title: Dose study of the multikinase inhibitor, LY2457546, in patients with relapsed acute myeloid leukemia to assess safety, pharmacokinetics, and pharmacodynamics.
abstract: BACKGROUND
  Acute myeloid leukemia (AML) is a life-threatening malignancy with limited treatment options in chemotherapy-refractory patients. A first-in-human dose study was designed to investigate a safe and biologically effective dose range for LY2457546, a novel multikinase inhibitor, in patients with relapsed AML.
  
  
  METHODS
  In this nonrandomized, open-label, dose escalation Phase I study, LY2457546 was administered orally once a day. Safety, pharmacokinetics, changes in phosphorylation of target kinases in AML blasts, and risk of drug-drug interactions (DDI) were assessed.
  
  
  RESULTS
  Five patients were treated at the starting and predicted minimal biologically effective dose of 50 mg/day. The most commonly observed adverse events were febrile neutropenia, epistaxis, petechiae, and headache. The majority of adverse events (81%) were Grade 1 or 2. One patient had generalized muscle weakness (Grade 3), which was deemed to be a dose-limiting toxicity. Notably, the pharmacokinetic profile of LY2457546 showed virtually no elimination of LY2457546 within 24 hours, and thus prevented further dose escalation. No significant DDI were observed. Ex vivo flow cytometry studies showed downregulation of the phosphoproteins, pcKIT, pFLT3, and pS6, in AML blasts after LY2457546 administration. No medically relevant responses were observed in the five treated patients.
  
  
  CONCLUSIONS
  No biologically effective dose could be established for LY2457546 in chemotherapy-resistant AML patients. Lack of drug clearance prevented safe dose escalation, and the study was terminated early. Future efforts should be made to develop derivatives with a more favorable pharmacokinetic profile.
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel, Vienna, Austria;
authors.forename: Volker
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authors.lastname: Wacheck
authors.forename: Michael
authors.initials: M
authors.lastname: Lahn
authors.forename: Gemma
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authors.lastname: Dickinson
authors.forename: Wolfgang
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authors.lastname: Füreder
authors.forename: Renata
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authors.lastname: Meyer
authors.forename: Susanne
authors.initials: S
authors.lastname: Herndlhofer
authors.forename: Thorsten
authors.initials: T
authors.lastname: Füreder
authors.forename: Georg
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authors.lastname: Dorfner
authors.forename: Sada
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authors.lastname: Pillay
authors.forename: Valérie
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authors.lastname: André
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Burkholder
authors.forename: Jacqueline K
authors.initials: JK
authors.lastname: Akunda
authors.forename: Leann
authors.initials: L
authors.lastname: Flye-Blakemore
authors.forename: Dirk
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authors.lastname: Van Bockstaele
authors.forename: Richard F
authors.initials: RF
authors.lastname: Schlenk
authors.forename: Wolfgang R
authors.initials: WR
authors.lastname: Sperr
authors.forename: Peter
authors.initials: P
authors.lastname: Valent