A Phase I Study of Foretinib, a Multi-Targeted Inhibitor of c-Met and Vascular Endothelial Growth Factor Receptor 2
A Phase I Study of Foretinib, a Multi-Targeted Inhibitor of c-Met and Vascular Endothelial Growth Factor Receptor 2
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DOI：
10.1158/1078-0432.ccr-10-0574
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发表时间：
2010-07-01
影响因子：
11.5
通讯作者：
LoRusso, Patricia M.
中科院分区：
文献类型：
--
作者：
Eder, Joseph Paul;Shapiro, Geoffrey I.;LoRusso, Patricia M.
目的：福维替尼是一种针对Met、RON、Axl和血管内皮生长因子受体的口服多激酶抑制剂。我们进行了一项第一阶段的人类首次临床试验，使用递增剂量的口服福维替尼。主要目的是确定福维替尼的最大耐受量并确定其安全性。次要目标包括评价血浆药代动力学、重复给药后的长期安全性、初步抗肿瘤活性和药效学活性。实验设计：患者有组织学证实的转移或不能切除的实体肿瘤，但没有标准措施。所有患者均口服福维替尼，每14天一次，连续5天。剂量递增遵循传统的“3+3”设计。结果：40名患者在8个剂量队列中接受治疗。最大耐受量为3.6 mg/kg，最大给药量为4.5 mg/kg。剂量限制性毒性包括天冬氨酸氨基转移酶和脂肪酶的3级升高。其他非剂量限制的不良反应包括高血压、乏力、腹泻、呕吐、蛋白尿和血尿。观察到2例乳头状肾细胞癌和1例甲状腺髓样癌患者的疗效。22例患者病情稳定。福维替尼的药代动力学随剂量的增加呈线性增加。药效学评估显示，亚极量剂量的福维替尼可抑制MET的磷酸化，抑制肿瘤组织的增殖。结论：福维替尼的推荐剂量为240 mg，在14天周期的前5天给药。该剂量和时间表被确定为具有可接受的安全性和药代动力学，并将作为后续II期试验使用的剂量。临床癌症资源；16(13)；3507-16。(C)2010年AACR。
Purpose: Foretinib is an oral multikinase inhibitor targeting Met, RON, Axl, and vascular endothelial growth factor receptor. We conducted a phase I, first-time-in-human, clinical trial using escalating doses of oral foretinib. The primary objectives are to identify a maximum tolerated dose and determine the safety profile of foretinib. Secondary objectives included evaluation of plasma pharmacokinetics, long-term safety after repeated administration, preliminary antitumor activity, and pharmacodynamic activity.Experimental Design: Patients had histologically confirmed metastatic or unresectable solid tumors for which no standard measures exist. All patients received foretinib orally for 5 consecutive days every 14 days. Dose escalation followed a conventional "3+3" design.Results: Forty patients were treated in eight dose cohorts. The maximum tolerated dose was defined as 3.6 mg/kg, with a maximum administered dose of 4.5 mg/kg. Dose-limiting toxicities included grade 3 elevations in aspartate aminotransferase and lipase. Additional non-dose-limiting adverse events included hypertension, fatigue, diarrhea, vomiting, proteinuria, and hematuria. Responses were observed in two patients with papillary renal cell cancer and one patient with medullary thyroid cancer. Stable disease was identified in 22 patients. Foretinib pharmacokinetics increased linearly with dose. Pharmacodynamic evaluation indicated inhibition of MET phosphorylation and decreased proliferation in select tumor biopsies at submaximal doses.Conclusions: The recommended dose of foretinib was determined to be 240 mg, given on the first 5 days of a 14-day cycle. This dose and schedule were identified as having acceptable safety and pharmacokinetics, and will be the dose used in subsequent phase II trials. Clin Cancer Res; 16(13); 3507-16. (C) 2010 AACR.