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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, 2006August 10, 2006; DOI 10.1182/blood-2006-02-005702.
 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 DeAngelo*, Richard M. Stone, Mark L. Heaney, Stephen D. Nimer, Ronald L. Paquette, Rebecca J. Bruner-Klisovic, Michael A Caligiuri, Michael R Cooper, Jean-Michel Lecerf, Michael R Karol, 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.
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