title: Phase I clinical and pharmacologic study of weekly cisplatin and irinotecan combined with amifostine for refractory solid tumors.
abstract: OBJECTIVE
  This Phase I study was designed primarily to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of irinotecan and cisplatin with and without amifostine in children with refractory solid tumors.
  
  
  METHODS
  Cisplatin, at a fixed dose of 30 mg/m(2), and escalating doses of irinotecan (starting dose, 40 mg/m(2)) were administered weekly for four consecutive weeks, every 6 weeks. After the MTD of irinotecan plus cisplatin was determined, additional cohorts of patients were enrolled with amifostine (825 mg/m(2)) support. Leukocyte DNA-platinum adducts and pharmacokinetics of cisplatin and WR-1065 (amifostine-active metabolite) were also determined.
  
  
  RESULTS
  Twenty-four patients received 43 courses of therapy. The MTD for irinotecan administered in combination with cisplatin (30 mg/m(2)) was 50 mg/m(2). The DLTs of this combination were neutropenia and thrombocytopenia. With the addition of amifostine, at an irinotecan dose of 65 mg/m(2) and cisplatin dose of 30 mg/m(2), the DLT was hypocalcemia. Although no objective responses were observed, six patients received at least three courses of therapy. The amounts of platinum adducts (mean +/- SD) were 10 +/- 20 molecules/10(6) nucleotides. The maximum plasma concentrations (C(max)) for free cisplatin and WR-1065 were 4.5 +/- 1.6 micro M and approximately 89 +/- 10 micro M, respectively. The half-life (t(1/2)) for free plasma cisplatin was 25.4 +/- 5.4 min. The initial t(1/2) for plasma WR-1065 was approximately 7 min and terminal t(1/2) approximately 24 min.
  
  
  CONCLUSIONS
  The combination of cisplatin and irinotecan administered weekly for 4 weeks in children with refractory cancer is well tolerated. Amifostine offers some myeloprotection, likely permitting >/=30% dose escalation for irinotecan, when administered in a combination regimen with cisplatin. However, effective antiemetics and calcium supplementation are necessary with the use of amifostine. Further escalation of irinotecan dosing, using these precautions for amifostine administration, may be possible.
authors.affiliation: Department of Pediatric Hematology/Oncology, State University of New York Upstate Medical University, Syracuse, New York 13210, USA.
authors.forename: Abdul-Kader
authors.initials: AK
authors.lastname: Souid
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Dubowy
authors.forename: Susan M
authors.initials: SM
authors.lastname: Blaney
authors.forename: Linda
authors.initials: L
authors.lastname: Hershon
authors.forename: Jim
authors.initials: J
authors.lastname: Sullivan
authors.forename: Wendy D
authors.initials: WD
authors.lastname: McLeod
authors.forename: Mark L
authors.initials: ML
authors.lastname: Bernstein
mesh_terms: D000293:Adolescent; D000328:Adult; D004999:Amifostine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity*; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D015331:Cohort Studies; D018736:DNA Adducts / Q000097:blood; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008657:Metabolic Clearance Rate; D009369:Neoplasms / Q000145:classification / Q000188:drug therapy*; D012449:Safety
chemical_list: D018736:DNA Adducts; D000077146:Irinotecan; D004999:Amifostine; D002945:Cisplatin; D002166:Camptothecin