title: Dose escalation of intravenous irinotecan using oral cefpodoxime: a phase I study in pediatric patients with refractory solid tumors.
abstract: BACKGROUND
  Administration of an oral cephalosporin allowed advancement of the dosage of oral irinotecan. This study investigates whether administration of an oral cephalosporin increases the maximum tolerated dose (MTD) of intravenous irinotecan.
  
  
  METHODS
  Irinotecan was administered intravenously on Days 1-5 and Days 8-12 of a 21-day cycle with continuous oral cefpodoxime starting 2 days prior to irinotecan. Cohorts of 3-6 pediatric patients with refractory solid tumors were enrolled at 4 dosage levels, starting at the single-agent irinotecan MTD of 20 mg/m(2) /dose.
  
  
  RESULTS
  The 17 evaluable patients received 39 courses of therapy. None of the patients treated with 20 mg/m(2) /dose experienced dose-limiting toxicity (DLT). One of six patients treated at 30 mg/m(2) /dose experienced dose-limiting neutropenia. Two of three patients treated with 45 mg/m(2) /dose and two of five treated with 40 mg/m(2) /dose experienced dose-limiting diarrhea, with associated dehydration and anorexia. Two unconfirmed partial responses were observed after one course in a patient with Ewing sarcoma and one with paraganglioma. A child with refractory neuroblastoma had disease stabilization through 12 courses of therapy. Median (range) systemic exposure to SN-38 at the MTD (30 mg/m(2) /dose) was 67 ng-h/mL (36 to 111 ng-h/mL).
  
  
  CONCLUSIONS
  The MTD of intravenous irinotecan administered on a protracted schedule was increased by 50% from 20 to 30 mg/m(2) /dose with the addition of oral cefpodoxime. The most prominent DLT remained diarrhea. High interpatient variability in irinotecan pharmacokinetics was observed; however, SN-38 exposure at the MTD was greater than most reported exposures with the 20 mg/m(2) dosage.
authors.affiliation: Department of Oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA. lisa.mcgregor@stjude.org
authors.forename: Lisa M
authors.initials: LM
authors.lastname: McGregor
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
authors.forename: Kristine R
authors.initials: KR
authors.lastname: Crews
authors.forename: Michael
authors.initials: M
authors.lastname: Tagen
authors.forename: Amy
authors.initials: A
authors.lastname: Wozniak
authors.forename: Jianrong
authors.initials: J
authors.lastname: Wu
authors.forename: M Beth
authors.initials: MB
authors.lastname: McCarville
authors.forename: Fariba
authors.initials: F
authors.lastname: Navid
authors.forename: Victor M
authors.initials: VM
authors.lastname: Santana
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
authors.forename: Wayne L
authors.initials: WL
authors.lastname: Furman
authors.forename: Carlos
authors.initials: C
authors.lastname: Rodriguez-Galindo
mesh_terms: D000293:Adolescent; D019072:Antibiotic Prophylaxis; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D015296:Ceftizoxime / Q000008:administration & dosage / Q000031:analogs & derivatives; D002648:Child; D002675:Child, Preschool; D003967:Diarrhea / Q000139:chemically induced / Q000517:prevention & control*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy*; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D055815:Young Adult; D000097623:Cefpodoxime
chemical_list: D002166:Camptothecin; D015296:Ceftizoxime; D000077146:Irinotecan; D059004:Topoisomerase I Inhibitors; D000097623:Cefpodoxime