A Phase I Dose-Escalation Study of Regorafenib (BAY 73-4506), an Inhibitor of Oncogenic, Angiogenic, and Stromal Kinases, in Patients with Advanced Solid Tumors
A Phase I Dose-Escalation Study of Regorafenib (BAY 73-4506), an Inhibitor of Oncogenic, Angiogenic, and Stromal Kinases, in Patients with Advanced Solid Tumors
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DOI：
10.1158/1078-0432.ccr-11-1900
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发表时间：
2012-05-01
影响因子：
11.5
通讯作者：
Christensen, Olaf
中科院分区：
文献类型：
--
作者：
Mross, Klaus;Frost, Annette;Christensen, Olaf
目的：瑞戈非尼是一种新型的血管生成（VEGFR 1 -3、TIE 2）、基质（PDGFR-β、FGFR）和致癌激酶（KIT、RET和RAF）的口服多激酶抑制剂。这第一次在人，I期剂量递增研究评估的安全性，药代动力学，药效学，和疗效概况regorafenib在晚期solid tumors.Patients和方法：患者年龄18岁或以上的晚期实体瘤难治性标准治疗招募。瑞戈非尼口服给药21天/停药7天，重复周期，直至因毒性或肿瘤进展而停药。使用美国国家癌症研究所不良事件通用术语标准v3.0评估不良事件（AE）。在单次给药后和第21天测量药代动力学特征。药效学和疗效评价包括使用动态对比增强MRI的肿瘤灌注评估、血浆细胞因子和使用RECIST（v1.0）的肿瘤反应。未来研究的推荐剂量确定为每日160 mg，治疗方案为21天给药/7天停药，重复28天周期。最常见的药物相关3级或4级AE为皮肤病AE（手足皮肤反应、皮疹）、高血压和腹泻。药代动力学分析显示，母体化合物和两种非活性代谢产物在稳态时的暴露量相似。肿瘤灌注和血浆细胞因子分析显示瑞格非尼具有生物学活性。47例可评价患者中有3例获得部分缓解（肾细胞癌、结直肠癌和骨肉瘤）。结论：瑞戈非尼在实体瘤患者中显示出可接受的安全性和抗肿瘤活性的初步证据。临床癌症研究; 18（9）; 2658-67。（C）2012年AACR。
Purpose: Regorafenib is a novel oral multikinase inhibitor of angiogenic (VEGFR1-3, TIE2), stromal (PDGFR-beta, FGFR), and oncogenic kinases (KIT, RET, and RAF). This first-in-man, phase I dose-escalation study assessed the safety, pharmacokinetic, pharmacodynamic, and efficacy profiles of regorafenib in patients with advanced solid tumors.Patients and Methods: Patients aged 18 years or older with advanced solid tumors refractory to standard treatment were recruited. Regorafenib was administered orally for 21 days on/seven days off in repeating cycles, until discontinuation due to toxicity or tumor progression. Adverse events (AE) were assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. Pharmacokinetic profiles were measured after a single dose and on day 21. Pharmacodynamic and efficacy evaluations included tumor perfusion assessment using dynamic contrast-enhanced MRI, plasma cytokines, and tumor response using RECIST (v1.0).Results: Fifty-three patients were enrolled into eight cohorts at dose levels from 10 to 220 mg daily. The recommended dose for future studies was determined to be 160 mg daily, with a treatment schedule of 21 days on/seven days off in repeating 28-day cycles. The most common drug-related grade 3 or 4 AEs were dermatologic AEs (hand-foot skin reaction, rash), hypertension, and diarrhea. Pharmacokinetic analysis revealed a similar exposure at steady state for the parent compound and two pharmacologically active metabolites. Tumor perfusion and plasma cytokine analysis showed biologic activity of regorafenib. Three of 47 evaluable patients achieved a partial response (renal cell carcinoma, colorectal carcinoma, and osteosarcoma).Conclusion: Regorafenib showed an acceptable safety profile and preliminary evidence of antitumor activity in patients with solid tumors. Clin Cancer Res; 18(9); 2658-67. (C)2012 AACR.