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

• 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
• 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

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。尽管全脑放疗（WBRT）已成为标准使用，但脑转移患者的预后仍然很差。脑转移瘤的生长和发展严重依赖于功能性血液供应。实体瘤中的血管生成是由 VEGF 通过内皮生长因子受体 VEGFR2 驱动的。 VEGFR2 是 VEGF-A 对内皮细胞的多种生理和病理作用的主要介质，包括增殖、存活、迁移和通透性。 VEGF 信号通路作为晚期 NSCLC 的靶点最近在贝伐珠单抗（一种针对 VEFG-A 的单克隆抗体）与铂类化疗联合的随机 III 期研究中得到了验证。 AZD2171 是一种口服高效泛 VEGF 受体酪氨酸激酶抑制剂，已被证明能够显着抑制所有受检人类肿瘤异种移植物的肿瘤生长，包括肺癌、结肠癌、前列腺、卵巢和乳腺癌，并增强肺癌模型中的放射效应。我们提出了一项 AZD2171 联合 WBRT 治疗 NSCLC 患者新发脑转移的 II 期研究。本研究的主要目的是测量总体中位生存期。为了评估 AZD2171 在 NSCLC 脑转移瘤中的抗血管生成作用，我们将进行系列非侵入性磁共振成像 (MRI) 来测量 AZD2171 对脑转移瘤的潜在血管作用。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，以检测肿瘤灌注、渗透性和血流的变化。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，并且我们具有独特的优势，可以将这些技术扩展到 AZD2171 在脑转移中的研究。 公共卫生相关性：肺癌是美国癌症死亡的主要原因，也是扩散（转移）至大脑的最常见癌症。脑转移通常是致命的，迫切需要新的疗法。我们建议研究 AZD2171，这是一种作用于肿瘤血液供应的实验疗法，用于治疗患有脑转移的肺癌患者。