title: Phase I trial of 13-cis-retinoic acid in children with neuroblastoma following bone marrow transplantation.
abstract: OBJECTIVE
  Treatment of neuroblastoma cell lines with 13-cis-retinoic acid (cis-RA) can cause sustained inhibition of proliferation. Since cis-RA has demonstrated clinical responses in neuroblastoma patients, it may be effective in preventing relapse after cytotoxic therapy. This phase I trial was designed to determine the maximal-tolerated dosage (MTD), toxicities, and pharmacokinetics of cis-RA administered on an intermittent schedule in children with neuroblastoma following bone marrow transplantation (BMT).
  
  
  METHODS
  Fifty-one assessable patients, 2 to 12 years of age, were treated with oral cis-RA administered in two equally divided doses daily for 2 weeks, followed by a 2-week rest period, for up to 12 courses. The dose was escalated from 100 to 200 mg/m2/d until dose-limiting toxicity (DLT) was observed. A single intrapatient dose escalation was permitted.
  
  
  RESULTS
  The MTD of cis-RA was 160 mg/m2/d. Dose-limiting toxicities in six of nine patients at 200 mg/m2/d included hypercalcemia (n = 3), rash (n = 2), and anemia/thrombocytopenia/emesis/rash (n = 1). All toxicities resolved after cis-RA was discontinued. Three complete responses were observed in marrow metastases. Serum levels of 7.4 +/- 3.0 mumol/L (peak) and 4.0 +/- 2.8 mumol/L (trough) at the MTD were maintained during 14 days of therapy. The DLT correlated with serum levels > or = 10 mumol/L.
  
  
  CONCLUSIONS
  The MTD of cis-RA given on this intermittent schedule was 160 mg/m2/d. Serum levels known to be effective against neuroblastoma in vitro were achieved at this dose. The DLT included hypercalcemia, and may be predicted by serum cis-RA levels. Monitoring of serum calcium and cis-RA levels is indicated in future trials.
authors.affiliation: Department of Pediatrics, Childrens Hospital, Los Angeles, CA 90027-6016, USA.
authors.forename: J G
authors.initials: JG
authors.lastname: Villablanca
authors.forename: A A
authors.initials: AA
authors.lastname: Khan
authors.forename: V I
authors.initials: VI
authors.lastname: Avramis
authors.forename: R C
authors.initials: RC
authors.lastname: Seeger
authors.forename: K K
authors.initials: KK
authors.lastname: Matthay
authors.forename: N K
authors.initials: NK
authors.lastname: Ramsay
authors.forename: C P
authors.initials: CP
authors.lastname: Reynolds
mesh_terms: D016026:Bone Marrow Transplantation; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D006934:Hypercalcemia / Q000139:chemically induced; D015474:Isotretinoin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D009447:Neuroblastoma / Q000097:blood / Q000188:drug therapy* / Q000628:therapy; D012074:Remission Induction
chemical_list: D015474:Isotretinoin