TY - JOUR
T1 - Phase 1 study of GSK3368715, a type I PRMT inhibitor, in patients with advanced solid tumors
AU - El-Khoueiry, Anthony B.
AU - Clarke, James
AU - Neff, Tobias
AU - Crossman, Tim
AU - Ratia, Nirav
AU - Rathi, Chetan
AU - Noto, Paul
AU - Tarkar, Aarti
AU - Garrido-Laguna, Ignacio
AU - Calvo, Emiliano
AU - Rodón, Jordi
AU - Tran, Ben
AU - O’Dwyer, Peter J.
AU - Cuker, Adam
AU - Abdul Razak, Albiruni R.
N1 - Funding Information:
Authors who are or were employees of GSK contributed to the design of the study, analysis of the data, and in the decision to publish. Funding for this study (NCT03666988 available from www.clinicaltrials.gov ) was provided by GSK. Open access funding provided by SCELC, Statewide California Electronic Library Consortium.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/8/10
Y1 - 2023/8/10
N2 - 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. [Figure not available: see fulltext.]
AB - 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. [Figure not available: see fulltext.]
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U2 - 10.1038/s41416-023-02276-0
DO - 10.1038/s41416-023-02276-0
M3 - Article
C2 - 37237172
AN - SCOPUS:85160219192
SN - 0007-0920
VL - 129
SP - 309
EP - 317
JO - British journal of cancer
JF - British journal of cancer
IS - 2
ER -