Brain Tumor Clinical and Clinical Research Program (Clinical Support Services)

NOB在建立必要的基础设施方面取得了重大进展，以履行其为患有脑髓和脊髓肿瘤的儿童和成人开发新的和改进的治疗方法的使命。2014年11月，Gilbert博士来到NIH，他重建了脑肿瘤临床和临床研究项目：一个高度协作、强大的转化研究项目，专注于寻找大脑和其他中枢神经系统肿瘤的治疗方法。除了开展基础研究和转译研究外，NOB已成为全国公认的患者信息和第二意见转诊资源。除了观察和治疗脑肿瘤患者外，Gilbert博士目前还进行了大量的国家临床试验，并帮助组织和管理几个大型的国家神经肿瘤学转化科学计划。最近，Gilbert博士领导了RTOG 0825，在一项双盲安慰剂对照随机III期试验中评估了抗血管生成剂贝伐单抗在新诊断的胶质母细胞瘤患者中的作用。该研究共收集了973例患者，并通过两个分子参数成功地纳入了前期分层，因为肿瘤组织提交的依从性为100%。这项研究没有证明贝伐单抗有生存获益，但证明了接受贝伐单抗治疗的患者神经认知能力下降，症状负担和生活质量恶化。这项研究在ASCO全体会议上发表，并发表在《新英格兰医学杂志》上。这些努力使我领导了NRG BN002，这是一项临床试验，正在测试在新诊断的胶质母细胞瘤患者中添加免疫检查点抑制剂ipilimumab（抗ctla -4）和nivolumab（抗pd -1）的安全性。这是预期的4组随机、安慰剂对照II期试验的前奏，该试验将选择最佳实验组（ipilimumab、nivolumab或联合用药）进行III期安慰剂对照注册试验。二期和三期试验的一个关键组成部分将是免疫监测，这将包括对肿瘤组织的免疫反应介质的检测，以及对外周血单个核细胞的连续监测，作为治疗对“免疫能力”影响的指标。这项工作将在神经肿瘤学分支实验室进行，与Jeffrey Schlom博士领导的肿瘤免疫学和生物学实验室密切合作，并与Christopher Heery博士直接合作。他还从安德森癌症中心转移到脑肿瘤试验合作中心。这是一个建立在慈善支持基础上的全国性联盟。BTTC的使命是快速开发和完成针对原发性脑肿瘤患者的创新临床试验。迄今为止，BTTC已经完成了一项使用析因设计的研究（同时评估8个治疗组）和一项使用自适应随机设计的试验（使用患者对患者再平衡的方法根据治疗效果分配患者）。这项工作目前正从安德森癌症中心转移到NCI。目前有3项正在进行的研究，一旦重新启动，预计将有更多的研究概念。参与计划的地点名单如下：美国国立卫生研究院贝勒大学西北大学，范伯格医学院凯斯西储SOM俄亥俄州立大学雪松西奈医学中心拉什大学癌症中心克利夫兰诊所德州肿瘤哥伦比亚大学卫理公会医院达纳法伯癌症研究所北卡罗来纳大学亨利福特健康系统堪萨斯大学南卡罗来纳医科大学犹他大学奥兰多健康大学华盛顿梅奥诊所UT md安德森癌症中心北岸大学健康系统UT该NOB已经创建了一个充满活力，稳健和临床繁忙的神经肿瘤学卓越中心，为中枢神经系统恶性肿瘤患者（无论他们的支付能力如何）提供信息，咨询，临床试验或转介到当地的卓越中心进行临床护理和nci赞助的试验。这是一项重要的成就，因为：NCI的部分使命应该是为社区中不常见的致命肿瘤类型的患者和医生提供专业知识，并且标准治疗方案有限。一个繁忙而强大的临床项目确保了原发性中枢神经系统肿瘤患者的稳定流动，通过确保快速的临床试验患者积累，有效的基础和转化研究组织获取，以及吸引制药/生物技术公司与NOB和NCI共同开发新型中枢神经系统肿瘤药物，从而刺激临床和转化研究。多学科肿瘤委员会每隔一周召开一次会议，与会人员包括神经肿瘤学家、放射肿瘤学家、神经外科医生、神经病理学家和实验室调查员。介绍和讨论复杂和具有挑战性的患者，优化个体患者护理，并导致许多合作互动和研究项目。该肿瘤委员会由每两周一次的病理审查补充，NIH神经病理学家准备来自活跃临床患者的标本，进行显微镜检查，并与脑肿瘤临床小组成员一起讨论形态学和遗传特征。此外，一个分子肿瘤委员会正在开发中，该委员会将汇编来自个体患者肿瘤的所有可用分子信息，以便在这些信息的背景下考虑治疗。以下是在三个不同的NCI分支机构（ROB， MOCRU， CCRLP），六个不同的NIH机构（NCI， NINDS， NEI， NHLBI， NIMH）和五个不同的临床中心项目（神经放射学，精神病学，疼痛与缓和，康复医学，社会工作）积极参与下建立的NIH范围内多学科脑肿瘤诊所的部分成就列表。临床专家包括肿瘤内科、放射肿瘤学、神经外科、神经病学、眼科、心脏病学、精神病学、内分泌学、社会工作和康复医学；组建了一个初级神经肿瘤临床护理/研究团队，目前包括4名神经肿瘤学家，4名nob培训的神经肿瘤执业护士，2名研究护士，1名神经肿瘤学研究员，2名患者协调员，2名临床试验专家和2名数据管理员；此外，NOB还为贝塞斯达的沃尔特里德医疗中心提供神经肿瘤学服务；与约翰霍普金斯医疗中心、乔治华盛顿医疗中心、费尔法克斯Inova和华盛顿医院中心以及当地和全国范围内广泛的私人神经外科、放射和肿瘤实践小组建立了密切的合作临床项目；在美国国立卫生研究院和约翰霍普金斯医学中心之间建立了一个神经肿瘤学奖学金培训项目。

The NOB has made substantial progress towards building an infrastructure necessary for fulfilling its mission of developing new and improved therapies for children and adults with brain and spinal cord tumors. When Dr. Gilbert came to the NIH in November 2014, he has rebuilt the Brain Tumor Clinical and Clinical Research Program: a highly collaborative, robust translational research program centered on finding treatments for brain and other central nervous system tumors. In addition to conducting basic and translational research, the NOB has become a nationally recognized resource for patient information and referrals for second opinions. In addition to seeing and treating brain tumor patients, Dr. Gilbert currently runs a significant number of national clinical trials and helps organize and administrate over several large national Neuro-Oncology translational science initiatives. Most recently, Dr. Gilbert led RTOG 0825 which evaluated the role of the anti-angiogenic agent, bevacizumab, in patients with newly diagnosed glioblastoma in a double-blind placebo controlled randomized phase III trial. This study accrued 973 patients and successfully incorporated upfront stratification by two molecular parameters, as there was 100% compliance with tumor tissue submission. This study, which did not demonstrate a surivival benefit for bevacizumab, demonstrated neurocognitive decline and worsened symptom burden and quality of life in the patients treated with bevacizumab. This study was presented at the Plenary Session at ASCO and published in the New England Journal of Medicine. These efforts have led to my leadership of NRG BN002, a clinical trial that is testing the safety of adding the immune checkpoint inhibitors, ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) in patients with newly diagnosed glioblastoma. This is the prelude to an anticipated 4-arm randomized, placebo-controlled phase II trial that will pick the best experiment arm (ipilimumab, nivolumab or the combination) to test in a phase III placebo controlled registration trial. A critical component of the phase II and phase III trial will be the immunologic monitoring which will comprise testing of tumor tissue for mediators of immune-reactivity and serial monitoring of peripheral blood mononuclear cells as an indicator of the impact of treatment on "immune competence". This work will be done in the Neuro-Oncology Branch Laboratory in close collaboration with the Laboratory of Tumor Immunology and Biology led by Dr. Jeffrey Schlom, with direct collaboration with Dr. Christopher Heery. Dr. Gilbert has also transitioned the Brain Tumor Trials Collaborative from M. D. Anderson Cancer Center. This is a national consortium that was founded on philanthropic support. The mission of the BTTC is to rapidly develop and complete innovative clinical trials for patients with primary brain tumors. To date, the BTTC has completed a study that used a factorial design (8 treatment arms were evaluated simultaneously) and a trial that used an adaptive randomized design (patient allocation based on treatment efficacy using patient by patient rebalancing). This effort is currently being transferred from the M. D. Anderson Cancer Center to the NCI. There are currently 3 active studies and once re-launched, addition study concepts are anticipated. The list of participating sites is provided below: Aurora Advanced Healthcare National Institutes of Health Baylor University Northwestern University, Feinberg School of Medicine Case Western Reserve SOM Ohio State University Cedar-Sinai Medical Center Rush University Cancer Center Cleveland Clinic Texas Oncology Columbia University The Methodist Hospital Dana Farber Cancer Institute University of North Carolina Henry Ford Health System University of Kansas Medical University of South Carolina University of Utah Orlando Health University of Washington Mayo Clinic UT M. D. Anderson Cancer Center Northshore University Health System UT Southwestern Medical Center at Dallas The NOB has created a vibrant, robust and clinically busy center for neuro-oncology excellence that serves as a national resource for patients with CNS malignancies (regardless of their ability to pay), for information, consultation, clinical trials or referrals to their local centers of excellence for clinical care and NCI-sponsored trials. This was an important accomplishment because: Part of the mission of the NCI should be to provide expertise to patients and physicians for a lethal tumor type not frequently seen in the community and for whom standard treatment options are limited. A busy and robust clinical program ensures a steady flow of patients with primary CNS tumors imperative for stimulating clinical and translational research by ensuring rapid patient accrual to clinical trials, efficient acquisition of tissue for basic and translational research, and for enticing pharmaceutical/biotechnology companies to co-develop novel CNS tumor agents with the NOB and the NCI at large. A multi-disciplinary tumor board convenes every other week and is attended by neuro-oncologists, radiation oncologists, neurosurgeons, neuropathologists and laboratory investigators. Complex and challenging patients are presented and discussed, optimizing individual patient care and leading to many collaborative interactions and research projects. This Tumor Board is complemented by a bi-weekly pathology review where NIH neuropathologists prepare specimens from active clinical patients that are examined microscopically and morphologic and genetic features are discussed in conjunction with members of the Brain Tumor Clinical Team. Additionally, a Molecular Tumor Board is under development that will compile all of the available molecular information from individual patient's tumors so that therapies can be considered in the context of this information. Below are partial lists of accomplishments in the building of an NIH-wide multidisciplinary Brain Tumor Clinic with active participation from three different NCI Branches (ROB, MOCRU, CCRLP), six different NIH Institutions (NCI, NINDS, NEI, NHLBI, NIMH), and five different Clinical Center Programs (Neuroradiology, Psychiatry, Pain and Palliation, Rehabilitation Medicine, Social Work). Expertise represented in the clinic includes Medical Oncology, Radiation Oncology, Neurosurgery, Neurology, Ophthalmology, Cardiology, Psychiatry, Endocrinology, Social Work, and Rehabilitation Medicine; Assembled a primary neuro-oncology clinical care/research team, which now consists of 4 neuro-oncologists, 4 NOB-trained neuro-oncology nurse practitioners, 2 research nurses, 1 neuro-oncology fellow, 2 patient coordinators, 2 clinical trials specialists and 2 data managers; Additionally, the NOB provides neuro-oncology services for Walter Reed Medical Center, in Bethesda; established close collaborative clinical programs with Johns Hopkins Medical Center, George Washington Medical Center, Fairfax Inova and Washington Hospital Center and a wide array of private neurosurgical, radiation, and oncology practice groups locally and nationally; created a neuro-oncology fellowship training program between the NIH and the Johns Hopkins Medical Center.