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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 10, 2006August 15, 2006; DOI 10.1182/blood-2006-02-005702. This Article 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 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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by De Angelo, D. J Articles by Heinrich, M. C Search for Related Content PubMed PubMed Citation Articles by De Angelo, D. J Articles by Heinrich, M. C Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 23, 2006 Accepted July 18, 2006 Phase I 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 De Angelo*, 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 Dana-Farber Cancer Institute, Boston, MA Memorial Sloan-Kettering Cancer Center, New York, NY UCLA Medical Center, Los Angeles, CA Ohio State University Comprehensive Cancer Center, Columbus, OH Millennium Pharmaceuticals Inc., Cambridge, MA Oregon Health & Science University, Portland, OR * Corresponding author; email: ddeangelo{at}partners.org. 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 I 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 b.i.d. The principal dose-limiting toxicity (DLT) of tandutinib was reversible generalized muscular weakness and/or fatigue, occurring at doses of 525 mg and 700 mg b.i.d. Tandutinib’ s pharmacokinetics were characterized by slow elimination, with achievement of steady-state plasma concentrations requiring > 1 week of dosing. Western blotting demonstrated 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 anti-leukemic effect. Two of the 5 patients, treated at 525 mg and 700 mg b.i.d., demonstrated evidence of anti-leukemic activity, with decreases in both peripheral and bone marrow blasts. Tandutinib at the MTD (525 mg b.i.d) should be evaluated more extensively in AML patients with FLT3-ITD mutations to better define its anti-leukemic activity. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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