Dose study of the multikinase inhibitor, LY2457546, in patients with relapsed acute myeloid leukemia to assess safety, pharmacokinetics, and pharmacodynamics

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Authors: Wacheck V, Lahn M, Dickinson G, Füreder W, Meyer R, Herndlhofer S, Füreder T, Dorfner G, Pillay S, André V, Burkholder TP, Akunda JK, Flye-Blakemore L, Van Bockstaele D, Schlenk RF, Sperr W, Valent P

Published Date May 2011 Volume 2011:3 Pages 157 - 175

DOI: http://dx.doi.org/10.2147/CMAR.S19341

Volker Wacheck¹, Michael Lahn², Gemma Dickinson³, Wolfgang Füreder⁴, Renata Meyer⁴, Susanne Herndlhofer⁴, Thorsten Füreder¹, Georg Dorfner⁵, Sada Pillay², Valérie André⁶, Timothy P Burkholder⁷, Jacqueline K Akunda⁸, Leann Flye-Blakemore⁹, Dirk Van Bockstaele⁹, Richard F Schlenk¹⁰, Wolfgang R Sperr⁴, Peter Valent^4,11
1Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel, Vienna, Austria; ²Early Oncology Clinical Investigation, Eli Lilly and Company, Indianapolis, IN, USA; ³Department of Pharmacokinetics, Eli Lilly and Company, Erl Wood Research Centre, Windlesham, Surrey, UK; ⁴Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Währinger Gürtel, Vienna, Austria; ⁵Eli Lilly GesmbH, Medical Department, Vienna, Austria; ⁶Department of Statistics, Eli Lilly and Company, Erl Wood Research Centre, Surrey, UK; ⁷Discovery Chemistry Research and Technology, Eli Lilly and Company, Indianapolis, IN, USA; ⁸Nonclinical Toxicology, Eli Lilly and Company, Indianapolis, IN, USA; ⁹Flow Cytometry and Cell Analysis, Esoterix Clinical Trials Services, Mechelen, Belgium; ¹⁰Universitätsklinikum Ulm, Klinik für Innere Medizin III, Ulm, Germany; ¹¹Ludwig Boltzmann Cluster Oncology, Vienna, Austria

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.
Conclusion: 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.

Keywords: multikinase inhibitor, pharmacokinetics, safety, acute myeloid leukemia, pharmacodynamics

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