A pharmacodynamic study of sorafenib in patients with relapsed and refractory acute leukemias

K. W. Pratz, E. Cho, M. J. Levis, J. E. Karp, S. D. Gore, M. McDevitt, A. Stine, M. Zhao, S. D. Baker, M. A. Carducci, J. J. Wright, M. A. Rudek, B. D. Smith

Research output: Contribution to journalArticlepeer-review

Abstract

We report the results of a phase I dose escalation trial of the multikinase inhibitor sorafenib in relapsed and refractory acute leukemia patients using an intermittent dosing regimen. Fifteen patients with advanced leukemia (12 with acute myeloid leukemia, 2 with acute lymphoblastic leukemia, 1 with biphenotypic) and a median age of 63 (range 37-85) years were enrolled and treated on a dose escalation trial. Toxicities grade 3 were present in 55% of cycles and the maximum tolerated dose (MTD) was determined to be 400 mg b.i.d. × 21days in a 28-day cycle. Plasma inhibitory assays of kinase targets extracellular signal-regulated kinase (ERK) and FLT3-internal tandem duplication (ITD) showed excellent target inhibition, with FLT3-ITD silencing occurring below the MTD. The N-oxide metabolite of sorafenib seemed to be a more potent inhibitor of FLT3-ITD than the parent compound. Despite marked ex vivo FLT-3 ITD inhibition, no patients met the criteria for complete or partial response in this monotherapy study. Out of 15 patients, 11 experienced stable disease as best response. Although sorafenib showed only modest clinical activity as a single agent in this heavily treated population, robust inhibition of FLT3 and ERK suggests that there may be a potential important role in combination therapies.

Original languageEnglish (US)
Pages (from-to)1437-1444
Number of pages8
JournalLeukemia
Volume24
Issue number8
DOIs
StatePublished - Aug 2010

Keywords

  • FLT3 targeted therapy
  • acute myeloid leukemia
  • clinical trial
  • signal transduction inhibitors

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'A pharmacodynamic study of sorafenib in patients with relapsed and refractory acute leukemias'. Together they form a unique fingerprint.

Cite this