title: A first-in-human phase I dose-escalation, pharmacokinetic, and pharmacodynamic evaluation of intravenous LY2090314, a glycogen synthase kinase 3 inhibitor, administered in combination with pemetrexed and carboplatin.
abstract: OBJECTIVE
  LY2090314 (LY) is a glycogen synthase kinase 3 inhibitor with preclinical efficacy in xenograft models when combined with platinum regimens. A first-in-human phase 1 dose-escalation study evaluated the combination of LY with pemetrexed/carboplatin.
  
  
  METHODS
  Forty-one patients with advanced solid tumors received single-dose LY monotherapy lead-in and 37 patients received LY (10-120 mg) plus pemetrexed/carboplatin (500 mg/m(2) and 5-6 AUC, respectively) across 8 dose levels every 21 days. Primary objective was maximum tolerated dose (MTD) determination; secondary endpoints included safety, antitumor activity, pharmacokinetics, and beta-catenin pharmacodynamics.
  
  
  RESULTS
  MTD of LY with pemetrexed/carboplatin was 40 mg. Eleven dose-limiting toxicities (DLTs) occurred in ten patients. DLTs during LY monotherapy occurred at ≥ 40 mg: grade 2 visual disturbance (n = 1) and grade 3/4 peri-infusional thoracic pain during or shortly post infusion (n = 4; chest, upper abdominal, and back pain). Ranitidine was added after de-escalation to 80 mg LY to minimize peri-infusional thoracic pain. Following LY with pemetrexed/carboplatin therapy, DLTs included grade 3/4 thrombocytopenia (n = 4) and grade 4 neutropenia (n = 1). Best overall response by RECIST included 5 confirmed partial responses (non-small cell lung cancer [n = 3], mesothelioma, and breast cancer) and 19 patients having stable disease. Systemic LY exposure was approximately linear over dose range studied. Transient upregulation of beta-catenin measured in peripheral blood mononuclear cells (PBMCs) occurred at 40 mg LY.
  
  
  CONCLUSIONS
  The initial safety profile of LY2090314 was established. MTD LY dose with pemetrexed/carboplatin is 40 mg IV every 3 weeks plus ranitidine. Efficacy of LY plus pemetrexed/carboplatin requires confirmation in randomized trials.
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Jhanelle E
authors.initials: JE
authors.lastname: Gray
authors.affiliation: Sarah Cannon Research Institute and Tennessee Oncology, 250 25th Avenue North, Suite 200, Nashville, TN, 37203, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.|Infinity Pharmaceuticals, Cambridge, MA, USA.
authors.forename: Les H
authors.initials: LH
authors.lastname: Brail
authors.affiliation: MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: George R
authors.initials: GR
authors.lastname: Simon
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Jennifer F
authors.initials: JF
authors.lastname: Cooksey
authors.affiliation: Sarah Cannon Research Institute and Tennessee Oncology, 250 25th Avenue North, Suite 200, Nashville, TN, 37203, USA.
authors.forename: Suzanne F
authors.initials: SF
authors.lastname: Jones
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Daphne L
authors.initials: DL
authors.lastname: Farrington
authors.affiliation: DOCS, San Diego, CA, USA.|Stat4ward LLC, Pittsburgh, PA, USA.
authors.forename: Adeline
authors.initials: A
authors.lastname: Yeo
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Kimberley A
authors.initials: KA
authors.lastname: Jackson
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: Kay H
authors.initials: KH
authors.lastname: Chow
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.|GlaxoSmithKline, Research Triangle Park, North Caroline, USA.
authors.forename: Maciej J
authors.initials: MJ
authors.lastname: Zamek-Gliszczynski
authors.affiliation: Sarah Cannon Research Institute and Tennessee Oncology, 250 25th Avenue North, Suite 200, Nashville, TN, 37203, USA. howard.burris@scresearch.net.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016190:Carboplatin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008301:Maleimides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D000068437:Pemetrexed / Q000008:administration & dosage* / Q000493:pharmacokinetics
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; D006575:Heterocyclic Compounds, 3-Ring; D008301:Maleimides; D000068437:Pemetrexed; D016190:Carboplatin; D038362:Glycogen Synthase Kinase 3
keywords: Glycogen synthase kinase 3 inhibitor; LY2090314; Phase 1; Solid tumors