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
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
复制标题
DOI：
10.1182/blood-2006-02-005702
复制
发表时间：
2006-12-01
期刊：
影响因子：
20.3
通讯作者：
Heinrich, Michael C.
中科院分区：
文献类型：
--
作者：
DeAngelo, Daniel J.;Stone, Richard M.;Heinrich, Michael C.
坦度替尼（MLN 518/CT 53518）是一种新型喹唑啉类III型受体酪氨酸激酶抑制剂：FMS样酪氨酸激酶3（FILT 3）、血小板衍生生长因子受体（PDGFR）和KIT。由于FILT 3内部串联重复（ITD）突变与急性髓性白血病（AML）预后不良之间的相关性，我们在40例AML或高危骨髓增生异常综合征（MDS）患者中进行了一项tandutinib的I期试验。Tandutinib口服给药，剂量范围为50 mg至700 mg，每日两次。Tandutinib的主要剂量限制性毒性（DLT）为可逆性全身性肌无力、疲劳或两者兼有，剂量为525 mg和700 mg，每日两次。Tandutinib的药代动力学特征为消除缓慢，需要超过1周的给药才能达到稳态血药浓度。Western印迹显示，tandutinib抑制循环白血病原始细胞中FLT 3的磷酸化。8例患者有FLT 3-ITD突变;其中5例可用于评估tandutinib的抗白血病作用。5例患者中的2例接受525 mg和700 mg每日2次治疗，显示出抗白血病活性的证据，外周和骨髓原始细胞均减少。应在伴有FLT 3-ITD突变的AML患者中更广泛地评估MTD（525 mg，每日两次）的Tandutinib，以更好地确定其抗白血病活性。
Tandutinib (MLN518/CT53518) is a novel quinazoline-based inhibitor of the type III receptor tyrosine kinases: FMS-like tyrosine kinase 3 (FILT3), platelet-derived growth factor receptor (PDGFR), and KIT. Because of the correlation between FILT3 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.