Phase I Study of Dovitinib (TKI258), an Oral FGFR, VEGFR, and PDGFR Inhibitor, in Advanced or Metastatic Renal Cell Carcinoma
Phase I Study of Dovitinib (TKI258), an Oral FGFR, VEGFR, and PDGFR Inhibitor, in Advanced or Metastatic Renal Cell Carcinoma
复制标题
DOI：
10.1158/1078-0432.ccr-12-2885
复制
发表时间：
2013-03-01
影响因子：
11.5
通讯作者：
Escudier, Bernard
中科院分区：
文献类型：
--
作者：
Angevin, Eric;Lopez-Martin, Jose A.;Escudier, Bernard
目的：通过成纤维细胞生长因子（FGF）途径的信号传导可能解释了肿瘤对靶向VEGF途径的抗血管生成治疗的耐药性。dovitinib （TKI258）是一种有效的口服FGF受体、VEGF受体（VEGFR）和血小板衍生生长因子受体酪氨酸激酶抑制剂，在一项剂量递增试验中被研究。实验设计：以透明细胞组织学为主的晚期或转移性肾细胞癌（RCC）患者口服多维替尼500或600mg /天（5天开/2天停）治疗。结果：纳入了20例重度预处理患者（中位数为3个先前方案），其中分别有16例、11例和12例患者先前接受过至少1种VEGFR抑制剂、mTOR抑制剂和免疫治疗。15名和5名患者分别接受500毫克和600毫克的治疗。3例患者出现剂量限制性毒性：2级心动过缓（500 mg）， 4级高血压危象（600 mg）， 3级虚弱伴2级恶心和呕吐（600 mg）。与dovitinib相关的最常见不良事件是恶心（75%）、腹泻（70%）、呕吐（70%）和虚弱（50%），其中大多数是轻度（1级或2级），3级事件占5%或更少（除了虚弱，15%），只有1个4级事件（高血压危像）。2例患者达到部分缓解（500 mg）， 12例患者病情稳定，其中2例患者在500 mg队列中病情持续稳定（bb10 1年）。结论：在重度预处理的RCC患者中，Dovitinib是耐受的，并且在最大耐受剂量为500mg、5天开/2天停的情况下显示出抗肿瘤活性。临床癌症研究；19 (5);1257 - 68。(c) 2012年aacr。
Purpose: Signaling through the fibroblast growth factor (FGF) pathway may account for tumor resistance to antiangiogenic therapies targeting the VEGF pathway. Here, dovitinib (TKI258), a potent oral inhibitor of FGF receptor, VEGF receptor (VEGFR), and platelet-derived growth factor receptor tyrosine kinases, is studied in a dose escalation trial.Experimental Design: Patients with advanced or metastatic renal cell carcinoma(RCC) with predominant clear cell histology were treated with oral dovitinib 500 or 600 mg/day (5-days-on/2-days-off schedule).Results: Twenty heavily pretreated patients (median 3 prior regimens) were enrolled, with 16, 11, and 12 patients having previously received at least 1: VEGFR inhibitor, mTOR inhibitor, and immunotherapy, respectively. Fifteen and 5 patients were treated in 500-and 600-mg cohorts, respectively. Three patients experienced dose-limiting toxicities: grade 2 bradycardia (500 mg), grade 4 hypertensive crisis (600 mg), and grade 3 asthenia with grade 2 nausea and vomiting (600 mg). The most common adverse events related to dovitinib were nausea (75%), diarrhea (70%), vomiting (70%), and asthenia (50%), the majority of which were mild (grade 1 or 2), with grade 3 events 5% or less (except asthenia, 15%) and only one grade 4 event (hypertensive crisis). Two patients achieved a partial response (500 mg), and 12 patients had stable disease, including 2 patients with long lasting disease stabilizations (>1 year) in the 500-mg cohort.Conclusions: Dovitinib was tolerable and showed antitumor activity at a maximum tolerated dose of 500mg on a 5-days-on/2-days-off schedule in heavily pretreated RCC patients. Clin Cancer Res; 19(5); 1257-68. (C) 2012 AACR.