Detection of Phosphorylated and Total FLT3 and STAT5 in Whole Blood;
Modulation by Quizartinib (AC220) from Phase I and II Trials in AML
The pharmacodynamic effects of quizartinib treatment in AML patients was assessed using whole blood samples from patients enrolled in a previously performed Phase 1 study, and from the 62 patient subset in the Phase 2 study described above. Proprietary and customized immunoassays were developed, optimized and validated at Ambit to detect both total (t) and phosphorylated (p) levels of FLT3, as well as the downstream signaling protein STAT5. Blood samples were examined prior to treatment with quizartinib on Day 1 of treatment and again after either 8 or 15 days of treatment, depending upon study.
Results from this assay demonstrated that following administration of quizartinib there was a profound, immediate and sustained pharmacodynamic effect in inhibiting both FLT3 and the subsequent downstream phosphorylation of the biologically important signaling protein, STAT5. A mean pFLT3 inhibition of 80 percent was observed within 24-hours of the first dose, and there was a strong correlation with inhibiting phosphorylation of STAT5 (p < 0.007). These findings support the linkage between FLT3 activation and downstream STAT5 activation, and demonstrate the ability of quizartinib to inhibit both of these important signaling molecules that are involved in the pathology of FLT3-ITD positive AML. Results at later time points showed that approximately one half (47 per
|SOURCE Ambit Biosciences|
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