An innovative phase I clinical study demonstrates inhibition of FLT3 phosphorylation by SU11248 in acute myeloid leukemia patients
| Autor: | Anne-Marie, O'Farrell, James M, Foran, Walter, Fiedler, Hubert, Serve, Ron L, Paquette, Maureen A, Cooper, Helene A, Yuen, Sharianne G, Louie, Heidi, Kim, Susan, Nicholas, Michael C, Heinrich, Wolfgang E, Berdel, Carlo, Bello, Mark, Jacobs, Paul, Scigalla, William C, Manning, Stephen, Kelsey, Julie M, Cherrington |
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| Rok vydání: | 2003 |
| Předmět: |
Adult
Male Indoles Genotype Metabolic Clearance Rate Administration Oral Receptor Protein-Tyrosine Kinases Middle Aged Leukemia Myeloid Acute fms-Like Tyrosine Kinase 3 Proto-Oncogene Proteins Sunitinib Humans Female Pyrroles Enzyme Inhibitors Mitogen-Activated Protein Kinases Phosphorylation Blast Crisis Aged |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 9(15) |
| ISSN: | 1078-0432 |
| Popis: | Obtaining direct and rapid proof of molecular activity in early clinical trials is critical for optimal clinical development of novel targeted therapies. SU11248 is an oral multitargeted kinase inhibitor with selectivity for fms-related tyrosine kinase 3/Flk2 (FLT3), platelet-derived growth factor receptor alpha/beta, vascular endothelial growth factor receptor 1/2, and KIT receptor tyrosine kinases. FLT3 is a promising candidate for targeted therapy in acute myeloid leukemia (AML), because activating mutations occur in up to 30% of patients. We conducted an innovative single-dose clinical study with a primary objective to demonstrate inhibition of FLT3 phosphorylation by SU11248 in AML.Twenty-nine AML patients each received a single dose of SU11248, escalated from 50 to 350 mg, in increments of 50 mg and cohorts of three to six patients. FLT3 phosphorylation and plasma pharmacokinetics were evaluated at seven time points over 48 h after SU11248 administration, and FLT3 genotype was determined. Study drug-related adverse events occurred in 31% of patients, mainly grade 1 or 2 diarrhea and nausea, at higher dose levels.Inhibition of FLT3 phosphorylation was apparent in 50% of FLT3-wild-type (WT) patients and in 100% of FLT3-mutant patients. FLT3 internal tandem duplication (ITD) mutants showed increased sensitivity relative to FLT3-WT, consistent with preclinical predictions. The primary end point, strong inhibition of FLT3 phosphorylation in50% patients, was reached in 200 mg and higher dose cohorts. Downstream signaling pathways were also inhibited; signal transducer and activator of transcription 5 (STAT5) was reduced primarily in internal tandem duplication patients and at late time points in FLT3-WT patients, whereas extracellular signal-regulated kinase (ERK) activity was reduced in the majority of patients, independent of FLT3 inhibition.This novel translational study bridges preclinical models to the patient setting and provides the first evidence of anti-FLT3 activity in patients. Proof of target inhibition accomplishes a crucial milestone in the development of novel oncology therapeutics. |
| Databáze: | OpenAIRE |
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