Phase 1 study of GSK3368715, a type I PRMT inhibitor, in patients with advanced solid tumors

El-Khoueiry, AB; Clarke, J; Neff, T; Crossman, T; Ratia, N; Rathi, C; Noto, P; Tarkar, A; Garrido-Laguna, I; Calvo, E; Rodon, J; Tran, B; O&#39;Dwyer, PJ; Cuker, A; Abdul Razak, AR

Author(s): El-Khoueiry, AB; Clarke, J; Neff, T; Crossman, T; Ratia, N; Rathi, C; Noto, P; Tarkar, A; Garrido-Laguna, I; Calvo, E; Rodon, J; Tran, B; O'Dwyer, PJ; Cuker, A; Abdul Razak, AR;
Details: Publication Year 2023-08,Volume 129,Issue #2,Page 309-317
Journal Title: British Journal of Cancer
Publication Type: Research article
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.
Publisher: Springer Nature
Keywords: Adult; Humans; *Antineoplastic Agents/adverse effects; Enzyme Inhibitors/adverse effects; Maximum Tolerated Dose; *Neoplasms/pathology; Treatment Outcome
Department(s): Medical Oncology
PubMed ID: 37237172
Publisher's Version: https://doi.org/10.1038/s41416-023-02276-0
Open Access at Publisher's Site: https://doi.org/10.1038/s41416-023-02276-0
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-09-14 03:09:10

Last Modified: 2023-09-14 03:09:44