Multicenter phase 2 trial of sirolimus for tuberous sclerosis: kidney angiomyolipomas and other tumors regress and VEGF- D levels decrease

• Published in: PloS one Vol. 6; no. 9; p. e23379
• Main Authors: Dabora, Sandra L, Franz, David Neal, Ashwal, Stephen, Sagalowsky, Arthur, DiMario, Jr, Francis J, Miles, Daniel, Cutler, Drew, Krueger, Darcy, Uppot, Raul N, Rabenou, Rahmin, Camposano, Susana, Paolini, Jan, Fennessy, Fiona, Lee, Nancy, Woodrum, Chelsey, Manola, Judith, Garber, Judy, Thiele, Elizabeth A
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 06.09.2011; Public Library of Science (PLoS)
• Subjects: Adolescent; Adult; Adults; Aged; Anemia; Angiomyolipoma; Angiomyolipoma - chemically induced; Angiomyolipoma - metabolism; Anti-Bacterial Agents - adverse effects; Anti-Bacterial Agents - therapeutic use; Biomarkers; Bone marrow; Brain; Brain cancer; Brain tumors; Care and treatment; Children; Children & youth; Collaboration; Confidence intervals; Correlation analysis; Correlation coefficient; Correlation coefficients; Cysts; Female; Genes; Genetic disorders; Headache; Hospitals; Humans; Hypercholesterolemia; Hypertriglyceridemia; Kidney cancer; Kidney Neoplasms - chemically induced; Kidney Neoplasms - metabolism; Kidneys; Kinases; Leukopenia; Liver; Liver Neoplasms - chemically induced; Liver Neoplasms - metabolism; Lungs; Lymphopenia; Male; Medicine; Middle Aged; Mutation; Myelosuppression; Neutropenia; Pain; Patients; Proteinuria; Quality; Rapamycin; Regression; Respiratory function; Signaling; Sirolimus - adverse effects; Sirolimus - therapeutic use; Statistical analysis; Stomatitis; TOR protein; Toxicity; Transplants & implants; Tuberous sclerosis; Tuberous Sclerosis - drug therapy; Tuberous Sclerosis - metabolism; Tuberous Sclerosis Complex 1; Tuberous Sclerosis Complex 2; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor D - metabolism; Womens health; Young Adult; New York; United States > US; Massachusetts; Connecticut; Loma Linda California; Ohio; California
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0023379

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.