title: Phase I trial and pharmacokinetic study of all-trans-retinoic acid administered on an intermittent schedule in combination with interferon-alpha2a in pediatric patients with refractory cancer.
abstract: OBJECTIVE
  To determine the maximum-tolerated dose (MTD) of all-trans-retinoic acid (ATRA) administered on an intermittent oral schedule with interferon-alpha2a (IFN-alpha2a) in children with refractory cancer, and whether the marked reduction in plasma ATRA concentrations observed with chronic daily oral dosing could be circumvented with an intermittent dosing schedule.
  
  
  METHODS
  Thirty-three children with refractory cancer (stratified by age, < or = 12 and > 12 years) were treated with ATRA 3 consecutive days per week and IFN-alpha2a 3 x 10(6) U/m2 5 consecutive days per week, both repeated weekly. The starting dose of ATRA was 60 mg/m2/d divided into three doses, with planned escalations to 90 and 120 mg/m2/d. Because severe headaches have been noted to occur on the initial day of ATRA administration, only two of three doses of ATRA were administered on day 1 of each week.
  
  
  RESULTS
  Pseudotumor cerebri or dose-limiting headache was observed in two of five patients older than 12 years treated at the 120-mg/m2/d dose level and in one of six < or = 12 years at the 90-mg/m2/d level. Other non-dose-limiting toxicities of ATRA included reversible elevations in hepatic transaminases and triglycerides, dry skin, cheilitis, and nausea/vomiting. One child with recurrent neuroblastoma had an objective response of 6 months' duration, and one with recurrent Wilms' tumor had histologic maturation of multiple tumors. This intermittent schedule allowed for exposure to relatively high plasma concentrations of ATRA on a repetitive basis. Following 30-mg/m2 doses, the ATRA area under the concentration-time curve (AUC) decreased from 96 +/- 14 micromol/L/min on day 1 to 26 +/- 24 micromol/L/min by day 3 of drug administration, but on day 1 of the fourth consecutive week of therapy, the AUC averaged 110 +/- 16 micromol/L/min. The recommended pediatric phase II dose of ATRA administered on this schedule is 90 mg/m2/d.
  
  
  CONCLUSIONS
  An intermittent schedule of ATRA administration appears to circumvent the low plasma drug exposure that is a result of the sustained upregulation of metabolism when this drug is administered on a chronic daily schedule. Based on the results of this trial, a phase II trial of ATRA/IFN-alpha2a in neuroblastoma and Wilms' tumor using this schedule is in progress.
authors.affiliation: Pediatric Branch, National Cancer Institute, Bethesda, MD 20892, USA. adamsonp@pbmac.nci.nih.gov
authors.forename: P C
authors.initials: PC
authors.lastname: Adamson
authors.forename: G
authors.initials: G
authors.lastname: Reaman
authors.forename: J Z
authors.initials: JZ
authors.lastname: Finklestein
authors.forename: J
authors.initials: J
authors.lastname: Feusner
authors.forename: S L
authors.initials: SL
authors.lastname: Berg
authors.forename: S M
authors.initials: SM
authors.lastname: Blaney
authors.forename: M
authors.initials: M
authors.lastname: O'Brien
authors.forename: R F
authors.initials: RF
authors.lastname: Murphy
authors.forename: F M
authors.initials: FM
authors.lastname: Balis
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019540:Area Under Curve; D002648:Child; D002851:Chromatography, High Pressure Liquid; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage*; D008297:Male; D009369:Neoplasms / Q000378:metabolism / Q000628:therapy*; D011994:Recombinant Proteins; D014212:Tretinoin / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D009396:Wilms Tumor / Q000473:pathology / Q000628:therapy
chemical_list: D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D014212:Tretinoin