Phase II study evaluating the efficacy, safety, and pharmacodynamic correlative study of dual antiangiogenic inhibition using bevacizumab in combination with sorafenib in patients with advanced malignant melanoma
Phase II study evaluating the efficacy, safety, and pharmacodynamic correlative study of dual antiangiogenic inhibition using bevacizumab in combination with sorafenib in patients with advanced malignant melanoma
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DOI：
10.1007/s00280-014-2479-8
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发表时间：
2014-07-01
影响因子：
3
通讯作者：
Sarantopoulos, John
中科院分区：
文献类型：
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作者：
Mahalingam, Devalingam;Malik, Laeeq;Sarantopoulos, John
黑色素瘤是一种血管性肿瘤，其BRAF突变驱动肿瘤增殖的发生率很高。完全抑制血管内皮生长因子（VEGF）信号具有增强抗肿瘤疗效的潜力。患有晚期黑色素瘤且器官功能正常的患者符合条件。索拉非尼口服，BiD 200mg，每周5天；贝伐单抗每14天静脉给药5mg /kg。主要目的是确定临床生物活性。次要目标是安全性、耐受性和进展时间（TTP）。药效学分析包括基线、C1D15和C2D1时血清VEGF和可溶性VEGF受体-1和VEGF受体-2。该研究在Simon两阶段设计的第一阶段结束，在计划的21名受试者中有14名被招募。在接受治疗的14例患者中，没有观察到客观的肿瘤反应。57%的患者在16周内观察到疾病稳定（SD），其中包括3例SD持续1年。中位TTP为32周。最常见的药物相关不良事件（ae）是手足综合征（57.1%）、疲劳（57.1%）、高血压（64.3%）和蛋白尿（35.7%）。3/4级药物相关ae为高血压（14.2%）、手足综合征、蛋白尿和血小板减少症（各占7%）。低VEGF患者（< 300 pg/ml）的TTP时间长于高VEGF患者[中位50周vs. 15周，p = 0.02]。在VEGFR1和VEGFR2中也发现了类似的模式，尽管没有达到统计学意义。贝伐单抗联合索拉非尼阻断VEGF/VEGFR显示出临床活性。VEGF水平与肿瘤进展时间之间的联系有待进一步探讨。
Melanomas are vascular tumors with a high incidence of BRAF mutations driving tumor proliferation. Complete inhibition of vascular endothelial growth factor (VEGF) signaling has potential for enhanced antitumor efficacy.Patients with advanced melanoma and adequate organ function were eligible. Sorafenib was given orally at 200 mg BiD for 5 days every week; bevacizumab was administered 5 mg/kg intravenously every 14 days. The primary objective was to determine clinical biological activity. The secondary objectives were safety, tolerability, and time to progression (TTP). Pharmacodynamic analysis included serum VEGF and soluble VEGF receptor-1 and VEGF receptor-2 performed at baseline, C1D15 and C2D1. The study was terminated during the first stage of a Simon two-stage design, after 14 of planned 21 subjects were enrolled.Of the 14 patients who received treatment, no objective tumor responses were observed. Stable disease (SD) a parts per thousand yen16 weeks was observed in 57 % patients, including three patients with SD lasting a parts per thousand yen1 year. Median TTP was 32 weeks. The most frequently reported drug-related adverse events (AEs) were hand-foot syndrome (57.1 %), fatigue (57.1 %), hypertension (64.3 %), and proteinuria (35.7). Grade 3/4 drug-related AEs were hypertension (14.2 %), hand-foot syndrome, proteinuria, and thrombocytopenia (7 % each). Patients with low VEGF (< 300 pg/ml) experienced longer TTP than those with high VEGF [median 50 vs. 15 weeks, p = 0.02). A similar pattern was seen for VEGFR1 and VEGFR2, although it did not reach statistical significance.Combined VEGF/VEGFR blockade using bevacizumab with sorafenib shows clinical activity. The linkage between VEGF levels and time to tumor progression needs further exploration.