CLINICAL TRIAL: PBTC-022 PHASE II STUDY OF BEVACIZUMAB PLUS IRINOTECAN (CAMPTOS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 摘要 假设 贝伐珠单抗联合伊立替康（CPT-11）在复发性恶性胶质瘤和弥漫性脑干胶质瘤儿科患者中耐受性良好，并显示出客观肿瘤缓解。 具体目标 主要目标 1. 估计复发性/进行性/难治性恶性胶质瘤（A层）和内源性脑干胶质瘤（B层）患者接受贝伐珠单抗+伊立替康每2周一次静脉给药治疗第1年期间，疾病进展前观察到的持续客观缓解率 2. 记录第2次贝伐珠单抗给药后24-28小时内获得的MR灌注和弥散扫描与基线相比的变化，并与缓解相关。 次要目的 3.估计复发性/进行性/难治性恶性胶质瘤（HGG）和内源性脑干胶质瘤（BSG）患者接受贝伐珠单抗+伊立替康每2周一次静脉给药的治疗相关毒性发生率。 4.在复发性/进行性/难治性恶性胶质瘤（A层）和内源性脑干胶质瘤（B层）患者中，估计持续客观缓解的累积发生率，作为贝伐珠单抗联合伊立替康静脉给药每2周一次治疗长达2年的疗程的函数。 5.估计复发性/进行性/难治性HGG和BSG患者在方案治疗开始后2年的生存和无事件生存（EFS）分布。 6.使用MR灌注/扩散成像和氟脱氧葡萄糖（FDG）正电子发射断层扫描（PET）将肿瘤功能变化与贝伐珠单抗+伊立替康治疗反应相关联。 7.获得贝伐珠单抗在HGG或BSG儿童中的血清药代动力学。 8.估计治疗前外周血单核细胞（PBMC）中血管内皮生长因子受体2（VEGF-R2）的表达以及两次单药贝伐珠单抗给药后的下调，并将该结果与第二次贝伐珠单抗给药后24-48小时获得的MR灌注成像上肿瘤渗透性变化相关联。 背景和意义 复发性高级别胶质瘤和弥漫性脑干胶质瘤患者的预后差，治疗失败往往是由耐药性介导的。 需要新的策略来改善这些患者的结局。 肿瘤血管生成在肿瘤生长、侵袭和转移中起主要作用。 血管内皮生长因子（VEGF）是血管生成的主要介质，在脑肿瘤尤其是恶性胶质瘤中广泛表达。 贝伐珠单抗是一种人源化的单克隆抗体，是VEGF的特异性抑制剂，在临床前和临床研究中显示其本身或与标准化疗联合使用在控制肿瘤生长方面是安全和有用的。 贝伐珠单抗联合化疗有望在肿瘤控制方面产生协同效应。 随机III期研究表明，这种组合可以提高肿瘤反应率和生存率。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT HYPOTHESIS Bevacizumab in combination with irinotecan (CPT-11) will be well-tolerated and demonstrate objective tumor response in pediatric patients with recurrent malignant glioma and diffuse brain stem gliomas. SPECIFIC AIMS Primary Objectives 1. To estimate the rates of sustained objective response observed prior to disease progression during the first year of treatment with i.v. bevacizumab plus irinotecan given every two weeks in patients with recurrent/progressive/refractory malignant glioma (Stratum A) and intrinsic brain-stem gliomas (Stratm B) 2. To document changes in MR perfusion and diffusion scans obtained within 24-28 hours following the 2nd dose of bevacizumab as compared to baseline and correlate with response. Secondary Objectives 3. To estimate the rate of treatment-related toxicity with i.v. bevacizumab + irinotecan given every two weeks in patients with recurrent/progressive/refractory malignant glioma (HGG) and intrinsic brain-stem gliomas (BSG). 4. To estimate the cumulative incidence of sustained objective responses as a function of courses treatment with i.v. bevacizumab plus irinotecan given every two weeks for up to two years in patients with recurrent/progressive/refractory malignant glioma (Stratum A) and intrinsic brain-stem gliomas (Stratum B). 5. To estimate the distributions of survival and event-free survival (EFS) for two years following initiation of protocol treatment in patients with recurrent/progressive/refractory HGG and BSG. 6. To correlate functional changes in tumor with responses to treatment with bevacizumab + irinotecan using MR perfusion/diffusion imaging, and Fluorodeoxyglucose (FDG) positron emission tomography (PET). 7. To obtain serum pharmacokinetics of bevacizumab in children with HGG or BSG. 8. To estimate vascular endothelial growth factor receptor-2 (VEGF-R2) expression in peripheral blood mononuclear cells (PBMC) prior to treatment and its downregulation following two doses of single-agent bevacizumab and correlate this finding with permeability changes in the tumor on MR perfusion imaging obtained 24-48 hours following the 2nd dose bevacizumab. BACKGROUND AND SIGNIFICANCE The prognosis of patients with recurrent high-grade glioma and diffuse brain stem glioma is poor and treatment failure is frequently mediated by drug resistance. Novel strategies are required for improving outcome for these patients. Tumor angiogenesis plays a major role in tumor growth,invasion, and metastasis. Vascular endothelial growth factor (VEGF) is a major mediator of angiogenesis and is widely expressed in brain tumors especially malignant glioma. Bevazizumab is a humanized monoclonalantibody that is a pecific inhibitor of VEGF and has been shown in pre-clinical and clinical studies to be safe and useful in controlling tumor growth by itself or in combinationwith standard chemotherapy. The combination of Bevacizumab plus chemotherapy is expected to have a synergistic effect in tumor control. Randomized phase III studies have demonstrated that such a combination improves tumor response rates and survival.