title: Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial.
abstract: BACKGROUND
  Tuberous sclerosis complex is a genetic disorder leading to constitutive activation of mammalian target of rapamycin (mTOR) and growth of benign tumours in several organs. In the brain, growth of subependymal giant cell astrocytomas can cause life-threatening symptoms--eg, hydrocephalus, requiring surgery. In an open-label, phase 1/2 study, the mTOR inhibitor everolimus substantially and significantly reduced the volume of subependymal giant cell astrocytomas. We assessed the efficacy and safety of everolimus in patients with subependymal giant cell astrocytomas associated with tuberous sclerosis complex.
  
  
  METHODS
  In this double-blind, placebo-controlled, phase 3 trial, patients (aged 0-65 years) in 24 centres in Australia, Belgium, Canada, Germany, the UK, Italy, the Netherlands, Poland, Russian Federation, and the USA were randomly assigned, with an interactive internet-response system, in a 2:1 ratio to oral everolimus 4·5 mg/m(2) per day (titrated to achieve blood trough concentrations of 5-15 ng/mL) or placebo. Eligible patients had a definite diagnosis of tuberous sclerosis complex and at least one lesion with a diameter of 1 cm or greater, and either serial growth of a subependymal giant cell astrocytoma, a new lesion of 1 cm or greater, or new or worsening hydrocephalus. The primary endpoint was the proportion of patients with confirmed response--ie, reduction in target volume of 50% or greater relative to baseline in subependymal giant cell astrocytomas. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00789828.
  
  
  RESULTS
  117 patients were randomly assigned to everolimus (n=78) or placebo (n=39). 27 (35%) patients in the everolimus group had at least 50% reduction in the volume of subependymal giant cell astrocytomas versus none in the placebo group (difference 35%, 95% CI 15-52; one-sided exact Cochran-Mantel-Haenszel test, p<0·0001). Adverse events were mostly grade 1 or 2; no patients discontinued treatment because of adverse events. The most common adverse events were mouth ulceration (25 [32%] in the everolimus group vs two [5%] in the placebo group), stomatitis (24 [31%] vs eight [21%]), convulsion (18 [23%] vs ten [26%]), and pyrexia (17 [22%] vs six [15%]).
  
  
  CONCLUSIONS
  These results support the use of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis. Additionally, everolimus might represent a disease-modifying treatment for other aspects of tuberous sclerosis.
  
  
  BACKGROUND
  Novartis Pharmaceuticals.
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA. tsclinic@cchmc.org
authors.forename: David Neal
authors.initials: DN
authors.lastname: Franz
authors.forename: Elena
authors.initials: E
authors.lastname: Belousova
authors.forename: Steven
authors.initials: S
authors.lastname: Sparagana
authors.forename: E Martina
authors.initials: EM
authors.lastname: Bebin
authors.forename: Michael
authors.initials: M
authors.lastname: Frost
authors.forename: Rachel
authors.initials: R
authors.lastname: Kuperman
authors.forename: Olaf
authors.initials: O
authors.lastname: Witt
authors.forename: Michael H
authors.initials: MH
authors.lastname: Kohrman
authors.forename: J Robert
authors.initials: JR
authors.lastname: Flamini
authors.forename: Joyce Y
authors.initials: JY
authors.lastname: Wu
authors.forename: Paolo
authors.initials: P
authors.lastname: Curatolo
authors.forename: Petrus J
authors.initials: PJ
authors.lastname: de Vries
authors.forename: Vicky H
authors.initials: VH
authors.lastname: Whittemore
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Thiele
authors.forename: James P
authors.initials: JP
authors.lastname: Ford
authors.forename: Gaurav
authors.initials: G
authors.lastname: Shah
authors.forename: Helene
authors.initials: H
authors.lastname: Cauwel
authors.forename: David
authors.initials: D
authors.lastname: Lebwohl
authors.forename: Tarek
authors.initials: T
authors.lastname: Sahmoud
authors.forename: Sergiusz
authors.initials: S
authors.lastname: Jozwiak
mesh_terms: D000293:Adolescent; D000328:Adult; D001254:Astrocytoma / Q000150:complications / Q000188:drug therapy*; D002648:Child; D002675:Child, Preschool; D004311:Double-Blind Method; D000068338:Everolimus; D005260:Female; D005334:Fever / Q000139:chemically induced; D006801:Humans; D007223:Infant; D008297:Male; D019226:Oral Ulcer / Q000139:chemically induced; D012640:Seizures / Q000139:chemically induced; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013280:Stomatitis / Q000139:chemically induced; D016896:Treatment Outcome; D014402:Tuberous Sclerosis / Q000150:complications*; D055815:Young Adult
chemical_list: D000068338:Everolimus; D020123:Sirolimus