Artigo Acesso aberto Revisado por pares

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

2023; Springer Nature; Volume: 129; Issue: 2 Linguagem: Inglês

10.1038/s41416-023-02276-0

ISSN

1532-1827

Autores

Anthony B. El-Khoueiry, James S. Clarke, Tobias Neff, T. Crossman, Nirav Ratia, Chetan Rathi, Paul Noto, Aarti Tarkar, Ignacio Garrido‐Laguna, Emiliano Calvo, Jordi Rodón, Ben Tran, Peter J. O’Dwyer, Adam Cuker, Albiruni R. Abdul Razak,

Tópico(s)

Epigenetics and DNA Methylation

Resumo

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.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.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.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.NCT03666988.

Referência(s)