TRANSLATIONAL CLINICAL TRIALS FOR PRIMARY CNS TUMORS

原发性中枢神经系统肿瘤的转化临床试验

基本信息

批准号：
7738062
负责人：
DAVID A REARDON
金额：
$ 45.49万
依托单位：
DUKE UNIVERSITY
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：
2009-02-01 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7738062
关键词：
Achievement Affinity Albumins Applications Grants Award Blood - brain barrier anatomy Brain Neoplasms Bypass Catheters Cell Nucleus Cell surface Central Nervous System Neoplasms Chondroitin Sulfate Proteoglycan Clinical Trials Clinical Trials Design Collaborations Conduct Clinical Trials Convection Dendritic Cells Devices Doctor of Medicine Doctor of Philosophy Dose Drug Delivery Systems Electrons Eligibility Determination Engineering Epidermal Growth Factor Receptor Future Gangliosides Glioblastoma Glioma Glycoproteins Grant Heterogeneity Human poliovirus Image Immunotherapy Immunotoxins Infusion procedures Injection of therapeutic agent Instruction Label Malignant Glioma Malignant neoplasm of brain Modeling Molecular Analysis Molecular Weight Monoclonal Antibodies Monoclonal Antibody 81C6 Nuclear Translocation Operative Surgical Procedures Outcome Patients Peptide Vaccines Phase Phase III Clinical Trials Physiologic pulse Polioviruses Positron-Emission Tomography Primary Brain Neoplasms Primary Neoplasm Primates Prognostic Marker Quality of life Radiation therapy Radioactivity Radioimmunotherapy Radiolabeled Randomized Recombinants Resectable Resected Resistance Rhinovirus Safety Surface Surgically-Created Resection Cavity Tenascin Therapeutic Therapeutic Agents Therapeutic Index Toxic effect Toxin Treatment Protocols Tumor Stem Cells United States National Institutes of Health Vaccination Vaccines Validation base bevacizumab chemotherapy cytotoxic cytotoxicity design immunogenicity improved innovation melanoma mutant neoplastic cell novel novel strategies novel therapeutics palliative pre-clinical pressure programs radiotracer receptor receptor binding research clinical testing temozolomide translational clinical trial treatment strategy tumor vaccination strategy

项目摘要

Project 3. Translational Clinical Trials for Primary CMSTumors. David A. Reardon, M.D., Project Leader Despite standard post-surgical cytotoxic radiotherapy and chemotherapy, the outcome for patients with primary brain tumors remains dismal. To overcome the limitations of conventional approaches, we have developed innovative therapeutics including a peptide vaccine against the tumor-specific EGFRvlll mutant receptor and a regionally administered, radiolabeled anti-tenascin monoclonal antibody, that have each advanced to multi-center, randomized phase III studies based on highly encouraging improved survival and minimal toxicity observed in clinical trials conducted at our center. In this application, we will further advance these approaches by expanding our immunotherapy program to: evaluate dose intensive temozolomide or bevacizumab to enhance EGFRvlll vaccine immunogenicity; evaluate our EGFRvlll vaccine among patients with non-resectable tumors; and evaluate a novel brain tumor stem cell RNA-pulsed dendritic cell vaccination strategy. We will also evaluate several tumor-specific MAb immunotoxin constructs developed and extensively evaluated preclinically at our center that target EGFRvlll (MR1-1; BB-IND# 12589), wild-type EGFR and EGFRvlll (D2C7), glycoprotein non-metastatic B (F6V), gangliosides 3'-isoLM1 and 3'6'-isoLD1, and chondroitin proteoglycan sulfate (Me1-14, Me1-5, and 9.2.27), respectively. We will also evaluate three novel, regionally administered therapeutic strategies including Auger electron-labeled modular recombinant transporters (MRT) against EGFR (Project 1), a recombinant poliovirus/rhinovirus construct produced through the NCI RAID program, and a novel balloon catheter device for convection enhanced delivery (CED). Finally, we will also investigate potential limitations of CED by co-infusing a radiolabeled high molecular weight marker such as 124l-albumin imaged by positron emission tomography. We hypothesize that innovative therapeutics, appropriate clinical trial eligibility, rigorous target validation, and enhanced delivery strategies will improve overall survival and quality of life for patients with malignant glioma. Our Specific Aims are: 1. To conduct Phase I and II clinical trials to assess whether innovative therapeutics including vaccine immunotherapy strategies, novel immunotoxins, modular recombinant transporters and genetically modified poliovirus, can improve overall survival and quality of life for malignant glioma patients; 2. To conduct Phase I and II clinical trials designed to determine whether enhanced local delivery of novel therapeutics can be achieved in order to improve overall survival and quality of life for malignant glioma patients. RELEVANCE (See instructions): The clinical investigation studies in Project 3 are all designed to develop more effective and less toxic treatments for malignant brain tumors.

项目 3. 原发性 CMS 肿瘤的转化临床试验。 David A. Reardon，医学博士，项目负责人尽管进行了标准的术后细胞毒性放疗和化疗，但患者的结果原发性脑肿瘤仍然令人沮丧。为了克服传统方法的局限性，我们有开发了创新疗法，包括针对肿瘤特异性 EGFRvIII 突变体的肽疫苗受体和局部施用的放射性标记抗生腱蛋白单克隆抗体，它们各自具有进入多中心、随机 III 期研究，基于高度鼓舞的生存率改善和在我们中心进行的临床试验中观察到的毒性极小。在本次应用中，我们将进一步通过扩展我们的免疫治疗计划来推进这些方法：评估剂量密集型替莫唑胺或贝伐珠单抗增强 EGFRvIII 疫苗的免疫原性；评估我们的 EGFRvll 不可切除肿瘤患者的疫苗接种；并评估一种新型脑肿瘤干细胞 RNA 脉冲树突状细胞疫苗接种策略。我们还将评估几种肿瘤特异性 MAb 免疫毒素构建体我们的中心针对 EGFRvIII（MR1-1；BB-IND# 12589)、野生型 EGFR 和 EGFRvIII (D2C7)、糖蛋白非转移性 B (F6V)、神经节苷脂 3'-isoLM1 和 3'6'-isoLD1 和硫酸软骨素蛋白多糖（Me1-14、Me1-5 和 9.2.27）。我们将还评估了三种新颖的区域性治疗策略，包括俄歇电子标记针对 EGFR 的模块化重组转运蛋白 (MRT)（项目 1），一种重组脊髓灰质炎病毒/鼻病毒通过 NCI RAID 计划生产的结构，以及用于对流的新型球囊导管装置增强交付（CED）。最后，我们还将通过共同注入 CED 来研究 CED 的潜在局限性放射性标记的高分子量标记物，例如通过正电子发射断层扫描成像的 124l-白蛋白。我们假设创新的疗法、适当的临床试验资格、严格的目标验证、增强的递送策略将改善恶性癌症患者的总体生存率和生活质量神经胶质瘤。我们的具体目标是： 1. 进行I期和II期临床试验，以评估创新疗法是否包括疫苗免疫治疗策略、新型免疫毒素、模块化重组转运蛋白和转基因脊髓灰质炎病毒，可以提高恶性胶质瘤的总体生存率和生活质量患者; 2. 进行 I 期和 II 期临床试验，以确定是否可以增强局部给药可以实现新的治疗方法，以提高总体生存率和生活质量恶性胶质瘤患者。相关性（参见说明）：项目3的临床调查研究都是为了开发更有效、毒性更小的恶性脑肿瘤的治疗。