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 Druker, Michael Heinrich

Research output: Contribution to journalArticle

203 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3674-3681
Number of pages8
JournalBlood
Volume108
Issue number12
DOIs
StatePublished - Dec 1 2006
Externally publishedYes

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Pharmacodynamics
Pharmacokinetics
Myelodysplastic Syndromes
Acute Myeloid Leukemia
Protein-Tyrosine Kinases
Safety
Mutation
tandutinib
Quinazolines
Platelet-Derived Growth Factor Receptors
Muscle Fatigue
Phosphorylation
Muscle Weakness
Receptor Protein-Tyrosine Kinases
Toxicity
Bone
Bone Marrow
Western Blotting
Fatigue of materials

ASJC Scopus subject areas

  • Hematology

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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. / DeAngelo, Daniel J.; Stone, Richard M.; Heaney, Mark L.; Nimer, Stephen D.; Paquette, Ronald L.; Klisovic, Rebecca B.; Caligiuri, Michael A.; Cooper, Michael R.; Lecerf, Jean Michel; Karol, Michael D.; Sheng, Shihong; Holford, Nick; Curtin, Peter T.; Druker, Brian; Heinrich, Michael.

In: Blood, Vol. 108, No. 12, 01.12.2006, p. 3674-3681.

Research output: Contribution to journalArticle

DeAngelo, DJ, Stone, RM, Heaney, ML, Nimer, SD, Paquette, RL, Klisovic, RB, Caligiuri, MA, Cooper, MR, Lecerf, JM, Karol, MD, Sheng, S, Holford, N, Curtin, PT, Druker, B & Heinrich, M 2006, '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', Blood, vol. 108, no. 12, pp. 3674-3681. https://doi.org/10.1182/blood-2006-02-005702
DeAngelo, Daniel J. ; Stone, Richard M. ; Heaney, Mark L. ; Nimer, Stephen D. ; Paquette, Ronald L. ; Klisovic, Rebecca B. ; Caligiuri, Michael A. ; Cooper, Michael R. ; Lecerf, Jean Michel ; Karol, Michael D. ; Sheng, Shihong ; Holford, Nick ; Curtin, Peter T. ; Druker, Brian ; Heinrich, Michael. / 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. In: Blood. 2006 ; Vol. 108, No. 12. pp. 3674-3681.
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AU - Heaney, Mark L.

AU - Nimer, Stephen D.

AU - Paquette, Ronald L.

AU - Klisovic, Rebecca B.

AU - Caligiuri, Michael A.

AU - Cooper, Michael R.

AU - Lecerf, Jean Michel

AU - Karol, Michael D.

AU - Sheng, Shihong

AU - Holford, Nick

AU - Curtin, Peter T.

AU - Druker, Brian

AU - Heinrich, Michael

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