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

by Selleckchem | Sep 03 2023

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.

Comments:

The Phase 1 study (NCT03666988) evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of GSK3368715, a first-in-class reversible inhibitor of type I protein methyltransferases (PRMTs), in adults with advanced-stage solid tumors. The study was conducted in two parts.

In Part 1, escalating doses of oral once-daily GSK3368715 were tested, starting at 50 mg and increasing to 100 mg and 200 mg. However, enrollment was paused at the 200 mg dose level due to a higher-than-expected incidence of thromboembolic events (TEEs) among the first 19 participants. After a protocol amendment, the study resumed with a maximum dose of 100 mg.

The results showed that dose-limiting toxicities were reported in 3 out of 12 (25%) patients who received the 200 mg dose. Across all dose groups, 9 out of 31 (29%) patients experienced a total of 12 TEEs, including 8 grade 3 events and 1 grade 5 pulmonary embolism. The best response achieved was stable disease, which occurred in 9 out of 31 (29%) patients. However, Part 2 of the study, which aimed to evaluate preliminary efficacy, was not initiated.

Pharmacokinetic analysis revealed that GSK3368715 reached its maximum plasma concentration within 1 hour after dosing, both after single and repeat administration. Target engagement, as measured in the blood, was observed but was modest and variable in tumor biopsies at the 100 mg dose level.

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