title: Multicenter phase 2 trial of sirolimus for tuberous sclerosis: kidney angiomyolipomas and other tumors regress and VEGF- D levels decrease.
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.
  
  
  BACKGROUND
  Clinicaltrials.gov NCT00126672.
authors.affiliation: Biogen Idec Hemophilia, Weston, Massachusetts, United States of America. sandy.dabora@gmail.com
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Dabora
authors.forename: David Neal
authors.initials: DN
authors.lastname: Franz
authors.forename: Stephen
authors.initials: S
authors.lastname: Ashwal
authors.forename: Arthur
authors.initials: A
authors.lastname: Sagalowsky
authors.forename: Francis J
authors.initials: FJ
authors.lastname: DiMario
authors.forename: Daniel
authors.initials: D
authors.lastname: Miles
authors.forename: Drew
authors.initials: D
authors.lastname: Cutler
authors.forename: Darcy
authors.initials: D
authors.lastname: Krueger
authors.forename: Raul N
authors.initials: RN
authors.lastname: Uppot
authors.forename: Rahmin
authors.initials: R
authors.lastname: Rabenou
authors.forename: Susana
authors.initials: S
authors.lastname: Camposano
authors.forename: Jan
authors.initials: J
authors.lastname: Paolini
authors.forename: Fiona
authors.initials: F
authors.lastname: Fennessy
authors.forename: Nancy
authors.initials: N
authors.lastname: Lee
authors.forename: Chelsey
authors.initials: C
authors.lastname: Woodrum
authors.forename: Judith
authors.initials: J
authors.lastname: Manola
authors.forename: Judy
authors.initials: J
authors.lastname: Garber
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Thiele
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018207:Angiomyolipoma / Q000139:chemically induced* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000009:adverse effects* / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000139:chemically induced* / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020123:Sirolimus / Q000009:adverse effects* / Q000627:therapeutic use*; D014402:Tuberous Sclerosis / Q000188:drug therapy* / Q000378:metabolism; D042643:Vascular Endothelial Growth Factor D / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D042643:Vascular Endothelial Growth Factor D; D020123:Sirolimus