title: Phase II study of everolimus in children and adults with neurofibromatosis type 2 and progressive vestibular schwannomas.
abstract: BACKGROUND
  Activation of the mammalian target of rapamycin (mTOR) signaling pathway is thought to be a key driver of tumor growth in Merlin (NF2)-deficient tumors. Everolimus is an oral inhibitor of mTOR complex 1 (mTORC1) with antitumor activity in a variety of cancers.
  
  
  METHODS
  We conducted a single-institution, prospective, 2-stage, open-label phase II study to estimate the response rate to everolimus in neurofibromatosis type 2 (NF2) patients with progressive vestibular schwannoma (VS). Ten eligible patients were enrolled, including 2 pediatric patients. Everolimus was administered at a daily dose of 10 mg (adults) or 5 mg/m(2)/day (children <18 y) orally in continuous 28-day courses, for up to 12 courses. Response was assessed every 3 months with MRI, using 3-dimensional volumetric tumor analysis, and audiograms. Nine patients were evaluable for the primary response, defined as ≥15% decrease in VS volume. Hearing response was evaluable as a secondary endpoint in 8 patients.
  
  
  RESULTS
  None of the 9 patients with evaluable disease experienced a clinical or MRI response. No objective imaging or hearing responses were observed in stage 1 of the trial, and the study was closed according to predefined stopping rules.
  
  
  CONCLUSIONS
  Everolimus is ineffective for the treatment of progressive VS in NF2 patients. We are currently conducting a pharmacokinetic/pharmacodynamic ("phase 0") study of everolimus in presurgical VS patients to elucidate the biological basis for apparent treatment resistance to mTORC1 inhibition in these tumors.
authors: Corresponding author: Matthias A. Karajannis, MD, MS, NYU Langone Medical Center, Hassenfeld Children's Center for Cancer and Blood Disorders, 160 East 32nd Street, 2nd floor, New York, NY 10016. matthias.karajannis@nyumc.org.
authors: Matthias A
authors: MA
authors: Karajannis
authors: Geneviève
authors: G
authors: Legault
authors: Mari
authors: M
authors: Hagiwara
authors: Filippo G
authors: FG
authors: Giancotti
authors: Alexander
authors: A
authors: Filatov
authors: Anna
authors: A
authors: Derman
authors: Tsivia
authors: T
authors: Hochman
authors: Judith D
authors: JD
authors: Goldberg
authors: Emilio
authors: E
authors: Vega
authors: Jeffrey H
authors: JH
authors: Wisoff
authors: John G
authors: JG
authors: Golfinos
authors: Amanda
authors: A
authors: Merkelson
authors: J Thomas
authors: JT
authors: Roland
authors: Jeffrey C
authors: JC
authors: Allen
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002648:Child; D018450:Disease Progression; D000068338:Everolimus; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009367:Neoplasm Staging; D016518:Neurofibromatosis 2 / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D009464:Neuroma, Acoustic / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D011379:Prognosis; D011446:Prospective Studies; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015996:Survival Rate; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D000068338:Everolimus; D020123:Sirolimus
keywords: everolimus; mammalian target of rapamycin; neurofibromatosis type 2; phase II trial; vestibular schwannoma.