PMC: 11852820. DOI: 10.3390/biom15020185.

TRIM21-mediated PRMT1 degradation attenuates colorectal cancer malignant progression.

Cao M, Shao Z, Qian X, Chen M, Deng C, Chen X Cell Death Dis. 2025; 16(1):56.

PMID: 39890802 PMC: 11785787. DOI: 10.1038/s41419-025-07383-9.

Targeting RNA splicing modulation: new perspectives for anticancer strategy?.

Lv X, Sun X, Gao Y, Song X, Hu X, Gong L J Exp Clin Cancer Res. 2025; 44(1):32.

PMID: 39885614 PMC: 11781073. DOI: 10.1186/s13046-025-03279-w.

Fuel for thought: targeting metabolism in lung cancer.

Schneider J, Han S, Nabel C Transl Lung Cancer Res. 2025; 13(12):3692-3717.

PMID: 39830762 PMC: 11736591. DOI: 10.21037/tlcr-24-662.

Biomedical effects of protein arginine methyltransferase inhibitors.

Cao M, Nguyen T, Song J, Zheng Y J Biol Chem. 2025; 301(3):108201.

PMID: 39826691 PMC: 11871472. DOI: 10.1016/j.jbc.2025.108201.

References

Bedford M, Clarke S . Protein arginine methylation in mammals: who, what, and why. Mol Cell. 2009; 33(1):1-13. PMC: 3372459. DOI: 10.1016/j.molcel.2008.12.013. View

Infantino S, Light A, ODonnell K, Bryant V, Avery D, Elliott M . Arginine methylation catalyzed by PRMT1 is required for B cell activation and differentiation. Nat Commun. 2017; 8(1):891. PMC: 5638811. DOI: 10.1038/s41467-017-01009-1. View

Yang Y, Bedford M . Protein arginine methyltransferases and cancer. Nat Rev Cancer. 2012; 13(1):37-50. DOI: 10.1038/nrc3409. View

Yu Z, Chen T, Hebert J, Li E, Richard S . A mouse PRMT1 null allele defines an essential role for arginine methylation in genome maintenance and cell proliferation. Mol Cell Biol. 2009; 29(11):2982-96. PMC: 2681996. DOI: 10.1128/MCB.00042-09. View

Cheung N, Chan L, Thompson A, Cleary M, So C . Protein arginine-methyltransferase-dependent oncogenesis. Nat Cell Biol. 2007; 9(10):1208-15. DOI: 10.1038/ncb1642. View

Fedoriw A, Rajapurkar S, OBrien S, Gerhart S, Mitchell L, Adams N . Anti-tumor Activity of the Type I PRMT Inhibitor, GSK3368715, Synergizes with PRMT5 Inhibition through MTAP Loss. Cancer Cell. 2019; 36(1):100-114.e25. DOI: 10.1016/j.ccell.2019.05.014. View

Dhar S, Vemulapalli V, Patananan A, Huang G, Di Lorenzo A, Richard S . Loss of the major Type I arginine methyltransferase PRMT1 causes substrate scavenging by other PRMTs. Sci Rep. 2013; 3:1311. PMC: 3575585. DOI: 10.1038/srep01311. View

Marjon K, Cameron M, Quang P, Clasquin M, Mandley E, Kunii K . MTAP Deletions in Cancer Create Vulnerability to Targeting of the MAT2A/PRMT5/RIOK1 Axis. Cell Rep. 2016; 15(3):574-587. DOI: 10.1016/j.celrep.2016.03.043. View

Kryukov G, Wilson F, Ruth J, Paulk J, Tsherniak A, Marlow S . MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells. Science. 2016; 351(6278):1214-8. PMC: 4997612. DOI: 10.1126/science.aad5214. View

10.

Huang H, Li S, Yu S, Chou F, Tzeng C, Hu T . Homozygous deletion of MTAP gene as a poor prognosticator in gastrointestinal stromal tumors. Clin Cancer Res. 2009; 15(22):6963-72. DOI: 10.1158/1078-0432.CCR-09-1511. View

11.

Kirovski G, Stevens A, Czech B, Dettmer K, Weiss T, Wild P . Down-regulation of methylthioadenosine phosphorylase (MTAP) induces progression of hepatocellular carcinoma via accumulation of 5'-deoxy-5'-methylthioadenosine (MTA). Am J Pathol. 2011; 178(3):1145-52. PMC: 3069916. DOI: 10.1016/j.ajpath.2010.11.059. View

12.

Neuenschwander B, Branson M, Gsponer T . Critical aspects of the Bayesian approach to phase I cancer trials. Stat Med. 2008; 27(13):2420-39. DOI: 10.1002/sim.3230. View

13.

Khorana A, Kuderer N, Culakova E, Lyman G, Francis C . Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood. 2008; 111(10):4902-7. PMC: 2384124. DOI: 10.1182/blood-2007-10-116327. View

14.

Noto P, Sikorski T, Zappacosta F, Wagner C, Montes de Oca R, Szapacs M . Identification of hnRNP-A1 as a pharmacodynamic biomarker of type I PRMT inhibition in blood and tumor tissues. Sci Rep. 2020; 10(1):22155. PMC: 7746746. DOI: 10.1038/s41598-020-78800-6. View

15.

Mandala M, Clerici M, Corradino I, Vitalini C, Colombini S, Torri V . Incidence, risk factors and clinical implications of venous thromboembolism in cancer patients treated within the context of phase I studies: the 'SENDO experience'. Ann Oncol. 2011; 23(6):1416-21. DOI: 10.1093/annonc/mdr524. View

16.

Gao G, Zhang L, Villarreal O, He W, Su D, Bedford E . PRMT1 loss sensitizes cells to PRMT5 inhibition. Nucleic Acids Res. 2019; 47(10):5038-5048. PMC: 6547413. DOI: 10.1093/nar/gkz200. View

17.

Jensen-Pergakes K, Tatlock J, Maegley K, McAlpine I, McTigue M, Xie T . SAM-Competitive PRMT5 Inhibitor PF-06939999 Demonstrates Antitumor Activity in Splicing Dysregulated NSCLC with Decreased Liability of Drug Resistance. Mol Cancer Ther. 2021; 21(1):3-15. DOI: 10.1158/1535-7163.MCT-21-0620. View

18.

Brehmer D, Beke L, Wu T, Millar H, Moy C, Sun W . Discovery and Pharmacological Characterization of JNJ-64619178, a Novel Small-Molecule Inhibitor of PRMT5 with Potent Antitumor Activity. Mol Cancer Ther. 2021; 20(12):2317-2328. PMC: 9398174. DOI: 10.1158/1535-7163.MCT-21-0367. View