Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California 94143-1711, USA.
Cancer. 2011 Sep 15;117(18):4194-200. doi: 10.1002/cncr.25931. Epub 2011 Mar 8.
The current study was conducted to assess the maximum tolerated dose (MTD), safety, pharmacokinetics, and preliminary antitumor effect of everolimus, a mammalian target of rapamycin inhibitor, in combination with sorafenib, a tyrosine kinase inhibitor, in patients with metastatic clear cell renal cell carcinoma.
Sequential cohorts of patients received escalating doses of everolimus and sorafenib in 28-day cycles in the absence of a dose-limiting toxicity (DLT) or disease progression were examined.
Twenty patients with a median age of 65 years received therapy in 3 cohorts. Dose level 1 was comprised of everolimus at a dose of 2.5 mg daily and sorafenib at a dose of 400 mg twice daily (6 patients), dose level 2 was comprised of everolimus at a dose of 5 mg daily and sorafenib at a dose of 400 mg twice daily (8 patients), and dose level 3 was comprised of everolimus at a dose of 10 mg daily and sorafenib at a dose of 200 mg twice daily (6 patients). DLTs included grade 4 (according to National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]) hyperuricemia with grade 2 gout and grade 3 lipase associated with grade 2 pancreatitis at dose level 2, and grade 3 rash in 2 patients at dose level 3. Dose level 2 (everolimus at a dose of 5 mg daily and sorafenib at a dose of 400 mg twice daily) was established as the maximum tolerated dose. Treatment-related adverse events occurring in >20% of patients included diarrhea, hand-foot syndrome, hypertension, hypophosphatemia, hypothyroidism, and rash. Five of 20 patients achieved Response Evaluation Criteria In Solid Tumors (RECIST)-defined partial responses, all of which occurred in patients without a history of prior systemic therapy. Seven of 8 patients treated at dose level 2 experienced a partial response or stable disease. Pharmacokinetic analysis revealed no interaction between everolimus and sorafenib.
The combination of everolimus and sorafenib was associated with acceptable toxicity and evidence of antitumor activity in previously untreated patients with metastatic renal cell carcinoma.
本研究旨在评估依维莫司（一种哺乳动物雷帕霉素靶蛋白抑制剂）与索拉非尼（一种酪氨酸激酶抑制剂）联合应用于转移性透明细胞肾细胞癌患者的最大耐受剂量（MTD）、安全性、药代动力学和初步抗肿瘤疗效。
在没有剂量限制毒性（DLT）或疾病进展的情况下，对接受递增剂量依维莫司和索拉非尼治疗的 28 天周期的患者进行连续队列研究。
20 名中位年龄为 65 岁的患者在 3 个队列中接受了治疗。剂量水平 1 包括依维莫司每日 2.5mg 和索拉非尼每日 2 次 400mg（6 例），剂量水平 2 包括依维莫司每日 5mg 和索拉非尼每日 2 次 400mg（8 例），剂量水平 3 包括依维莫司每日 10mg 和索拉非尼每日 2 次 200mg（6 例）。剂量限制毒性包括 2 级（根据国家癌症研究所不良事件通用术语标准[版本 3.0]）高尿酸血症伴 2 级痛风和 3 级脂肪酶相关的 2 级胰腺炎（剂量水平 2），以及 3 级皮疹（剂量水平 3）。确定剂量水平 2（依维莫司每日 5mg 和索拉非尼每日 2 次 400mg）为最大耐受剂量。超过 20%的患者发生与治疗相关的不良反应包括腹泻、手足综合征、高血压、低磷血症、甲状腺功能减退和皮疹。20 例患者中有 5 例（均无既往系统治疗史）达到实体瘤反应评价标准（RECIST）定义的部分缓解。8 例接受剂量水平 2 治疗的患者中，有 7 例出现部分缓解或疾病稳定。药代动力学分析显示依维莫司与索拉非尼之间无相互作用。
依维莫司联合索拉非尼治疗既往未经治疗的转移性肾细胞癌患者，毒性可接受，且有抗肿瘤活性证据。
