Multicenter phase 2 trial of sirolimus for tuberous sclerosis: kidney angiomyolipomas and other tumors regress and VEGF- D levels decrease.
Multicenter phase 2 trial of sirolimus for tuberous sclerosis: kidney angiomyolipomas and other tumors regress and VEGF- D levels decrease.
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DOI：
10.1371/journal.pone.0023379
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Thiele EA
中科院分区：
文献类型：
--
作者：
Dabora SL;Franz DN;Ashwal S;Sagalowsky A;DiMario FJ Jr;Miles D;Cutler D;Krueger D;Uppot RN;Rabenou R;Camposano S;Paolini J;Fennessy F;Lee N;Woodrum C;Manola J;Garber J;Thiele EA
Tuberous sclerosis (TSC) related tumors are characterized by constitutively activated mTOR signaling due to mutations in TSC1 or TSC2. We completed a phase 2 multicenter trial to evaluate the efficacy and tolerability of the mTOR inhibitor, sirolimus, for the treatment of kidney angiomyolipomas. 36 adults with TSC or TSC/LAM were enrolled and started on daily sirolimus. The overall response rate was 44.4% (95% confidence intervals [CI] 28 to 61); 16/36 had a partial response. The remainder had stable disease (47.2%, 17/36), or were unevaluable (8.3%, 3/36). The mean decrease in kidney tumor size (sum of the longest diameters [sum LD]) was 29.9% (95% CI, 22 to 37; n = 28 at week 52). Drug related grade 1–2 toxicities that occurred with a frequency of >20% included: stomatitis, hypertriglyceridemia, hypercholesterolemia, bone marrow suppression (anemia, mild neutropenia, leucopenia), proteinuria, and joint pain. There were three drug related grade 3 events: lymphopenia, headache, weight gain. Kidney angiomyolipomas regrew when sirolimus was discontinued but responses tended to persist if treatment was continued after week 52. We observed regression of brain tumors (SEGAs) in 7/11 cases (26% mean decrease in diameter), regression of liver angiomyolipomas in 4/5 cases (32.1% mean decrease in longest diameter), subjective improvement in facial angiofibromas in 57%, and stable lung function in women with TSC/LAM (n = 15). A correlative biomarker study showed that serum VEGF-D levels are elevated at baseline, decrease with sirolimus treatment, and correlate with kidney angiomyolipoma size (Spearman correlation coefficient 0.54, p = 0.001, at baseline). Sirolimus treatment for 52 weeks induced regression of kidney angiomyolipomas, SEGAs, and liver angiomyolipomas. Serum VEGF-D may be a useful biomarker for monitoring kidney angiomyolipoma size. Future studies are needed to determine benefits and risks of longer duration treatment in adults and children with TSC. Clinicaltrials.gov NCT00126672
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影响因子：
158.5
作者：
Krueger, Darcy A.;Care, Marguerite M.;Franz, David Neal
通讯作者：
Franz, David Neal
DOI：
10.1164/ajrccm.164.4.2011025
发表时间：
2001-08-15
影响因子：
24.7
作者：
Franz, DN;Brody, A;McCormack, FX
通讯作者：
McCormack, FX
影响因子：
8.9
作者：
Costello, LC;Hartman, TE;Ryu, JH
通讯作者：
Ryu, JH
影响因子：
--
作者：
Haemel, Anna K.;O'Brian, Amy L.;Teng, Joyce M.
通讯作者：
Teng, Joyce M.
影响因子：
9.6
作者：
Glasgow, Connie G.;Avila, Nilo A.;Moss, Joel
通讯作者：
Moss, Joel