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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 贝伐单抗联合伊立替康(CPT-11)耐受性良好，在儿童复发性恶性胶质瘤和弥漫性脑干胶质瘤患者中显示出客观的肿瘤反应。 主要目标 1.评估在静脉注射治疗的第一年中，在疾病进展之前观察到的持续客观应答率。贝伐单抗加伊立替康治疗复发/进展期/难治性恶性胶质瘤(A层)和固有脑干胶质瘤(B层)患者每两周一次。2.记录在第二次贝伐单抗治疗后24-28小时内获得的MR灌注和弥散扫描的变化，与基线比较，并与反应相关。 次要目标3.静脉注射估计与治疗相关的毒性发生率。贝伐单抗伊立替康治疗复发/进展期/难治性恶性胶质瘤(HGG)和内源性脑干胶质瘤(BSG)的患者每两周一次。4.评估持续客观反应的累积发生率作为静脉注射治疗的函数。贝伐单抗加伊立替康治疗复发/进展性/难治性恶性胶质瘤(A层)和固有脑干胶质瘤(B层)患者，每两周服用一次，疗程长达两年。5.评估复发性/进展性/难治性HGG和BSG患者开始方案治疗后两年的生存和无事件生存(EFS)的分布。6.应用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)研究肿瘤功能改变与贝伐单抗伊立替康治疗反应的关系。7.研究贝伐单抗在HGG和BSG患儿体内的血药动学。 8.检测治疗前外周血单个核细胞(PBMC)中血管内皮生长因子受体-2(VEGFR-R2)的表达及两次单药贝伐单抗治疗后的下调情况，并将其与第二次贝伐单抗治疗后24-48小时MR灌注成像上肿瘤的通透性变化进行相关性分析。 复发的高级别胶质瘤和弥漫性脑干胶质瘤患者预后较差，治疗失败往往是由耐药引起的。需要新的策略来改善这些患者的预后。肿瘤血管生成在肿瘤的生长、侵袭和转移中起重要作用。血管内皮生长因子(VEGF)是血管生成的主要介质，广泛表达于脑肿瘤，尤其是恶性胶质瘤。 Bevazizumab是一种人源化的单抗，是一种特异性的血管内皮生长因子抑制剂，临床前和临床研究表明，Bevazizumab单独或联合标准化疗在控制肿瘤生长方面是安全有效的。贝伐单抗联合化疗有望在肿瘤控制方面起到协同作用。第三阶段的随机研究表明，这种联合疗法可以提高肿瘤的反应率和存活率。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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. 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 gkioma (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. 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.