Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Clin Cancer Res. 2010 Jan 1;16(1):358-66. doi: 10.1158/1078-0432.CCR-09-2103. Epub 2009 Dec 22.
To determine the maximum tolerated dose or maximal administered dose and pharmacokinetic and safety profiles of s.c. administered vascular endothelial growth factor Trap (aflibercept), a novel antiangiogenic agent.
In this open-label, dose-escalation study, patients with advanced solid tumors were treated with subcutaneous doses of aflibercept at seven dose levels. Patients received a single dose of aflibercept and then underwent safety and pharmacokinetic assessments over the next 4 weeks. Patients then received weekly or biweekly treatment over the subsequent 6 weeks. Patients tolerating and benefiting could continue on aflibercept at the same dose and schedule until progression of disease.
Thirty-eight patients received at least one dose of aflibercept. Maximum tolerated dose was not reached. Due to solubility/dosing limits with the subcutaneous formulation, 1,600 microg/kg/week was the maximal administered dose. The most common toxicities were proteinuria (37%), fatigue (32%), injection site reactions (18%), nausea (17%), myalgia and anorexia (16% each), hypertension (13%), and voice hoarseness (11%). Drug-related grade 3 to 4 toxicity was uncommon (7%) and reversible: dehydration, cerebral ischemia, proteinuria, hypertension, leukopenia, and pulmonary embolism. We identified dose-proportional increases in plasma concentrations of aflibercept bound to vascular endothelial growth factor with a t(1/2) of 18 days. No antiaflibercept antibodies were detected. Stable disease was maintained for at least 10 weeks in 18 patients (47%), and 2 patients maintained on study for >1 year.
Subcutaneous aflibercept was well tolerated and had manageable side effects. Its favorable pharmacokinetic profile and potential antitumor activity warrants further evaluation.
确定皮下给予血管内皮生长因子陷阱（阿柏西普）的最大耐受剂量或最大给药剂量、药代动力学和安全性特征，这是一种新型抗血管生成药物。
在这项开放性、剂量递增研究中，晚期实体瘤患者接受了七个剂量水平的皮下阿柏西普治疗。患者单次接受阿柏西普治疗，然后在接下来的 4 周内进行安全性和药代动力学评估。随后，在接下来的 6 周内每周或每两周接受一次治疗。耐受且受益的患者可以在疾病进展之前继续以相同的剂量和方案接受阿柏西普治疗。
38 名患者至少接受了一次阿柏西普治疗。未达到最大耐受剂量。由于皮下制剂的溶解度/剂量限制，1600μg/kg/周是最大给药剂量。最常见的毒性是蛋白尿（37%）、疲劳（32%）、注射部位反应（18%）、恶心（17%）、肌痛和厌食（各 16%）、高血压（13%）和声音嘶哑（11%）。药物相关的 3 至 4 级毒性并不常见（7%）且是可逆的：脱水、脑缺血、蛋白尿、高血压、白细胞减少和肺栓塞。我们发现阿柏西普与血管内皮生长因子结合的血浆浓度与剂量呈比例增加，半衰期为 18 天。未检测到抗阿柏西普抗体。18 名患者（47%）至少 10 周维持稳定疾病，2 名患者维持研究>1 年。
皮下给予阿柏西普具有良好的耐受性，副作用可管理。其良好的药代动力学特征和潜在的抗肿瘤活性值得进一步评估。
