A phase Ib/II study of AZD2171 and radiation for new brain metastases from NSCLC

描述(申请人提供)：脑转移是非小细胞肺癌(NSCLC)患者成功治疗的重要限制因素。尽管全脑放射治疗(WBRT)已成为标准治疗手段，但脑转移瘤患者的预后仍然很差。脑转移瘤的生长和发展严重依赖于有功能的血液供应。实体肿瘤中的血管生成是由血管内皮生长因子通过内皮生长因子受体VEGFR2驱动的。血管内皮生长因子受体2是血管内皮细胞生长、存活、迁移和通透性等多种生理和病理效应的主要介体。作为晚期非小细胞肺癌靶点的血管内皮生长因子信号通路最近在抗VEFG-A的单抗贝伐单抗联合铂类化疗的随机III期研究中得到验证。AZD2171是一种口服的、高效的泛血管内皮生长因子受体酪氨酸激酶抑制剂，已被证明在所有被检查的人肿瘤移植瘤中都能显著抑制肿瘤生长，包括肺、结肠、前列腺、卵巢和乳腺，并在肺癌模型中增强放射的影响。我们建议对非小细胞肺癌患者进行AZD2171联合WBRT治疗新的脑转移瘤的II期研究。这项研究的主要目标是衡量总体中位生存期。为了评估AZD2171在非小细胞肺癌脑转移瘤中的抗血管生成作用，我们将进行一系列无创性磁共振成像(MRI)，以评估AZD2171在脑转移瘤中的潜在血管作用。将使用的MRI技术包括动态对比增强成像、动脉自旋标记和灌注加权成像，以努力检测肿瘤灌注、渗透性和血流量的变化。我们机构最近证明了这些相关成像技术在胶质母细胞瘤患者中的可行性和实用性，我们能够将这些技术扩展到脑转移瘤AZD2171的研究中是独一无二的。 公共卫生相关性：肺癌是美国癌症死亡的主要原因，也是最常见的扩散(转移)到大脑的癌症。脑转移往往是致命的，迫切需要新的治疗方法。我们建议研究AZD2171，一种作用于肿瘤血液供应的实验性疗法，用于肺癌脑转移患者。

DESCRIPTION (provided by applicant): Brain metastases are an important limiting factor in the successful treatment of patients with non-small cell lung cancer (NSCLC). Despite the standard use of whole brain radiotherapy (WBRT), the prognosis of patients with brain metastases remains dismal. The growth and development of brain metastases is critically dependent on a functional blood supply. Angiogenesis in solid tumors is driven by VEGF via the endothelial growth factor receptor, VEGFR2. VEGFR2 is the major mediator of several physiological and pathological effects of VEGF-A on endothelial cells, including proliferation, survival, migration and permeability. The VEGF signaling pathway as a target in advanced NSCLC has recently been validated in a randomized phase III study of bevacizumab, a monoclonal antibody against VEFG-A, in combination with platinum-based chemotherapy. AZD2171 is an oral, highly potent pan-VEGF receptor tyrosine kinase inhibitor that has been shown to generate significant inhibition of tumor growth in all human tumor xenografts examined, including lung, colon, prostate, ovarian and breast, as well as potentiation of the effects of radiation in lung cancer models. We propose a Phase II study of AZD2171 with concomitant WBRT for new brain metastases in patients with NSCLC. The primary objective of this study is to measure the overall median survival. In order to assess the antiangiogenic effects of AZD2171 in brain metastases from NSCLC, we will conduct serial non-invasive magnetic resonance imaging (MRI) to measure the potential vascular effects of AZD2171 on brain metastases. MRI techniques that will be utilized include dynamic contrast enhanced imaging, arterial spin labeling and perfusion weighted imaging in an effort to detect changes in tumor perfusion, permeability and blood flow. Our institution has recently demonstrated the feasibility and utility of these correlative imaging techniques in patients with glioblastoma, and we are uniquely situated to extend these techniques to the study of AZD2171 in brain metastases. PUBLIC HEALTH RELEVANCE: Lung cancer is the leading cause of cancer deaths in the United States and the most common cancer to spread (metastasize) to the brain. Brain metastases are often fatal, and new therapies are desperately needed. We propose to study AZD2171, an experimental therapy that acts on tumor blood supply, in lung cancer patients with brain metastases.