Dose study of the multikinase inhibitor, LY2457546, in patients with relapsed acute myeloid leukemia to assess safety, pharmacokinetics, and pharmacodynamics.
Publication/Presentation Date
1-1-2011
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.
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.
Volume
3
First Page
157
Last Page
175
ISSN
1179-1322
Published In/Presented At
Wacheck, V., Lahn, M., Dickinson, G., Füreder, W., Meyer, R., Herndlhofer, S., Füreder, T., Dorfner, G., Pillay, S., André, V., Burkholder, T. P., Akunda, J. K., Flye-Blakemore, L., Van Bockstaele, D., Schlenk, R. F., Sperr, W. R., & Valent, P. (2011). Dose study of the multikinase inhibitor, LY2457546, in patients with relapsed acute myeloid leukemia to assess safety, pharmacokinetics, and pharmacodynamics. Cancer management and research, 3, 157–175. https://doi.org/10.2147/CMR.S19341
Disciplines
Medicine and Health Sciences
PubMedID
21625399
Department(s)
Department of Medicine
Document Type
Article