An open-label phase 2 study of glycogen synthase kinase-3 inhibitor LY2090314 in patients with acute leukemia

Abstract

This open-label, Phase-2 study investigated the safety of LY2090314 (GSK-3 inhibitor) in AML patients. Twenty patients received 40-mg LY2090314 (50-mg ranitidine pretreatment) as follows: Cohort 1 – days 1, 8, and 15 of a 28-d cycle (n = 7); Cohort 2 – days 1, 5, and 9 of a 21-d cycle (n = 6); Cohort 3 – days 1, 5, 9, and 12 of a 21-d cycle (n = 7). Decreased appetite (n = 7) and nausea (n = 4) were the most frequently reported possibly drug-related non-hematologic treatment-emergent adverse events (TEAEs). Hematologic TEAEs included febrile neutropenia (n = 2), thrombocytopenia (n = 1), and anemia (n = 1). Atrial flutter (n = 1), QT interval prolongation (n = 3), and visual disturbances (n = 2) were observed, but were not clinically significant (investigator assessed). Although β-catenin levels indicated an on-target effect, no complete or partial remissions were observed. Pharmacokinetics were consistent with a previous Phase 1 study. These data suggest that single-agent LY2090314 has acceptable safety but limited clinical benefit in AML patients at the dose/frequencies investigated.

Keywords:

• AML
• GSK-3
• Pharmacotherapy

Acknowledgements

The authors would like to thank the patients who participated in this trial. We also thank Elizabeth Kumm of InventivHealthClinical for work on the statistical analyses and Cindy Coe Taylor of ClinGenuity LLC for writing assistance.

This study was funded by Eli Lilly and Company. K. H. C., K. J., X. W., and L. B. are employees Eli Lilly and Company and are minor stockholders. L. B. was an employee and minor stockholder of Eli Lilly and Company at the time the study was conducted and is currently employed by Infinity Pharmaceuticals, Inc. L. M. was a subcontractor for Eli Lilly and Company for the length of this trial and is currently employed as a contractor for Janssen Pharmaceuticals, Inc. G. B. reports research support from Eli Lilly and Company. O. O. reports research funding paid to her institution from Eli Lilly, Geron, Astex, Celgene, Eisai, Sunesis, Incyte, Sanofi, Novartis, NS-Pharma, S*Bio, MEI-Pharma, Gilead, and participation in advisory boards convened by Spectrum Pharmaceuticals, Sunesis, Algeta, Sanofi, and Incyte. D. R. and S. C. report no conflicts of interest. Medical writing support was provided by ClinGenuity LLC and was funded by Eli Lilly and Company.

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article at http://dx.doi.org/10.3109/10428194.2015.1122781.