Multicenter clinical trials for TSC & related disorders

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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.