Multicenter clinical trials for TSC & related disorders

描述（申请人提供）：本项目的目的是实施针对多系统家族性肿瘤疾病结节性硬化症（TSC）的第一个多中心临床试验。TSC是一种常染色体显性遗传的肿瘤抑制基因疾病，其错构瘤病变常发生在肾脏、大脑和皮肤。由于TSC的最新研究进展，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表现的治疗选择是有限的，目前没有药物可用于治疗TSC中的潜在缺陷，因此人们对开发这种靶向治疗方法非常感兴趣。 我们已将6家领先的TSC诊所组织成一个联盟，以实施TSC的第一个多中心临床试验，这是一项雷帕霉素治疗与TSC相关的肾血管平滑肌脂肪瘤和相关肺部疾病淋巴管平滑肌瘤病（LAM）的II期试验。尽管该提案的重点几乎完全集中在最初的II期试验上，但我们的长期目标是使其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和相关疾病的全身治疗的新方法。该项目与NIH TSC研究目标和NIH转化研究路线图倡议一致。 本项目的具体目的是：1）确定雷帕霉素治疗TSC或LAM成人患者肾血管平滑肌脂肪瘤（AML）的疗效; 2）确定在该患者人群中使用雷帕霉素的安全性特征; 3）收集本研究治疗停止后12个月肾脏AML长期随访的数据; 4）评估其他TSC病变5）在该研究期间定期收集血液DNA、血清和尿液样品用于基因型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，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.