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

AZD2171 和放射治疗 NSCLC 新脑转移的 Ib/II 期研究

基本信息

批准号：
7737187
负责人：
April Fitzsimmons Eichler
金额：
$ 38.89万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-16 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7737187
关键词：
Angiogenesis Inhibitors Antibodies Arteriogram Blood Vessels Blood flow Brain Brain Neoplasms Breast Caliber Cancer Etiology Cancer Model Cancer Patient Cause of Death Cells Central Nervous System Diseases Cessation of life Chemosensitization Clinical Clinical Trials Combined Modality Therapy Correlative Study Cranial Irradiation Data Diffusion Magnetic Resonance Imaging Edema Endothelial Cells Endothelial Growth Factors Receptor Functional disorder Genus Cola Glioblastoma Growth and Development function Human Image Imaging Techniques Institution Investigational Therapies Lead Lung Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of lung Maps Measures Mediator of activation protein Metastatic malignant neoplasm to brain Methods Monoclonal Antibodies Neoplasm Metastasis Neoplasms in Vascular Tissue Neurologic Non-Small-Cell Lung Carcinoma Oral Outcome Ovarian Pan Genus Patients Perfusion Perfusion Weighted MRI Permeability Phase Phase II Clinical Trials Phase III Clinical Trials Physiological Platinum Pre-Clinical Model Progression-Free Survivals Prostate Radiation Radiation therapy Randomized Recurrence Relative (related person)Safety Signal Pathway Solid Neoplasm Spin Labels Steroids Techniques Toxic effect Translating Tumor Angiogenesis Tyrosine Kinase Inhibitor United States Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors Vascular Permeabilities Vascular blood supply Weight angiogenesis base bevacizumab chemotherapy effective therapy improved migration outcome forecast public health relevance radiation effect response tumor tumor growth tumor vascular supply tumor xenograft

项目摘要

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.

描述（由申请人提供）：脑转移是成功治疗非小细胞肺癌（NSCLC）的重要限制因素。尽管全脑放疗（WBRT）的标准使用，但脑转移患者的预后仍然令人沮丧。脑转移的生长和发育至关取决于功能性血液供应。实体瘤的血管生成是由VEGF通过内皮生长因子受体VEGFR2驱动的。 VEGFR2是VEGF-A对内皮细胞的几种生理和病理作用的主要介体，包括增殖，生存，迁移和渗透性。在晚期NSCLC中，VEGF信号通路作为靶标在贝伐单抗的随机III期研究中已得到验证，贝伐单抗是一种针对VEFG-A的单克隆抗体，结合了基于铂的化学疗法。 AZD2171是一种口服，高度有效的Pan-VeGF受体酪氨酸激酶抑制剂，已证明可以在所有检查的所有人类肿瘤异种移植物中产生对肿瘤生长的显着抑制作用，包括肺，结肠，前列腺，前列腺，卵巢，卵巢和乳腺癌，以及在肺癌模型中辐射的影响。我们提出了NSCLC患者的新脑转移的AZD2171对AZD2171的II期研究。这项研究的主要目的是衡量总体中值生存期。为了评估AZD2171在NSCLC的脑转移中的抗血管生成作用，我们将进行串行非侵入性磁共振成像（MRI），以测量AZD2171对脑转移的潜在血管作用。将要使用的MRI技术包括动态对比度增强成像，动脉自旋标记和灌注加权成像，以检测肿瘤灌注，渗透性和血液流动的变化。我们的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，并且我们独特地将这些技术扩展到对脑转移酶中AZD2171的研究。公共卫生相关性：肺癌是美国癌症死亡的主要原因，也是向大脑传播（转移）最常见的癌症。脑转移通常是致命的，迫切需要新的疗法。我们建议研究AZD2171，这是一种针对肿瘤血液供应的实验疗法。