Phase II Study of Cediranib, an Oral Pan-Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Recurrent Glioblastoma
Phase II Study of Cediranib, an Oral Pan-Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Recurrent Glioblastoma
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DOI：
10.1200/jco.2009.26.3988
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发表时间：
2010-06-10
影响因子：
45.3
通讯作者：
Jain, Rakesh K.
中科院分区：
文献类型：
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作者：
Batchelor, Tracy T.;Duda, Dan G.;Jain, Rakesh K.
目的胶质母细胞瘤是一种无法治愈的实体瘤，其特征是血管内皮生长因子（VEGF）表达增加。我们对复发性胶质母细胞瘤患者进行了西地尼布的 II 期研究。方法西地尼布（一种口服泛 VEGF 受体酪氨酸激酶抑制剂）给予复发性胶质母细胞瘤患者（45 mg/d），直至病情进展或出现不可接受的毒性。主要终点是 6 个月时存活且无进展的患者比例 (APF6)。我们在多个时间点进行了磁共振成像 (MRI) 以及血浆和尿液生物标志物评估。结果 纳入了 31 名复发性胶质母细胞瘤患者。西地尼布后的 APF6 为 25.8%。使用三维测量在 30 名可评估患者中的 17 名（56.7%）和使用二维测量的 30 名可评估患者中的 8 名（27%）通过 MRI 观察到放射线部分反应。对于进入研究的 15 名服用皮质类固醇的患者，剂量减少 (n = 10) 或停药 (n = 5)。毒性是可控的。 3/4 级毒性包括高血压（31 例中有 4 例；12.9%）；腹泻（31 例中有 2 例；6.4%）；和疲劳（31 例中有 6 例；19.4%）。 31 名患者中有 15 名 (48.4%) 需要至少减少一次剂量，15 名患者因毒性需要暂时中断用药。药物中断与结果无关。西地尼布治疗后血浆胎盘生长因子、碱性成纤维细胞生长因子、基质金属蛋白酶 (MMP) -2、可溶性 VEGF 受体 1、基质细胞衍生因子 1 α 和可溶性 Tek/Tie2 受体以及尿液 MMP-9/中性粒细胞明胶酶相关脂质运载蛋白活性的变化与放射学反应或生存相关。放射学反应的比例、6 个月无进展生存期以及类固醇节约效应和可控制的毒性。我们将循环分子的早期变化确定为西地尼布反应的潜在生物标志物。西地尼布的功效和这些候选生物标志物的预测价值将在前瞻性试验中进行探讨。 J 临床肿瘤杂志 28：2817-2823。 (C) 2010 年美国临床肿瘤学会
PurposeGlioblastoma is an incurable solid tumor characterized by increased expression of vascular endothelial growth factor (VEGF). We performed a phase II study of cediranib in patients with recurrent glioblastoma.MethodsCediranib, an oral pan-VEGF receptor tyrosine kinase inhibitor, was administered (45 mg/d) until progression or unacceptable toxicity to patients with recurrent glioblastoma. The primary end point was the proportion of patients alive and progression free at 6 months (APF6). We performed magnetic resonance imaging (MRI) and plasma and urinary biomarker evaluations at multiple time points.ResultsThirty-one patients with recurrent glioblastoma were accrued. APF6 after cediranib was 25.8%. Radiographic partial responses were observed by MRI in 17 (56.7%) of 30 evaluable patients using three-dimensional measurements and in eight (27%) of 30 evaluable patients using two-dimensional measurements. For the 15 patients who entered the study taking corticosteroids, the dose was reduced (n = 10) or discontinued (n = 5). Toxicities were manageable. Grade 3/4 toxicities included hypertension (four of 31; 12.9%); diarrhea (two of 31; 6.4%); and fatigue (six of 31; 19.4%). Fifteen (48.4%) of 31 patients required at least one dose reduction and 15 patients required temporary drug interruptions due to toxicity. Drug interruptions were not associated with outcome. Changes in plasma placental growth factor, basic fibroblast growth factor, matrix metalloproteinase (MMP) -2, soluble VEGF receptor 1, stromal cell-derived factor-1 alpha, and soluble Tek/Tie2 receptor and in urinary MMP-9/neutrophil gelatinase-associated lipocalin activity after cediranib were associated with radiographic response or survival.ConclusionCediranib monotherapy for recurrent glioblastoma is associated with encouraging proportions of radiographic response, 6-month progression-free survival, and a steroid-sparing effect with manageable toxicity. We identified early changes in circulating molecules as potential biomarkers of response to cediranib. The efficacy of cediranib and the predictive value of these candidate biomarkers will be explored in prospective trials. J Clin Oncol 28:2817-2823. (C) 2010 by American Society of Clinical Oncology