Feasibility, phase I, and phase II studies of tandutinib, an oral platelet-derived growth factor receptor-β tyrosine kinase inhibitor, in patients with recurrent glioblastoma
Feasibility, phase I, and phase II studies of tandutinib, an oral platelet-derived growth factor receptor-β tyrosine kinase inhibitor, in patients with recurrent glioblastoma
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DOI：
10.1093/neuonc/now185
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发表时间：
2017-04-01
期刊：
影响因子：
15.9
通讯作者：
Supko, Jeffrey G.
中科院分区：
文献类型：
--
作者：
Batchelor, Tracy T.;Gerstner, Elizabeth R.;Supko, Jeffrey G.
背景血小板源性生长因子（PDGF）信号传导在胶质瘤形成中是重要的，并且PDGF受体β在胶质母细胞瘤的大多数内皮细胞上表达。我们报告了tandutinib（MLN 518）在复发性胶质母细胞瘤患者中的可行性、I期和II期研究结果，MLN 518是一种口服生物可利用的III型受体酪氨酸激酶抑制剂，包括PDGF受体β、Fms样酪氨酸激酶3和c-Kit。在一项初步可行性研究中，6名患者在接受tandutinib 500 mg每日两次治疗7天后接受了复发性胶质母细胞瘤切除术。在6例患者中，4例患者的脑肿瘤与血浆中tandutinib浓度的平均比值为13.1 +/- 8.9。在I期研究中，19例患者接受了500、600和700 mg每日两次剂量水平的治疗。发现最大耐受剂量为600 mg每日两次，在II期研究中有30例患者接受了该剂量治疗。中期分析后，试验关闭，因为没有达到预先设定的患者存活和6个月无进展生存期的目标。生物标志物研究表明，tandutinib治疗可能导致血管破裂，而不是正常化，这与快速进展有关。口服给药后，Tandutinib容易分布到大脑中，肿瘤内的浓度超过了血浆中的相应浓度。由于缺乏疗效，II期研究在中期分析时关闭，尽管该研究未富集PDGF通路改变的胶质母细胞瘤。
Background. Platelet-derived growth factor (PDGF) signaling is important in gliomagenesis and PDGF receptor-beta is expressed on most endothelial cells in glioblastoma specimens.Methods. We report the results of feasibility, phase I, and phase II studies of tandutinib (MLN518), an orally bioavailable inhibitor of type III receptor tyrosine kinases including PDGF receptor-beta, Fms-like tyrosine kinase 3, and c-Kit in patients with recurrent glioblastoma.Results. In an initial feasibility study, 6 patients underwent resection for recurrent glioblastoma after receiving tandutinib 500mg twice daily for 7 days. The mean ratio of tandutinib concentration in brain tumor-to-plasma was 13.1 +/- 8.9 in 4 of the 6 patients. In the phase I study, 19 patients were treated at 500, 600, and 700mg twice daily dose levels. The maximum tolerated dose was found to be 600mg twice daily, and 30 patients were treated with this dose in the phase II study. The trial was closed after interim analysis, as the prespecified goal of patients alive and progression-free survival at 6 months was not achieved. Biomarker studies suggested that tandutinib treatment could lead to vascular disruption rather than normalization, which was associated with rapid progression.Conclusions. Tandutinib readily distributed into the brain following oral administration and achieved concentrations within the tumor that exceed the corresponding concentration in plasma. The phase II study was closed at interim analysis due to lack of efficacy, although this study was not enriched for glioblastomas with alterations of the PDGF pathway.