Phase II Study of Cediranib, an Oral Pan-Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Recurrent Glioblastoma

被引:400
作者
Batchelor, Tracy T. [1 ]
Duda, Dan G.
di Tomaso, Emmanuelle
Ancukiewicz, Marek
Plotkin, Scott R.
Gerstner, Elizabeth
Eichler, April F.
Drappatz, Jan
Hochberg, Fred H.
Benner, Thomas
Louis, David N.
Cohen, Kenneth S.
Chea, Houng
Exarhopoulos, Alexis
Loeffler, Jay S.
Moses, Marsha A.
Ivy, Percy
Sorensen, A. Gregory
Wen, Patrick Y.
Jain, Rakesh K.
机构
[1] Massachusetts Gen Hosp, Ctr Canc, Stephen E & Catherine Pappas Ctr Neurooncol, Boston, MA 02114 USA
基金
美国国家卫生研究院;
关键词
TUMOR VASCULATURE; RESPONSE CRITERIA; HUMAN GLIOMAS; NORMALIZATION; BEVACIZUMAB; PROGRESSION; BIOMARKERS; CANCER; ANGIOGENESIS; EXPRESSION;
D O I
10.1200/JCO.2009.26.3988
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose Glioblastoma 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. Methods Cediranib, 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. Results Thirty-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. Conclusion Cediranib 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
引用
收藏
页码:2817 / 2823
页数:7
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