title: Phase I trial and pharmacokinetics of fenretinide in children with neuroblastoma.
abstract: OBJECTIVE
  Fenretinide (4HPR), a synthetic retinoid, induces apoptosis in neuroblastoma cells. A Phase I study in children with neuroblastoma was designed to determine maximum tolerated dose, toxicity, and pharmacokinetics.
  
  
  METHODS
  Fifty-four patients received oral 4HPR, once daily, for 28 days, followed by a 7-day interruption, for up to 6 courses. The starting dose was 100 mg/m(2)/day. At least 3 patients were entered at each escalating 4HPR dose level. Pharmacokinetic sampling was performed on days 1 and 28 of the first course.
  
  
  RESULTS
  Fifty-four patients, of whom 53 were evaluable, received doses between 100 and 4000 mg/m(2)/day for a total of 168 courses. Additional dose escalation was precluded by capsule number intake. A total of 34 of 53 evaluable patients showed manageable, reversible toxicities, which were not dose related. One dose-limiting toxicity (nyctalopia grade 3) occurred after the 1000 mg/m(2)/day dose. Twelve patients showed grade 2 toxicity: skin xerosis (6 cases); nyctalopia (3 cases); hepatic toxicity (1 case); diarrhea (1 case); and headache (1 case). Stable disease was observed in 41 patients for a median period of 23 months (range 2-35+). After first administration, average 4HPR peak plasma levels ranged from 0.6 to 6 micro M (after 100 and 4000 mg/m(2)/day, respectively) and increased 2-fold (to 1.3 and 12.9 micro M, respectively) after the 28-day treatment. 4HPR half-life increased from 17 h after the first administration to 25 h after the 28(th) administration. Incidence of grade 2-3 toxicity was 0 of 12 (0%), 7 of 22 (31%), and 4 of 8 (50%) with peak 4HPR concentrations <3 micro M, 3-10 micro M, and >10 micro M, respectively. After repeated treatment, retinol levels decreased from 20 to 10% of pretreatment levels after all of the doses.
  
  
  CONCLUSIONS
  In children, 4HPR administration up to 4000 mg/m(2)/day over 28 days, followed by a 7-day interruption, results in manageable toxicity and in drug plasma concentrations comparable with those that induce apoptosis in neuroblastoma cell lines.
authors.affiliation: Department of Pediatric Hematology/Oncology, G. Gaslini Children's Hospital, Genova, Italy. albertogaraventa@ospedale-gaslini.ge.it
authors.forename: Alberto
authors.initials: A
authors.lastname: Garaventa
authors.forename: Roberto
authors.initials: R
authors.lastname: Luksch
authors.forename: Maria Serena
authors.initials: MS
authors.lastname: Lo Piccolo
authors.forename: Elena
authors.initials: E
authors.lastname: Cavadini
authors.forename: Paolo G
authors.initials: PG
authors.lastname: Montaldo
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Pizzitola
authors.forename: Luca
authors.initials: L
authors.lastname: Boni
authors.forename: Mirco
authors.initials: M
authors.lastname: Ponzoni
authors.forename: Andrea
authors.initials: A
authors.lastname: Decensi
authors.forename: Bruno
authors.initials: B
authors.lastname: De Bernardi
authors.forename: Franca Fossati
authors.initials: FF
authors.lastname: Bellani
authors.forename: Franca
authors.initials: F
authors.lastname: Formelli
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D017313:Fenretinide / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism; D014801:Vitamin A / Q000097:blood
chemical_list: D000970:Antineoplastic Agents; D014801:Vitamin A; D017313:Fenretinide