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.
Publication types
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Clinical Trial, Phase II
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Multicenter Study
MeSH terms
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Adult
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Aged
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Aged, 80 and over
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Anemia / chemically induced
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Anemia / epidemiology
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Anti-Ulcer Agents / therapeutic use
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / therapeutic use*
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
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Bone Marrow Cells / drug effects
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Carboplatin / therapeutic use
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Chemotherapy-Induced Febrile Neutropenia / epidemiology
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Cohort Studies
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Female
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Glycogen Synthase Kinase 3 / antagonists & inhibitors*
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Heterocyclic Compounds, 3-Ring / pharmacokinetics
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Heterocyclic Compounds, 3-Ring / therapeutic use*
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Humans
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Leukemia, Myeloid, Acute / drug therapy*
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Leukocytes, Mononuclear / drug effects
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Male
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Maleimides / pharmacokinetics
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Maleimides / therapeutic use*
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Middle Aged
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Pain, Procedural / prevention & control
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Pemetrexed / therapeutic use
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / therapeutic use*
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Ranitidine / therapeutic use
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Thrombocytopenia / chemically induced
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Thrombocytopenia / epidemiology
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beta Catenin / analysis
Substances
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3-(9-fluoro-2-(piperidin-1-ylcarbonyl)-1,2,3,4-tetrahydro(1,4)diazepino(6,7,1-hi)indol-7-yl)-4-imidazo(1,2-a)pyridin-3-yl-1H-pyrrole-2,5-dione
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Anti-Ulcer Agents
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Antineoplastic Agents
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CTNNB1 protein, human
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Heterocyclic Compounds, 3-Ring
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Maleimides
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Protein Kinase Inhibitors
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beta Catenin
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Pemetrexed
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Ranitidine
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Carboplatin
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Glycogen Synthase Kinase 3