title: Phase I and pharmacokinetic evaluation of all-trans-retinoic acid in pediatric patients with cancer.
abstract: OBJECTIVE
  Recent reports of the dramatic antitumor effect of all-trans-retinoic acid (RA) in patients with acute promyelocytic leukemia (APL) have renewed interest in the oncologic indications for retinoids. Furthermore, a variety of pediatric tumors are responsive to RA in vitro, which provides additional rationale for a phase I evaluation of RA in children with cancer that is refractory to standard therapy.
  
  
  METHODS
  A phase I trial of RA administered orally twice daily for 28-day treatment courses was performed. Cohorts of at least three pediatric cancer patients were entered at successive RA dose levels (from 45 to 80 mg/m2/d) until dose-limiting toxicity (DLT) was consistently observed.
  
  
  RESULTS
  The maximum-tolerated dose (MTD) of RA was 60 mg/m2/d. Three of eight patients at the 80-mg/m2/d dose level developed reversible pseudotumor cerebri that necessitated discontinuation of the agent. Both patients with APL achieved complete remission (CR), whereas no patients with solid tumors had objective responses. Pharmacokinetic studies demonstrated a relatively short terminal half-life for RA (45 minutes), with diminution in plasma levels after chronic dosing.
  
  
  CONCLUSIONS
  The MTD and recommended phase II dose for RA in children is 60 mg/m2/d given twice daily. Reversible CNS toxicity related to RA-induced pseudotumor cerebri is dose-limiting. Two children with APL achieved a CR to RA, which supports the inclusion of pediatric patients in clinical trials that evaluate the use of RA for patients with APL.
authors.affiliation: Pediatric Branch, National Cancer Institute, Bethesda, MD 20892.
authors.forename: M A
authors.initials: MA
authors.lastname: Smith
authors.forename: P C
authors.initials: PC
authors.lastname: Adamson
authors.forename: F M
authors.initials: FM
authors.lastname: Balis
authors.forename: J
authors.initials: J
authors.lastname: Feusner
authors.forename: L
authors.initials: L
authors.lastname: Aronson
authors.forename: R F
authors.initials: RF
authors.lastname: Murphy
authors.forename: M E
authors.initials: ME
authors.lastname: Horowitz
authors.forename: G
authors.initials: G
authors.lastname: Reaman
authors.forename: G D
authors.initials: GD
authors.lastname: Hammond
authors.forename: R M
authors.initials: RM
authors.lastname: Fenton
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D002214:Capsules; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004334:Drug Administration Schedule; D006207:Half-Life; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D011559:Pseudotumor Cerebri / Q000139:chemically induced; D014212:Tretinoin / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: D002214:Capsules; D014212:Tretinoin