title: 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.
authors.affiliation: a Duke University Medical Center , Durham , NC , USA ;
authors.forename: David A
authors.initials: DA
authors.lastname: Rizzieri
authors.affiliation: b University of Minnesota Masonic Cancer Center , Minneapolis , MN , USA ;
authors.forename: Sarah
authors.initials: S
authors.lastname: Cooley
authors.affiliation: c University of Chicago Medicine , Chicago , IL , USA ;
authors.forename: Olatoyosi
authors.initials: O
authors.lastname: Odenike
authors.affiliation: d Eli Lilly and Company , Indianapolis , IN , USA ;
authors.forename: Lisette
authors.initials: L
authors.lastname: Moonan
authors.affiliation: e Eli Lilly and Company Limited , Windlesham , UK , Surrey ;
authors.forename: Kay Hoong
authors.initials: KH
authors.lastname: Chow
authors.affiliation: e Eli Lilly and Company Limited , Windlesham , UK , Surrey ;
authors.forename: Kimberley
authors.initials: K
authors.lastname: Jackson
authors.affiliation: d Eli Lilly and Company , Indianapolis , IN , USA ;
authors.forename: Xuejing
authors.initials: X
authors.lastname: Wang
authors.affiliation: d Eli Lilly and Company , Indianapolis , IN , USA ;
authors.forename: Leslie
authors.initials: L
authors.lastname: Brail
authors.affiliation: f Department of Leukemia , University of Texas, MD Anderson Cancer Center , Houston , TX , USA.
authors.forename: Gautam
authors.initials: G
authors.lastname: Borthakur
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000139:chemically induced / Q000453:epidemiology; D000897:Anti-Ulcer Agents / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001854:Bone Marrow Cells / Q000187:drug effects; D016190:Carboplatin / Q000627:therapeutic use; D064146:Chemotherapy-Induced Febrile Neutropenia / Q000453:epidemiology; D015331:Cohort Studies; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006575:Heterocyclic Compounds, 3-Ring / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008297:Male; D008301:Maleimides / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008875:Middle Aged; D000073818:Procedural Pain / Q000517:prevention & control; D000068437:Pemetrexed / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011899:Ranitidine / Q000627:therapeutic use; D013921:Thrombocytopenia / Q000139:chemically induced / Q000453:epidemiology; D051176:beta Catenin / Q000032:analysis
chemical_list: C584053:3-(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; D000897:Anti-Ulcer Agents; D000970:Antineoplastic Agents; C495270:CTNNB1 protein, human; D006575:Heterocyclic Compounds, 3-Ring; D008301:Maleimides; D047428:Protein Kinase Inhibitors; D051176:beta Catenin; D000068437:Pemetrexed; D011899:Ranitidine; D016190:Carboplatin; D038362:Glycogen Synthase Kinase 3
keywords: AML; GSK-3; Pharmacotherapy