title: Phase I dose escalation and pharmacokinetic evaluation of two different schedules of LY2334737, an oral gemcitabine prodrug, in patients with advanced solid tumors.
abstract: BACKGROUND
  This Phase-I-study aimed to determine the recommended Phase-II-dosing-schedule of LY2334737, an oral gemcitabine prodrug, in patients with advanced/metastatic solid tumors. Pharmacokinetics, cytokeratin-18 (CK18) levels, genetic polymorphisms, and antitumor activity were additionally evaluated.
  
  
  METHODS
  Patients received escalating doses of LY2334737 either every other day for 21 days (d) followed by 7 days-drug-free period (QoD-arm) or once daily for 7 days every other week (QD-arm). The 28 days-cycles were repeated until disease progression or unacceptable toxicity. Standard 3 + 3 dose-escalation was succeeded by a dose-confirmation phase (12 additional patients to be enrolled on the maximum tolerated dose [MTD]).
  
  
  RESULTS
  Forty-one patients received QoD- (40-100 mg) and 32 QD-dosing (40-90 mg). On QoD, 3/9 patients experienced dose-limiting toxicities (DLTs) on the 100 mg dose (2 × G3 diarrhea, 1 × G3 transaminase increase); 1 additional DLT (G3 diarrhea) occurred during dose confirmation at 90 mg (12 patients). On QD, 1 patient each experienced DLTs on 60 mg (G3 transaminase increase) and 80 mg (G3 prolonged QTcF-interval); 2/7 patients had 3 DLTs on the 90 mg dose (diarrhea, edema, liver-failure; all G3). The MTD was established at 90 mg for the QoD-arm. Seven patients on QoD and 4 on QD achieved SD (no CR + PR). Pharmacokinetics showed a dose-proportional increase in exposure of LY2334737 and dFdC without accumulation after repeated dosing. Significant increases in CK18 levels were observed. Genetic polymorphism of the cytidine deaminase gene (rs818202) could be associated with ≥ G3 hepatotoxicity.
  
  
  CONCLUSIONS
  Both schedules displayed linear pharmacokinetics and acceptable safety profiles. The recommended dose and schedule of LY2334737 for subsequent Phase-II-studies is 90 mg given QoD for 21 day.
authors.affiliation: Department of Medical Oncology, Beaujon University Hospital, Clichy, France.
authors.forename: Sandrine J
authors.initials: SJ
authors.lastname: Faivre
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Olszanski
authors.affiliation: Medizinische Klinik 5, Paracelsus Medical University, Nürnberg, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Weigang-Köhler
authors.affiliation: Medical Department, Division of Hematology, Oncology and Tumor Immunology, Charite Campus Virchow Hospital, Berlin, Germany.
authors.forename: Hanno
authors.initials: H
authors.lastname: Riess
authors.affiliation: Division of Hematology-Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Roger B
authors.initials: RB
authors.lastname: Cohen
authors.affiliation: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA.
authors.forename: Xuejing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Myrand
authors.affiliation: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA.
authors.forename: Enaksha R
authors.initials: ER
authors.lastname: Wickremsinhe
authors.affiliation: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA.
authors.forename: Candice L
authors.initials: CL
authors.lastname: Horn
authors.affiliation: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA.
authors.forename: Haojun
authors.initials: H
authors.lastname: Ouyang
authors.affiliation: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA.
authors.forename: Sophie
authors.initials: S
authors.lastname: Callies
authors.affiliation: Medical Oncology, Lilly France, Neuilly-sur Seine Cedex, France.
authors.forename: Karim A
authors.initials: KA
authors.lastname: Benhadji
authors.affiliation: Department of Medical Oncology, Beaujon University Hospital, Clichy, France. prof.raymond@gmail.com.|Hospital Beaujon, 100 Bd du General Leclerc, 92118, Clichy, France. prof.raymond@gmail.com.
authors.forename: Eric
authors.initials: E
authors.lastname: Raymond
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D003857:Deoxyuridine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D011355:Prodrugs / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000093542:Gemcitabine
chemical_list: C569272:LY2334737; D011355:Prodrugs; D003841:Deoxycytidine; D003857:Deoxyuridine; D000093542:Gemcitabine
keywords: Oral gemcitabine prodrug; Pharmacogenomics; Pharmacokinetics; Phase I study; Solid tumors