西地尼布联合西仑吉肽治疗复发性胶质母细胞瘤的I期研究。
A phase I study of cediranib in combination with cilengitide in patients with recurrent glioblastoma.
作者信息
Gerstner Elizabeth R, Ye Xiaobu, Duda Dan G, Levine Michael A, Mikkelsen Tom, Kaley Thomas J, Olson Jeffrey J, Nabors Burt L, Ahluwalia Manmeet S, Wen Patrick Y, Jain Rakesh K, Batchelor Tracy T, Grossman Stuart
机构信息
Massachusetts General Hospital Cancer Center, Boston, Massachusetts (E.R.G., D.G.D., R.K.J., T.T.B.); Johns Hopkins Medical Center, Baltimore, Maryland (X.Y., S.G.); Martinos Center for Biomedical Imaging, Charlestown, Massachusetts (E.R.G., M.A.L.); Henry Ford Hospital, Detroit, Michigan (T.M.); Memorial Sloan Kettering Cancer Center, New York, New York (T.J.K.); Emory University, Atlanta, Georgia (J.J.O.); University of Alabama, Birmingham, Alabama (B.L.N.); Case Comprehensive Cancer Center, Cleveland, Ohio (M.S.A.); Dana-Farber Cancer Institute, Boston, Massachusetts (P.Y.W.).
出版信息
Neuro Oncol. 2015 Oct;17(10):1386-92. doi: 10.1093/neuonc/nov085. Epub 2015 May 24.
BACKGROUND
Despite being a highly vascularized tumor, glioblastoma response to anti-vascular endothelial growth factor (VEGF) therapy is transient, possibly because of tumor co-option of preexisting blood vessels and infiltration into surrounding brain. Integrins, which are upregulated after VEGF inhibition, may play a critical role in this resistance mechanism. We designed a study of cediranib, a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor, combined with cilengitide, an integrin inhibitor.
METHODS
This phase I study was conducted through the Adult Brain Tumor Consortium in patients with recurrent glioblastoma. Once the maximum tolerated dose was determined, 40 patients enrolled in a dose expansion cohort with 20 being exposed to anti-VEGF therapy and 20 being naive. The primary endpoint was safety. Secondary endpoints included overall survival, proportion of participants alive and progression free at 6 months, radiographic response, and exploratory analyses of physiological imaging and blood biomarkers.
RESULTS
Forty-five patients enrolled, and no dose toxicities were observed at a dose of cediranib 30 mg daily and cilengitide 2000 mg twice weekly. Complete response was seen in 2 participants, partial response in 2, stable disease in 13, and progression in 21; 7 participants were not evaluable. Median overall survival was 6.5 months, median progression-free survival was 1.9 months, and progression-free survival at 6 months was 4.4%. Plasma-soluble VEGFR2 decreased with treatment and placental growth factor, carbonic anhydrase IX, and SDF1α, and cerebral blood flow increased.
CONCLUSIONS
The combination of cediranib with cilengitide was well tolerated and associated with changes in pharmacodynamic blood and imaging biomarkers. However, the survival and response rates do not warrant further development of this combination.
背景
尽管胶质母细胞瘤是一种血管高度丰富的肿瘤，但它对抗血管内皮生长因子（VEGF）治疗的反应是短暂的，这可能是由于肿瘤对既有血管的利用以及向周围脑组织浸润。整合素在VEGF抑制后上调，可能在这种耐药机制中起关键作用。我们设计了一项关于西地尼布（一种血管内皮生长因子受体（VEGFR）酪氨酸激酶抑制剂）联合西仑吉肽（一种整合素抑制剂）的研究。
方法
这项I期研究通过成人脑肿瘤协作组在复发性胶质母细胞瘤患者中进行。一旦确定了最大耐受剂量，40名患者进入剂量扩展队列，其中20名接受抗VEGF治疗，20名未接受过该治疗。主要终点是安全性。次要终点包括总生存期、6个月时存活且无进展的参与者比例、影像学反应以及生理成像和血液生物标志物的探索性分析。
结果
45名患者入组，在西地尼布每日30 mg和西仑吉肽每周两次2000 mg的剂量下未观察到剂量毒性。2名参与者出现完全缓解，2名出现部分缓解，13名病情稳定，21名病情进展；7名参与者无法评估。中位总生存期为6.5个月，中位无进展生存期为1.9个月，6个月时的无进展生存率为4.4%。血浆可溶性VEGFR2随治疗降低，胎盘生长因子、碳酸酐酶IX和SDF1α以及脑血流量增加。
结论
西地尼布与西仑吉肽联合耐受性良好，并与药效学血液和成像生物标志物的变化相关。然而，生存率和反应率不支持进一步开发这种联合方案。
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