Phase I clinical and pharmacokinetic study of the novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors
Phase I clinical and pharmacokinetic study of the novel Raf kinase and vascular endothelial growth factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors
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DOI：
10.1200/jco.2005.06.124
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发表时间：
2005-02-10
影响因子：
45.3
通讯作者：
Seeber, S
中科院分区：
文献类型：
--
作者：
Strumberg, D;Richly, H;Seeber, S
目的BAY 43-9006是一种新型的Raf激酶和血管内皮生长因子受体双重抑制剂，具有抑制肿瘤细胞增殖和血管生成的作用。本研究建立了安全性和药代动力学的BAY 43-9006在69例晚期难治性实体tumors.Patients和方法BAY 43-9006（50至800毫克）给药一次或两次，每天不同的每周时间表。在所有患者中进行药代动力学采样;还评估了初步肿瘤缓解。BAY 43-9006对佛波醇肉豆蔻酸酯醋酸酯刺激的ERK磷酸化在外周血淋巴细胞中的作用进行了研究，使用流式cytometry.Results轻度至中度腹泻是最常见的（55%）治疗相关的不良事件。最大耐受剂量为400 mg bid连续给药。剂量限制性毒性为800 mg bid时的3级腹泻和疲劳，以及600 mg bid时的3级皮肤毒性。BAY 43-9006单次和多次给药的药代动力学变化很大，毒性似乎不具有剂量依赖性。佛波醇肉豆蔻酸酯醋酸酯刺激的ERK磷酸化显著降低（P <6个月和5个月>12个月）。18例患者有进展性疾病，肿瘤反应不能在一个patient.Conclusion口服BAY 43-9006是耐受性良好，并出现提供了一些临床效益。根据本研究的结果，建议将BAY 43-9006 400 mg bid连续用于正在进行的和未来的研究。(C)2005年，美国临床肿瘤学会。
Purpose BAY 43-9006 is a novel dual-action Raf kinase and vascular endothelial growth factor receptor inhibitor that inhibits tumor cell proliferation and angiogenesis. This study established the safety and pharmacokinetics of BAY 43-9006 in 69 patients with advanced refractory solid tumors.Patients and Methods BAY 43-9006 (50 to 800 mg) was administered once or twice daily on a varying weekly schedule. Pharmacokinetic sampling was performed in all patients; preliminary tumor response was also assessed. The effect of BAY 43-9006 on phorbol myristate acetate-stimulated ERK phosphorylation in peripheral blood lymphocytes was studied using flow cytometry.Results Mild to moderate diarrhea was the most common (55%) treatment-related adverse event. The maximum-tolerated dose was 400 mg bid continuous. Dose-limiting toxicities were grade 3 diarrhea and fatigue at 800 mg bid, and grade 3 skin toxicity at 600 mg bid. BAY 43-9006 pharmacokinetics were highly variable for single and multiple dosing, and toxicity did not appear to be dose dependent. Significant decreases of phorbol myristate acetate-stimulated ERK phosphorylation (P 6 months and five for >12 months. Eighteen patients had progressive disease, and tumor response could not be evaluated in one patient.Conclusion Oral BAY 43-9006 was well tolerated and appeared to provide some clinical benefits. Based on the results of this study, BAY 43-9006 at 400 mg bid continuous is recommended for ongoing and future studies. (C) 2005 by American Society of Clinical Oncology.