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Phase 1 study of GSK3368715, a type I PRMT inhibitor, in patients with advanced solid tumors
Anthony B El-Khoueiry1, James Clarke2, Tobias Neff3,4
1University of Southern California Norris Comprehensive Cancer Center, 1441 Eastlake Ave, Los Angeles, CA, USA. elkhouei@med.usc.edu.
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.
Insights
The investigational cancer drug GSK3368715 showed safety concerns, including thromboembolic events, and limited efficacy in a Phase 1 trial. The study was terminated early due to these findings and modest target engagement.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- GSK3368715 is a novel, reversible inhibitor of type I protein methyltransferases (PRMTs).
- Preclinical studies indicated anticancer activity for GSK3368715.
- This Phase 1 study assessed the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of GSK3368715 in adults with advanced solid tumors.
Purpose of the Study:
- Evaluate the safety and tolerability of escalating oral doses of GSK3368715.
- Assess the pharmacokinetics and pharmacodynamics of GSK3368715.
- Determine preliminary efficacy signals of GSK3368715 in patients with advanced solid tumors.
Main Methods:
- Phase 1, open-label, dose-escalation study (NCT03666988).
- Oral GSK3368715 administered once daily at doses of 50, 100, and 200 mg.
- Study enrollment paused at 200 mg due to thromboembolic events (TEEs), resuming at 100 mg after protocol amendment.
Main Results:
- Dose-limiting toxicities observed in 25% of patients at 200 mg.
- 29% of patients experienced 12 TEEs, including a grade 5 pulmonary embolism.
- Best overall response was stable disease in 29% of patients; target engagement was modest and variable.
Conclusions:
- The study was terminated early due to a high incidence of TEEs and limited clinical efficacy.
- Risk/benefit analysis indicated that GSK3368715 did not demonstrate sufficient therapeutic potential.
- Further development of GSK3368715 was halted based on safety and efficacy findings.
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