Safety and pharmacokinetics of the dual action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43-9006, in patients with advanced, refractory solid tumors
Safety and pharmacokinetics of the dual action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43-9006, in patients with advanced, refractory solid tumors
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DOI：
10.1158/1078-0432.ccr-04-2658
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发表时间：
2005-08-01
影响因子：
11.5
通讯作者：
Lenz, HJ
中科院分区：
文献类型：
--
作者：
Clark, JW;Eder, JP;Lenz, HJ
目的：BAY 43-9006是一种新型多激酶抑制剂，通过结合两种抗肿瘤活性来防止肿瘤生长：抑制肿瘤细胞增殖和肿瘤血管生成。这项1期、开放标签、非随机、非对照、单臂、剂量递增研究是为了确定BAY 43-9006在19名晚期难治性实体瘤患者中的最大耐受剂量（MTD）、安全性特征、药代动力学变量、对生物标志物的影响和肿瘤应答。BAY 43-9006以1周给药/1周停药的重复周期口服给药。该研究包括5个剂量水平，范围为100 mg每日两次（bid）至800 mg bid。每个患者的治疗持续到不可接受的毒性，肿瘤进展，或death.Results：皮疹和高血压的剂量限制性毒性在800毫克bid剂量需要研究药物停药，因此，在这项研究中的最大耐受剂量BAY 43-9006被确定为600毫克bid。BAY 43-9006通常耐受性良好，具有轻度至中度毒性。药代动力学分析显示吸收早期，其次是次要峰延迟和终末消除缓慢。稳定的疾病，实现了五名患者：一名患者表现出降低肿瘤活性（正电子发射断层扫描）和减少有丝分裂原活化蛋白激酶信号传导（低磷酸化ERK）;一名患者继续治疗，直到研究终点。结论：结果证实了良好的安全性，BAY 43-9006和支持开发这种化合物用于治疗实体瘤。
Purpose: BAY 43-9006, a novel multikinase inhibitor, prevents tumor growth by combining two antitumor activities: inhibition of both tumor cell proliferation and tumor angiogenesis. This phase 1, open-label, nonrandomized, noncontrolled, single-arm, dose escalation study was done to determine the maximum tolerated dose (MTD), safety profile, pharmacokinetic variables, effect on biomarkers, and tumor response with BAY 43-9006 in 19 patients with advanced, refractory solid tumors.Experimental Design: BAY 43-9006 was given orally in repeated cycles of 1-week on/1-week off. The study comprised five dose levels, ranging from 100 mg twice daily (bid) to 800 mg bid. Treatment of each patient continued until unacceptable toxicity, tumor progression, or death.Results: Rash and hypertension were the dose-limiting toxicities at the 800 mg bid dose requiring study drug discontinuation; therefore, the MTD of BAY 43-9006 in this study was determined to be 600 mg bid. BAY 43-9006 was generally well tolerated, with mild to moderate toxicities. Pharmacokinetic analysis showed early absorption followed by delayed secondary peaks and slow terminal elimination. Stable disease was achieved in five patients: one patient showed reduced tumor activity (positron emission tomography scan) and reduced mitogen-activated protein kinase signaling (lower phospho-ERK); one patient remained on treatment until study end point.Conclusions: The results confirm the favorable safety profile of BAY 43-9006 and support the development of this compound for the treatment of solid tumors.