title: Phase I trial of oral fenretinide in children with high-risk solid tumors: a report from the Children's Oncology Group (CCG 09709).
abstract: OBJECTIVE
  To determine the maximal tolerated dosage (MTD) of oral fenretinide given as intact capsules for 7 days, repeated every 21 days, in children with high-risk solid tumors.
  
  
  METHODS
  Children 21 years of age or younger received daily doses from 350 mg/m2 to 3,300 mg/m2 (divided into two or three doses), with pharmacokinetics during course one. The MTD was defined as zero to one of six patients with dose-limiting toxicity (DLT), with at least two of three or two of six DLT at next higher dose.
  
  
  RESULTS
  Fifty-four patients, age 2 years to 20 years (median, 9 years), were treated: neuroblastoma (n = 39), Ewing sarcoma (n = 5), and other (n = 10). Prior therapy included autologous stem cell transplantation (n = 42), 13-cis-RA (n = 35), and 9-cis-RA (n = 1). One of four patients at 1,050 mg/m2 with prior liver transplant had grade 3 ALT/abdominal pain/nausea/dehydration and grade 4 AST/emesis. At 1,860 mg/m2, one of seven patients had grade 3 hypoalbuminemia/hypophosphatemia. At 2,475 mg/m2, one of eight patients had grade 3 alkaline phosphatase; three of five patients had DLT at 3,300 mg/m2: grade 3 AST/ALT (n = 1), grade 4 bilirubin/grade 3 AST/ALT (n = 1), pseudotumor cerebri (n = 1). Pseudotumor cerebri also occurred at 600 mg/m2 and 800 mg/m2. There was one complete response and 13 patients with stable disease (SD) for 8 or more courses in 30 assessable neuroblastoma patients. SD for 8 or more courses was seen in one of five Ewing sarcoma patients and one melanoma patient. Mean N-4-hydroxyphenyl retinamide plasma level (day 7, steady-state concentration) was 9.9 mumol/L at MTD.
  
  
  CONCLUSIONS
  The pediatric MTD of oral capsular fenretinide was 2,475 mg/m2 per day, which achieved levels active against neuroblastoma in vitro with minimal toxicity. Response data support a phase II trial in neuroblastoma.
authors.affiliation: Children's Hospital Los Angeles and the Department Pediatrics, University of Southern California Keck School of Medicine, Los Angeles, USA. jvillablanca@chla.usc.edu
authors.forename: Judith G
authors.initials: JG
authors.lastname: Villablanca
authors.forename: Mark D
authors.initials: MD
authors.lastname: Krailo
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Ames
authors.forename: Joel M
authors.initials: JM
authors.lastname: Reid
authors.forename: Gregory H
authors.initials: GH
authors.lastname: Reaman
authors.forename: C Patrick
authors.initials: CP
authors.lastname: Reynolds
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Reynolds
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D005260:Female; D017313:Fenretinide / Q000008:administration & dosage* / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D009369:Neoplasms / Q000188:drug therapy*; D009447:Neuroblastoma / Q000188:drug therapy; D016896:Treatment Outcome; D014801:Vitamin A / Q000097:blood
chemical_list: D000970:Antineoplastic Agents; D014801:Vitamin A; D017313:Fenretinide