Multicenter clinical trials for TSC & related disorders

描述(申请人提供)：该项目的目标是实施首个多系统家族性肿瘤疾病结节性硬化症(TSC)的多中心临床试验。TSC是一种常染色体显性遗传的抑癌基因紊乱，常见于肾脏、脑和皮肤。由于最近对TSC的研究进展，有大量数据表明mTOR抑制剂雷帕霉素可能在TSC中提供治疗益处。TSC的治疗选择有限，目前还没有治疗TSC潜在缺陷的药物，因此开发这种靶向治疗方法非常有兴趣。 我们组织了6家领先的TSC诊所组成一个联合体，实施TSC的第一个多中心临床试验，即雷帕霉素治疗与TSC相关的肾血管肌脂肪瘤和相关的肺部疾病-淋巴管肌瘤病(LAM)的II期试验。尽管这项提案的重点几乎完全放在初始的II期试验上，但我们的长期目标是成为许多精心设计的多中心临床试验中的第一个，旨在开发针对TSC和相关疾病的系统治疗的新方法。该项目与NIH的TSC研究目标和NIH翻译研究路线图倡议是一致的。 本项目的具体目标是：1)确定雷帕霉素治疗成人TSC或LAM患者肾脏血管肌脂肪瘤(AML)的疗效；2)确定雷帕霉素在该患者群体中的安全性；3)收集本研究停止治疗后12个月肾脏AMLS长期随访的数据；4)评估LAM患者的其他TSC病变(结节、室管膜下巨细胞星形细胞瘤、面部血管纤维瘤、肾囊肿)和肺部疾病的治疗效果；5)在本研究期间定期采集血DNA、血清和尿样进行基因分析和生物标志物研究；6)确定后续试验的临床试验优先顺序，并启动这些方案的设计和实施。

DESCRIPTION (provided by applicant): The goal of this project is to implement the first multicenter clinical trial for the multisystem familial tumor disorder, tuberous sclerosis (TSC). TSC is tumor a suppressor gene disorder with autosomal dominant inheritance in which hamartomatous lesions occur frequently in the kidneys, brain and skin. Because of recent research advances in TSC, there is substantial data suggesting the mTOR inhibitor, rapamycin, may provide therapeutic benefit in TSC. Treatment options for manifestations of TSC are limited and there are no drugs currently available that treat the underlying defect in TSC, so there is great interest in the development of such targeted therapeutic approaches. We have organized 6 leading TSC clinics into a consortium for implementing the first multicenter clinical trial for TSC, a phase II trial of rapamycin for the treatment of kidney angiomyolipomas associated with TSC and the related pulmonary disorder, lymphangioleiomyomatosis (LAM). Although the focus of this proposal is almost entirely on an initial phase II trial, our longer term goal is for this to be the first of many well designed multicenter clinical trials aimed at developing novel approaches to systemic therapy for TSC and related disorders. This project is consistent with NIH goals for TSC research and the NIH roadmap initiative on translational research. The specific aims of this project are: 1) Determine the efficacy of rapamycin for the treatment of kidney angiomyolipomas (AMLs) in adult patients with TSC or LAM; 2) Determine the safety profile of using rapamycin in this patient population; 3) Collect data on long term follow up of kidney AMLs for 12 months after treatment on this study is discontinued; 4) Evaluate other TSC lesions (tubers, subependymal giant cell astrocytomas, facial angiofibromas, kidney cysts) and pulmonary disease in LAM patients for evidence of response to treatment; 5) Collect blood DNA, serum and urine samples periodically during this study for genotype analyses and biomarker studies; 6) Determine clinical trial priorities for subsequent trials and initiate the design and implementation of these protocols.