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

临床试验：贝伐珠单抗加伊立替康 (CAMPTOS) 的 PBTC-022 II 期研究

基本信息

批准号：
8356679
负责人：
SUSAN M. BLANEY
金额：
$ 0.91万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-12-01 至 2011-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8356679
关键词：
Brain Neoplasms Brain Stem Glioma Child Childhood Clinical Research Clinical Trials Diffuse Diffusion Disease Progression Disease-Free Survival Dose Down-Regulation Drug Kinetics Drug resistance Funding Glioma Grant Hour Image Incidence Malignant Glioma Mediating Mediator of activation protein National Center for Research Resources Neoplasm Metastasis Outcome Patients Perfusion Peripheral Blood Mononuclear Cell Permeability Play Principal Investigator Randomized Recurrence Refractory Research Research Infrastructure Resources Role Scanning Serum Source Survival Rate Toxic effect Treatment Failure Treatment Protocols Tumor Angiogenesis United States National Institutes of Health Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors angiogenesis bevacizumab chemotherapy cost fluorodeoxyglucose positron emission tomography improved inhibitor/antagonist irinotecan novel strategies outcome forecast phase 2 study phase 3 study pre-clinical response tumor tumor growth

项目摘要

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.

该子项目是利用资源的众多研究子项目之一由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持并且子项目的主要研究者可能是由其他来源提供的，包括其他 NIH 来源。子项目可能列出的总成本代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。抽象的假设贝伐珠单抗与伊立替康 (CPT-11) 联合用药对复发性恶性神经胶质瘤和弥漫性脑干神经胶质瘤儿科患者具有良好的耐受性，并显示出客观的肿瘤反应。具体目标主要目标 1. 估计静脉注射治疗第一年期间疾病进展前观察到的持续客观缓解率。复发性/进行性/难治性恶性神经胶质瘤（A 层）和内在性脑干神经胶质瘤（B 层）患者每两周给予贝伐单抗加伊立替康一次 2. 记录第二次贝伐单抗给药后 24-28 小时内获得的 MR 灌注和扩散扫描与基线相比的变化，并与反应相关。次要目标 3. 估计静脉注射治疗相关毒性的发生率贝伐珠单抗 + 伊立替康每两周给予复发/进展/难治性恶性胶质瘤 (HGG) 和内在脑干胶质瘤 (BSG) 患者。 4. 估计持续客观反应的累积发生率作为静脉注射疗程的函数。对于复发性/进行性/难治性恶性神经胶质瘤（A 层）和内在性脑干神经胶质瘤（B 层）患者，每两周给予贝伐单抗加伊立替康治疗，持续长达两年。 5. 评估复发性/进行性/难治性 HGG 和 BSG 患者在开始方案治疗后两年内的生存率和无事件生存率 (EFS) 的分布。 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) 将肿瘤的功能变化与贝伐单抗 + 伊立替康治疗的反应关联起来。 7. 获得贝伐珠单抗在 HGG 或 BSG 儿童中的血清药代动力学。 8. 评估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) 的表达以及两剂单药贝伐单抗后血管内皮生长因子受体 2 (VEGF-R2) 的下调，并将这一发现与肿瘤通透性变化相关联。第 2 剂贝伐单抗后 24-48 小时获得 MR 灌注成像。一、背景及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较差，治疗失败常常是由耐药性引起的。需要新的策略来改善这些患者的治疗结果。肿瘤血管生成在肿瘤的生长、侵袭和转移中发挥着重要作用。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单克隆抗体，是 VEGF 的特异性抑制剂，临床前和临床研究已表明，单独或与标准化疗联合使用可安全有效地控制肿瘤生长。贝伐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。