Clark Jeffrey W, Eder Joseph P, Ryan David, Lathia Chetan, Lenz Heinz-Josef
Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114, USA.
Clin Cancer Res. 2005 Aug 1;11(15):5472-80. doi: 10.1158/1078-0432.CCR-04-2658.
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 I, 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.
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.
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.
The results confirm the favorable safety profile of BAY 43-9006 and support the development of this compound for the treatment of solid tumors.
新型多激酶抑制剂BAY 43 - 9006通过结合两种抗肿瘤活性来抑制肿瘤生长，即抑制肿瘤细胞增殖和肿瘤血管生成。本I期开放标签、非随机、非对照、单臂剂量递增研究旨在确定19例晚期难治性实体瘤患者使用BAY 43 - 9006的最大耐受剂量（MTD）、安全性、药代动力学变量、对生物标志物的影响以及肿瘤反应。
BAY 43 - 9006以1周用药/1周停药的重复周期口服给药。该研究包括五个剂量水平，范围从每日两次（bid）100毫克至每日两次800毫克。每位患者的治疗持续至出现不可接受的毒性、肿瘤进展或死亡。
每日两次800毫克剂量时，皮疹和高血压是导致研究药物停用的剂量限制性毒性；因此，本研究中BAY 43 - 9006的MTD确定为每日两次600毫克。BAY 43 - 9006总体耐受性良好，毒性为轻度至中度。药代动力学分析显示早期吸收，随后出现延迟的二次峰和缓慢的终末消除。5例患者病情稳定：1例患者肿瘤活性降低（正电子发射断层扫描）且丝裂原活化蛋白激酶信号传导降低（磷酸化细胞外信号调节激酶水平降低）；1例患者持续治疗至研究终点。
结果证实了BAY 43 - 9006良好的安全性，并支持该化合物用于治疗实体瘤的研发。
