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.

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.

• Authors: 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, Michael C Heinrich
• Journal: Blood (Blood) Vol. 108 Issue 12 Pg. 3674-81 (Dec 01 2006) ISSN: 0006-4971 [Print] United States
• PMID: 16902153 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Piperazines
• Protein Kinase Inhibitors
• Quinazolines
• tandutinib
• FLT3 protein, human
• Proto-Oncogene Proteins c-kit
• Receptors, Platelet-Derived Growth Factor
• fms-Like Tyrosine Kinase 3

Topics

• Administration, Oral
• Adult
• Aged
• Aged, 80 and over
• Bone Marrow (metabolism, pathology)
• Dose-Response Relationship, Drug
• Drug-Related Side Effects and Adverse Reactions
• Female
• Humans
• Leukemia, Myeloid, Acute (blood, complications, drug therapy, genetics, pathology)
• Male
• Middle Aged
• Mutation
• Myelodysplastic Syndromes (blood, complications, drug therapy, genetics, pathology)
• Phosphorylation (drug effects)
• Piperazines (administration & dosage, adverse effects, pharmacokinetics)
• Protein Kinase Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Protein Processing, Post-Translational (drug effects)
• Proto-Oncogene Proteins c-kit (metabolism)
• Quinazolines (administration & dosage, adverse effects, pharmacokinetics)
• Receptors, Platelet-Derived Growth Factor (antagonists & inhibitors, metabolism)
• fms-Like Tyrosine Kinase 3 (antagonists & inhibitors, genetics, metabolism)