Phase I Trial of Bevacizumab Plus Escalated Doses of Sunitinib in Patients With Metastatic Renal Cell Carcinoma
Phase I Trial of Bevacizumab Plus Escalated Doses of Sunitinib in Patients With Metastatic Renal Cell Carcinoma
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DOI：
10.1200/jco.2008.19.0108
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发表时间：
2009-03-20
影响因子：
45.3
通讯作者：
Motzer, Robert J.
中科院分区：
文献类型：
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作者：
Feldman, Darren R.;Baum, Michael S.;Motzer, Robert J.
目的贝伐单抗和舒尼替尼均可靶向血管内皮生长因子通路，对晚期肾细胞癌（RCC）具有抗肿瘤活性。在这项I期研究中，研究了舒尼替尼联合贝伐单抗在晚期肾癌患者中的最大耐受剂量（MTD）和安全性。患者和方法3组3 - 6例患者接受每日递增剂量口服舒尼替尼（即，25mg, 37.5 mg, 50mg）治疗4周，随后休息2周，并每2周静脉注射一次固定剂量的贝伐单抗（10mg /kg）。在第一个周期中评估剂量限制性毒性（dlt）以确定MTD，并对扩大的队列进行治疗以获得额外的安全性信息。在26名研究参与者中，25人接受了三种剂量水平之一的治疗。4级出血，确定为DLT，在队列2和3中各发生1例患者。MTD被确定为舒尼替尼50mg /贝伐单抗10mg /kg，但在该剂量水平下的慢性治疗经常导致3至4级高血压和血液和血管毒性。总体而言，48%的患者因不良事件而停止治疗。完全缓解1例，部分缓解12例，客观缓解率为52%。在这项转移性肾癌患者的I期试验中，舒尼替尼和贝伐单抗联合使用在最高剂量水平下引起高度高血压和血管和血液毒性。我们不打算在这些剂量下对RCC患者进行该方案的进一步研究。
PurposeBoth bevacizumab and sunitinib target the vascular endothelial growth factor pathway and demonstrate activity against advanced renal cell carcinoma (RCC). In this phase I study, the maximum-tolerated dose (MTD) and safety of sunitinib in combination with bevacizumab were examined in patients with advanced RCC.Patients and MethodsThree cohorts of three to six patients were treated with escalated doses of daily oral sunitinib (ie, 25 mg, 37.5 mg, 50 mg) for 4 weeks followed by a 2-week break and with fixed doses of bevacizumab (10 mg/kg) intravenously once every 2 weeks. Dose-limiting toxicities (DLTs) were assessed during the first cycle to determine the MTD, and an expanded cohort was treated to obtain additional safety information.ResultsOf 26 study participants, 25 received treatment at one of three dose levels. Grade 4 hemorrhage, identified as a DLT, occurred in one patient in each of cohorts 2 and 3. The MTD was determined to be sunitinib 50 mg/bevacizumab 10 mg/kg, but chronic therapy at this dose level frequently resulted in grades 3 to 4 hypertension and hematologic and vascular toxicities. Overall, 48% of patients discontinued treatment because of adverse events. One complete and 12 partial responses were observed, which provided an objective response rate of 52%.ConclusionIn this phase I trial of patients with metastatic RCC, the combination of sunitinib and bevacizumab caused a high degree of hypertension and vascular and hematologic toxicities at the highest dose level. We do not plan to pursue additional study of this regimen at these doses in patients with RCC.