title: Phase II trial of pirfenidone in children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas.
abstract: BACKGROUND
  Pirfenidone, an oral anti-inflammatory, antifibrotic agent with activity in idiopathic pulmonary fibrosis, may mediate anti-tumor activity in neurofibromatosis type 1 (NF1) and plexiform neurofibromas (PN) by inhibition of fibroblast proliferation and collagen synthesis. The primary objective of this open label, single arm phase II trial was to evaluate the activity of pirfenidone in children and young adults with inoperable PN.
  
  
  METHODS
  Patients (3-21 years) with NF1-related progressive PN received pirfenidone at the previously determined optimal dose (500 mg/m(2) orally, q8h) on a continuous dosing schedule (one cycle = 28 days). Volumetric MRI analysis was used to assess response. Progression was defined as ≥ 20% PN volume increase compared to baseline. Pirfenidone would be considered active if it doubled the median time to progression (TTP) compared to the TTP on the placebo arm of a phase II trial with the farnesyltransferase inhibitor tipifarnib, which used near identical eligibility criteria. Toxicities, objective response rate, and quality of life (QOL) also were evaluated.
  
  
  RESULTS
  Thirty-six patients were enrolled and tolerated pirfenidone well with intermittent nausea and vomiting as the most frequent toxicities. A dose reduction was required in only three patients. The median TTP for pirfenidone was 13.2 months compared to 10.6 months for the placebo control group from the tipifarnib trial (two-tailed P = 0.92; one-tailed P = 0.46). No objective responses were observed.
  
  
  CONCLUSIONS
  Pirfenidone was well tolerated, but did not demonstrate activity as defined in this trial and does not warrant further evaluation in children with NF1 and progressive PN.
authors.affiliation: Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland.
authors.forename: Brigitte C
authors.initials: BC
authors.lastname: Widemann
authors.forename: Dusica
authors.initials: D
authors.lastname: Babovic-Vuksanovic
authors.forename: Eva
authors.initials: E
authors.lastname: Dombi
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Wolters
authors.forename: Stewart
authors.initials: S
authors.lastname: Goldman
authors.forename: Staci
authors.initials: S
authors.lastname: Martin
authors.forename: Anne
authors.initials: A
authors.lastname: Goodwin
authors.forename: Wendy
authors.initials: W
authors.lastname: Goodspeed
authors.forename: Mark W
authors.initials: MW
authors.lastname: Kieran
authors.forename: Bruce
authors.initials: B
authors.lastname: Cohen
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
authors.forename: Allison
authors.initials: A
authors.lastname: King
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Solomon
authors.forename: Nicholas
authors.initials: N
authors.lastname: Patronas
authors.forename: Frank M
authors.initials: FM
authors.lastname: Balis
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fox
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Packer
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D009367:Neoplasm Staging; D018318:Neurofibroma, Plexiform / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009456:Neurofibromatosis 1 / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D011728:Pyridones / Q000627:therapeutic use*; D011788:Quality of Life; D015996:Survival Rate; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D011728:Pyridones; D014409:Tumor Necrosis Factor-alpha; C093844:pirfenidone
keywords: neurofibromatosis type 1; phase II trial; plexiform neurofibroma; progression free survival; time to progression; volumetric MRI analysis
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