title: A phase I trial and pharmacokinetic study of 9-cis-retinoic acid (ALRT1057) in pediatric patients with refractory cancer: a joint Pediatric Oncology Branch, National Cancer Institute, and Children's Cancer Group study.
abstract: OBJECTIVE
  To determine the maximum tolerated dose and describe the toxicities of 9-cis-retinoic acid (9cRA, ALRT1057) administered p.o. tid in pediatric patients with refractory cancer and to study the pharmacokinetics of 9cRA and determine whether systemic drug exposure changes with chronic dosing.
  
  
  METHODS
  Children with refractory cancer (stratified by age, < or =12 and >12 years) were treated with p.o. 9cRA for 28 consecutive days. The starting dose was 50 mg/m(2)/day divided into 3 doses with planned escalations to 65, 85, and 110 mg/m(2)/day. Pharmacokinetic sampling was performed on days 1 and 29 of the first cycle.
  
  
  RESULTS
  Of the 37 patients entered, 18 patients < or =12 years of age and 11 patients >12 years of age were evaluable for toxicity. In patients >12 years of age, dose-limiting headache occurred in 2/2 patients at the 110 mg/m(2)/day dose level; 1/8 patients at 85 mg/m(2)/day developed dose-limiting pseudotumor cerebri. In patients < or =12 years of age, 3/5 patients at the starting dose level of 50 mg/m(2)/day developed dose-limiting pseudotumor cerebri; and 0/6 patients experienced dose-limiting toxicity at 35 mg/m(2)/day. Reversible non-dose-limiting hepatotoxicity was observed in 15 patients across all of the dose levels. There was considerable interpatient variability in 9cRA plasma concentrations. Peak plasma concentrations of 9cRA occurred at a median of 1.5 h after a p.o. dose, and the harmonic-mean terminal half-life was 43 min. By day 29 of 9cRA administration, the plasma 9cRA area under the curve declined by an average of 65% from day 1 values.
  
  
  CONCLUSIONS
  The dose-limiting toxicity of 9cRA in pediatric patients was neurotoxicity, primarily pseudotumor cerebri. Younger children tolerate significantly lower doses of 9cRA than older children. Similar to all-trans-retinoic acid, the pharmacokinetics of 9cRA demonstrated a wide degree of interpatient variability and decreased over time when administered on a daily basis. The recommended Phase II dose of 9cRA in patients < or =12 and >12 years of age is 35 and 85 mg/m(2)/day, respectively.
authors.affiliation: Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD 20892, USA. adamson@email.chop.edu
authors.forename: P C
authors.initials: PC
authors.lastname: Adamson
authors.forename: B C
authors.initials: BC
authors.lastname: Widemann
authors.forename: G H
authors.initials: GH
authors.lastname: Reaman
authors.forename: N L
authors.initials: NL
authors.lastname: Seibel
authors.forename: R F
authors.initials: RF
authors.lastname: Murphy
authors.forename: A F
authors.initials: AF
authors.lastname: Gillespie
authors.forename: F M
authors.initials: FM
authors.lastname: Balis
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000077556:Alitretinoin; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D006261:Headache / Q000139:chemically induced; D006801:Humans; D008099:Liver / Q000201:enzymology; D008297:Male; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D012871:Skin Diseases / Q000139:chemically induced; D000637:Transaminases / Q000187:drug effects / Q000378:metabolism; D016896:Treatment Outcome; D014212:Tretinoin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014280:Triglycerides / Q000097:blood; D014839:Vomiting / Q000139:chemically induced
chemical_list: D000970:Antineoplastic Agents; D014280:Triglycerides; D000077556:Alitretinoin; D014212:Tretinoin; D000637:Transaminases