Phase I clinical and pharmacologic study of weekly cisplatin and irinotecan combined with amifostine for refractory solid tumors

Abdul Kader Souid, Ronald L. Dubowy, Susan M. Blaney, Linda Hershon, Jim Sullivan, Wendy D. McLeod, Mark L. Bernstein

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)

Abstract

Purpose: 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. Patients and methods: Cisplatin, at a fixed dose of 30 mg/m2, and escalating doses of irinotecan (starting dose, 40 mg/m2) 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/m2) 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/m2) was 50 mg/m2. The DLTs of this combination were neutropenia and thrombocytopenia. With the addition of amifostine, at an irinotecan dose of 65 mg/m2 and cisplatin dose of 30 mg/m2, 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/106 nucleotides. The maximum plasma concentrations (Cmax) for free cisplatin and WR-1065 were 4.5 ± 1.6 μM and ∼89 ± 10 μM, respectively. The half-life (t1/2) for free plasma cisplatin was 25.4 ± 5.4 min. The initial t1/2 for plasma WR-1065 was ∼7 min and terminal t1,2 ∼24 min. Conclusion: 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.

Original languageEnglish
Pages (from-to)703-710
Number of pages8
JournalClinical Cancer Research
Volume9
Issue number2
Publication statusPublished - Feb 1 2003
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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