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Blood, 1 December 2006, Vol. 108, No. 12, pp. 3674-3681. Prepublished online as a Blood First Edition Paper on August 15, 2006; DOI 10.1182/blood-2006-02-005702. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-02-005702v1 blood-2006-02-005702v2 108/12/3674    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by DeAngelo, D. J. Articles by Heinrich, M. C. Search for Related Content PubMed PubMed Citation Articles by DeAngelo, D. J. Articles by Heinrich, M. C. Related Collections Neoplasia Oncogenes and Tumor Suppressors Signal Transduction Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  CLINICAL TRIALS AND OBSERVATIONS Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics Daniel J. DeAngelo, Richard M. Stone, Mark L. Heaney, Stephen D. Nimer, Ronald L. Paquette, Rebecca B. Klisovic, Michael A. Caligiuri, Michael R. Cooper, Jean-Michel Lecerf, Michael D. Karol, Shihong Sheng, Nick Holford, Peter T. Curtin, Brian J. Druker, and Michael C. Heinrich From the Dana-Farber Cancer Institute, Boston, MA; the Memorial Sloan-Kettering Cancer Center, New York, NY; the University of California–Los Angeles (UCLA) Medical Center; The Ohio State University Comprehensive Cancer Center, Columbus; Millennium Pharmaceuticals, Cambridge, MA; the University of Auckland, New Zealand; the Oregon Health and Science University Cancer Institute, Portland; and the Portland Veterans Administration (VA) Medical Center, OR. Tandutinib (MLN518/CT53518) is a novel quinazoline-based inhibitor of the type III receptor tyrosine kinases: FMS-like tyrosine kinase 3 (FLT3), platelet-derived growth factor receptor (PDGFR), and KIT. Because of the correlation between FLT3 internal tandem duplication (ITD) mutations and poor prognosis in acute myelogenous leukemia (AML), we conducted a phase 1 trial of tandutinib in 40 patients with either AML or high-risk myelodysplastic syndrome (MDS). Tandutinib was given orally in doses ranging from 50 mg to 700 mg twice daily The principal dose-limiting toxicity (DLT) of tandutinib was reversible generalized muscular weakness, fatigue, or both, occurring at doses of 525 mg and 700 mg twice daily. Tandutinib's pharmacokinetics were characterized by slow elimination, with achievement of steady-state plasma concentrations requiring greater than 1 week of dosing. Western blotting showed that tandutinib inhibited phosphorylation of FLT3 in circulating leukemic blasts. Eight patients had FLT3-ITD mutations; 5 of these were evaluable for assessment of tandutinib's antileukemic effect. Two of the 5 patients, treated at 525 mg and 700 mg twice daily, showed evidence of antileukemic activity, with decreases in both peripheral and bone marrow blasts. Tandutinib at the MTD (525 mg twice daily) should be evaluated more extensively in patients with AML with FLT3-ITD mutations to better define its antileukemic activity. 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