title: The effect of everolimus on renal angiomyolipoma in patients with tuberous sclerosis complex being treated for subependymal giant cell astrocytoma: subgroup results from the randomized, placebo-controlled, Phase 3 trial EXIST-1.
abstract: BACKGROUND
  Tuberous sclerosis complex (TSC) is characterized by benign tumours in multiple organs, including the brain, kidneys, skin, lungs and heart. Our objective was to evaluate everolimus, an mTOR inhibitor, in the treatment of angiomyolipoma in patients with subependymal giant cell astrocytoma (SEGA) associated with TSC.
  
  
  METHODS
  EXamining everolimus In a Study of Tuberous Sclerosis Complex-1 (NCT00789828), a prospective, double-blind, randomized, placebo-controlled, Phase 3 study, examined everolimus in treating SEGA associated with TSC. Patients with serial SEGA growth from pre-baseline to baseline scans were randomly assigned (2:1) to receive 4.5 mg/m(2)/day everolimus (target blood trough: 5-15 ng/mL; n = 78) or placebo (n = 39). Angiomyolipoma response rates were analysed in patients (n = 44) with target baseline angiomyolipoma lesions (≥1 angiomyolipoma; longest diameter ≥1.0 cm). An angiomyolipoma response rate, defined as the proportion of patients with confirmed angiomyolipoma response, was assessed by kidney CT or MRI screening at baseline, at 12, 24 and 48 weeks and annually.
  
  
  RESULTS
  Angiomyolipoma response rates were 53.3% (16/30) and 0% (0/14) for everolimus- and placebo-treated patients, respectively. Angiomyolipoma reductions ≥50% in the sum of volumes of all target lesions were seen only in everolimus-treated patients (56.5, 78.3 and 80.0%) compared with placebo-treated patients (0% at each time point) at Weeks 12, 24 and 48, respectively. Greater percentages of everolimus-treated patients had angiomyolipoma reductions ≥30% at these same time points (82.6, 100 and 100% versus 8.3, 18.2 and 16.7% for everolimus versus placebo, respectively).
  
  
  CONCLUSIONS
  Everolimus showed efficacy in reducing angiomyolipoma lesion volume in patients with SEGA associated with TSC.The trial is registered with ClinicalTrials.gov, number NCT00789828; http://clinicaltrials.gov/ct2/show/NCT00789828?term=EXIST-1&rank=1.
authors.affiliation: Sussex Renal Unit, Royal Sussex County Hospital, Brighton, UK The Trafford Department of Renal Medicine, Royal Sussex County Hospital, Brighton BN2 5BE, UK.
authors.forename: J Chris
authors.initials: JC
authors.lastname: Kingswood
authors.affiliation: Department of Child Neurology, The Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Sergiusz
authors.initials: S
authors.lastname: Jozwiak
authors.affiliation: Moscow Research Institute of Pediatrics and Pediatric Surgery, Moscow, Russia.
authors.forename: Elena D
authors.initials: ED
authors.lastname: Belousova
authors.affiliation: Minnesota Epilepsy Group, St. Paul, MN, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Frost
authors.affiliation: Department of Neurology, Children's Hospital & Research Center Oakland, Oakland, CA, USA.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Kuperman
authors.affiliation: Department of Neurology, University of Alabama School of Medicine, Birmingham, AL, USA.
authors.forename: E Martina
authors.initials: EM
authors.lastname: Bebin
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Korf
authors.affiliation: Children's Healthcare of Atlanta, Atlanta, GA, USA.
authors.forename: J Robert
authors.initials: JR
authors.lastname: Flamini
authors.affiliation: University of Chicago Medicine Comer Children's Hospital, Chicago, IL, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Kohrman
authors.affiliation: Texas Scottish Rite Hospital for Children, Dallas, TX, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Sparagana
authors.affiliation: Division of Pediatric Neurology, Mattel Children's Hospital UCLA, Los Angeles, CA, USA.
authors.forename: Joyce Y
authors.initials: JY
authors.lastname: Wu
authors.affiliation: Novartis Pharmaceuticals S.A.S., Rueil-Malmaison, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Brechenmacher
authors.affiliation: Novartis Pharmaceuticals Corporation, Florham Park, NJ, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Stein
authors.affiliation: Novartis Pharmaceuticals Corporation, Florham Park, NJ, USA.
authors.forename: Noah
authors.initials: N
authors.lastname: Berkowitz
authors.affiliation: Present address: Division of Nephrology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA Present address: Division of Nephrology, Le Bonheur Children's Hospital and University of Tennessee College of Medicine, Memphis, TN, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Bissler
authors.affiliation: Department of Pediatrics and Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: David N
authors.initials: DN
authors.lastname: Franz
mesh_terms: D000328:Adult; D018207:Angiomyolipoma / Q000188:drug therapy*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001254:Astrocytoma / Q000453:epidemiology / Q000209:etiology*; D001921:Brain; D002675:Child, Preschool; D004311:Double-Blind Method; D000068338:Everolimus; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000150:complications / Q000188:drug therapy*; D008297:Male; D009378:Neoplasms, Multiple Primary / Q000188:drug therapy*; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome; D014402:Tuberous Sclerosis / Q000150:complications* / Q000453:epidemiology
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000068338:Everolimus; D020123:Sirolimus
keywords: everolimus; renal angiomyolipoma; tuberous sclerosis complex
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