A Phase I Pharmacokinetic and Pharmacodynamic Study of Dalotuzumab (MK-0646), an Anti-Insulin-like Growth Factor-1 Receptor Monoclonal Antibody, in Patients with Advanced Solid Tumors
A Phase I Pharmacokinetic and Pharmacodynamic Study of Dalotuzumab (MK-0646), an Anti-Insulin-like Growth Factor-1 Receptor Monoclonal Antibody, in Patients with Advanced Solid Tumors
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DOI：
10.1158/1078-0432.ccr-10-3336
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发表时间：
2011-10-01
影响因子：
11.5
通讯作者：
Baselga, Jose
中科院分区：
文献类型：
--
作者：
Atzori, Francesco;Tabernero, Josep;Baselga, Jose
目的：胰岛素样生长因子-1受体(IGF-1R)介导肿瘤的细胞过程，已被认为是一种治疗靶点。Dalotuzumab(MK-0646)是一种人源化的IgG1单抗，可与IGF-1R结合，防止受体激活。本研究旨在评价Dalotuzumab的安全性和耐受性，测定其药代动力学(PK)和药效学(PD)曲线，并确定推荐的II期剂量。实验设计：将表达IGF-1R蛋白的肿瘤患者分配到3名或更多患者的剂量递增队列中，每周静脉注射Dalotuzumab，每2或3周一次。采集血浆进行PK分析。收集配对的基线和治疗中的皮肤和肿瘤活检样本进行PD分析。结果：80例化疗无效的实体瘤患者入选。注意到了一种剂量限制性毒性，但没有确定最大耐受量。15例(19%)患者对二甲双胍有反应，出现1~3级高血糖。在剂量水平或大于5 mg/kg时，dalotuzumab的平均终末半衰期为95小时或更长，平均C-min大于25微克/毫升，清除量恒定，血清暴露大致成剂量比例。观察到肿瘤IGF-1R、下游受体信号转导和Ki67表达减少。F-18-氟代脱氧葡萄糖正电子发射断层扫描有3例患者出现代谢反应。1例尤文氏肉瘤患者表现出混合的放射反应。第二阶段剂量分别为每周10 mg/kg、每隔一周20 mg/kg和每3周30 mg/kg。结论：Dalotuzumab耐受性良好，呈现剂量比例PK，抑制IGF-1R通路信号转导和细胞增殖，具有临床活性。较低的清除率和较长的终端半衰期支持更长的给药间隔。临床癌症研究中心；17(19)；6304-12。(C)2011年AACR。
Purpose: Insulin-like growth factor-1 receptor (IGF-1R) mediates cellular processes in cancer and has been proposed as a therapeutic target. Dalotuzumab (MK-0646) is a humanized IgG1 monoclonal antibody that binds to IGF-1R preventing receptor activation. This study was designed to evaluate the safety and tolerability of dalotuzumab, determine the pharmacokinetic (PK) and pharmacodynamic (PD) profiles, and identify a recommended phase II dose.Experimental Design: Patients with tumors expressing IGF-1R protein were allocated to dose-escalating cohorts of three or more patients each and received intravenous dalotuzumab weekly, every 2 or 3 weeks. Plasma was collected for PK analysis. Paired baseline and on-treatment skin and tumor biopsy samples were collected for PD analyses.Results: Eighty patients with chemotherapy-refractory solid tumors were enrolled. One dose-limiting toxicity was noted, but a maximum-tolerated dose was not identified. Grade 1 to 3 hyperglycemia, responsive to metformin, occurred in 15 (19%) patients. At dose levels or more than 5 mg/kg, dalotuzumab mean terminal half-life was 95 hours or more, mean C-min was more than 25 mu g/mL, clearance was constant, and serum exposures were approximately dose proportional. Decreases in tumor IGF-1R, downstream receptor signaling, and Ki67 expression were observed. F-18-Fluorodeoxy-glucose positron emission tomography metabolic responses occurred in three patients. One patient with Ewing's sarcoma showed a mixed radiologic response. The recommended phase II doses were 10, 20, and 30 mg/kg for the weekly, every other week, and every third week schedules, respectively.Conclusions: Dalotuzumab was generally well-tolerated, exhibited dose-proportional PK, inhibited IGF-1R pathway signaling and cell proliferation in treated tumors, and showed clinical activity. The low clearance rate and long terminal half-life support more extended dosing intervals. Clin Cancer Res; 17(19); 6304-12. (C) 2011 AACR.