A Phase 2 Trial of Bevacizumab and High-dose Interferon Alpha 2B in Metastatic Melanoma
A Phase 2 Trial of Bevacizumab and High-dose Interferon Alpha 2B in Metastatic Melanoma
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DOI：
10.1097/cji.0b013e31821dcefd
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发表时间：
2011-07-01
影响因子：
3.9
通讯作者：
Carson, William E., III
中科院分区：
文献类型：
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作者：
Grignol, Valerie P.;Olencki, Thomas;Carson, William E., III
贝伐珠单抗是一种人源化重组单克隆抗体，可中和血管内皮生长因子（一种在黑色素瘤中具有促血管生成作用的药物）。干扰素α（IFN-α）通过其下调碱性成纤维细胞生长因子水平的能力具有抗血管生成特性。我们假设，这些药物的共同管理将导致肿瘤消退。转移性黑色素瘤患者在2周周期的第1天接受贝伐珠单抗15 mg/kg静脉给药。在第1周期，IFN-α每周皮下注射3次，剂量为5 MU/m2，在第2周期增加至10 MU/m2。患者每6个周期进行一次再分期。病情稳定或缓解的患者继续接受治疗。测定基线血清血管内皮生长因子和成纤维细胞生长因子。25例患者入组。平均年龄为58.4岁。11名患者由于毒性需要减少IFN-α剂量。与IFN-α相关的常见3级毒性包括疲劳和肌痛。贝伐单抗给药与6例患者的2-3级蛋白尿相关。4级不良事件为肺栓塞（1）、心肌梗死（1）和卒中（1）。6例患者部分缓解，5例患者病情稳定，持续时间超过24周（范围：30至122周）。中位无进展生存期和总生存期分别为4.8和17个月。与病情稳定或进展的患者相比，部分缓解患者的成纤维细胞生长因子水平显著降低（P = 0.040）。贝伐单抗与IFN联合给药导致24%的IV期黑色素瘤患者出现临床应答，另有20%的患者病情稳定。该方案在晚期黑色素瘤中具有活性。
Bevacizumab is a humanized recombinant monoclonal antibody that neutralizes vascular endothelial growth factor, an agent with proangiogenic effects in melanoma. Interferon alpha (IFN-alpha) has antiangiogenic properties through its ability to down-regulate basic-fibroblast growth factor levels. We hypothesized that the coadministration of these agents would lead to tumor regression. Patients with metastatic melanoma received bevacizumab 15 mg/kg intravenously on day 1 of the 2-week cycle. IFN-alpha was administered thrice weekly at 5MU/m(2) subcutaneously during cycle 1 and was increased to 10MU/m(2) during cycle 2. Patients were restaged every 6 cycles. Patients with stable disease or a response continued with therapy. Baseline serum vascular endothelial growth factor and fibroblast growth factor were measured. Twenty-five patients were accrued. Mean age was 58.4 years. Eleven patients required IFN-alpha dose reductions due to toxicity. Common grade 3 toxicities associated with IFN-alpha included fatigue and myalgia. Bevacizumab administration was associated with grade 2-3 proteinuria in 6 patients. Grade 4 adverse events were pulmonary embolus (1), myocardial infarction (1), and stroke (1). Six patients had a partial response, and 5 patients exhibited stable disease that lasted more than 24 weeks (range: 30 to 122 wk). Median progression-free survival and overall survival were 4.8 and 17 months, respectively. Significantly lower fibroblast growth factor levels were observed in patients with a partial response compared to those with stable or progressive disease (P = 0.040). Administration of bevacizumab with IFN led to a clinical response in 24% of patients with stage IV melanoma and stabilization of disease in another 20% of patients. This regimen has activity in advanced melanoma.