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

Sandra L. Dabora, David Neal Franz, Stephen Ashwal, Arthur I Sagalowsky, Francis J. DiMario, Daniel Miles, Drew Cutler, Darcy Krueger, Raul N. Uppot, Rahmin Rabenou, Susana Camposano, Jan Paolini, Fiona Fennessy, Nancy Lee, Chelsey Woodrum, Judith Manola, Judy Garber, Elizabeth A. Thiele

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Abstract

Background: Tuberous sclerosis (TSC) related tumors are characterized by constitutively activated mTOR signaling due to mutations in TSC1 or TSC2. Methods: We completed a phase 2 multicenter trial to evaluate the efficacy and tolerability of the mTOR inhibitor, sirolimus, for the treatment of kidney angiomyolipomas. Results: 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). Conclusions: 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. Trial Registration: Clinicaltrials.gov NCT00126672.

Original languageEnglish (US)
Article numbere23379
JournalPLoS One
Volume6
Issue number9
DOIs
StatePublished - 2011

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vascular endothelial growth factor D
Vascular Endothelial Growth Factor D
Angiomyolipoma
Tuberous Sclerosis
sclerosis
Sirolimus
Tumors
kidneys
Kidney
neoplasms
Biomarkers
Neoplasms
Liver
confidence interval
biomarkers
drugs
hypertriglyceridemia
neutropenia
headache
leukopenia

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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Multicenter phase 2 trial of sirolimus for tuberous sclerosis : Kidney angiomyolipomas and other tumors regress and VEGF- D levels decrease. / Dabora, Sandra L.; Franz, David Neal; Ashwal, Stephen; Sagalowsky, Arthur I; DiMario, 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.

In: PLoS One, Vol. 6, No. 9, e23379, 2011.

Research output: Contribution to journalArticle

Dabora, SL, Franz, DN, Ashwal, S, Sagalowsky, AI, DiMario, FJ, 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 2011, 'Multicenter phase 2 trial of sirolimus for tuberous sclerosis: Kidney angiomyolipomas and other tumors regress and VEGF- D levels decrease', PLoS One, vol. 6, no. 9, e23379. https://doi.org/10.1371/journal.pone.0023379
Dabora, Sandra L. ; Franz, David Neal ; Ashwal, Stephen ; Sagalowsky, Arthur I ; DiMario, 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. / Multicenter phase 2 trial of sirolimus for tuberous sclerosis : Kidney angiomyolipomas and other tumors regress and VEGF- D levels decrease. In: PLoS One. 2011 ; Vol. 6, No. 9.
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abstract = "Background: Tuberous sclerosis (TSC) related tumors are characterized by constitutively activated mTOR signaling due to mutations in TSC1 or TSC2. Methods: We completed a phase 2 multicenter trial to evaluate the efficacy and tolerability of the mTOR inhibitor, sirolimus, for the treatment of kidney angiomyolipomas. Results: 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). Conclusions: 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. Trial Registration: Clinicaltrials.gov NCT00126672.",
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T1 - Multicenter phase 2 trial of sirolimus for tuberous sclerosis

T2 - Kidney angiomyolipomas and other tumors regress and VEGF- D levels decrease

AU - Dabora, Sandra L.

AU - Franz, David Neal

AU - Ashwal, Stephen

AU - Sagalowsky, Arthur I

AU - DiMario, Francis J.

AU - Miles, Daniel

AU - Cutler, Drew

AU - Krueger, Darcy

AU - Uppot, Raul N.

AU - Rabenou, Rahmin

AU - Camposano, Susana

AU - Paolini, Jan

AU - Fennessy, Fiona

AU - Lee, Nancy

AU - Woodrum, Chelsey

AU - Manola, Judith

AU - Garber, Judy

AU - Thiele, Elizabeth A.

PY - 2011

Y1 - 2011

N2 - Background: Tuberous sclerosis (TSC) related tumors are characterized by constitutively activated mTOR signaling due to mutations in TSC1 or TSC2. Methods: We completed a phase 2 multicenter trial to evaluate the efficacy and tolerability of the mTOR inhibitor, sirolimus, for the treatment of kidney angiomyolipomas. Results: 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). Conclusions: 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. Trial Registration: Clinicaltrials.gov NCT00126672.

AB - Background: Tuberous sclerosis (TSC) related tumors are characterized by constitutively activated mTOR signaling due to mutations in TSC1 or TSC2. Methods: We completed a phase 2 multicenter trial to evaluate the efficacy and tolerability of the mTOR inhibitor, sirolimus, for the treatment of kidney angiomyolipomas. Results: 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). Conclusions: 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. Trial Registration: Clinicaltrials.gov NCT00126672.

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