Phase I and pharmacokinetic study of the topoisomerase II catalytic inhibitor fostriecin

Br J Cancer. 1999 Feb;79(5-6):882-7. doi: 10.1038/sj.bjc.6690141.

Abstract

We conducted a phase I and pharmacokinetic study of the topoisomerase II catalytic inhibitor fostriecin. Fostriecin was administered intravenously over 60 min on days 1-5 at 4-week intervals. Dose was escalated from 2 mg m(-2) day(-1) to 20 mg m(-2) day(-1) in 20 patients. Drug pharmacokinetics was analysed with high performance liquid chromatography with UV-detection. Plasma collected during drug administration was tested in vitro for growth inhibition of a teniposide-resistant small-cell lung cancer (SCLC) cell line. The predominant toxicities were elevated liver transaminases (maximum common toxicity criteria (CTC) grade 4) and serum creatinine (maximum CTC grade 2). These showed only a limited increase with increasing doses, often recovered during drug administration and were fully reversible. Duration of elevated alanine-amino transferase (ALT) was dose-limiting in one patient at 20 mg m(-2). Other frequent toxicities were grade 1-2 nausea/vomiting, fever and mild fatigue. Mean fostriecin plasma half-life was 0.36 h (initial; 95% CI, 0-0.76 h) and 1.51 h (terminal; 95% CI, 0.41-2.61 h). A metabolite, most probably dephosphorylated fostriecin, was detected in plasma and urine. No tumour responses were observed, but the plasma concentrations reached in the patients were insufficient to induce significant growth inhibition in vitro. The maximum tolerated dose (MTD) has not been reached, because drug supply was stopped at the 20 mg m(-2) dose level. However, further escalation seems possible and is warranted to achieve potentially effective drug levels. Fostriecin has a short plasma half-life and longer duration of infusion should be considered.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I

MeSH terms

  • Adult
  • Aged
  • Alanine Transaminase / blood
  • Alkenes / adverse effects
  • Alkenes / pharmacokinetics
  • Alkenes / toxicity
  • Antibiotics, Antineoplastic / adverse effects*
  • Antibiotics, Antineoplastic / pharmacokinetics*
  • Antibiotics, Antineoplastic / toxicity
  • Aspartate Aminotransferases / blood
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Small Cell
  • Colorectal Neoplasms / drug therapy
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm
  • Female
  • Half-Life
  • Humans
  • Lung Neoplasms / drug therapy
  • Male
  • Metabolic Clearance Rate
  • Middle Aged
  • Neoplasms / blood
  • Neoplasms / drug therapy*
  • Polyenes
  • Pyrones
  • Teniposide / toxicity
  • Topoisomerase II Inhibitors
  • Tumor Cells, Cultured

Substances

  • Alkenes
  • Antibiotics, Antineoplastic
  • Polyenes
  • Pyrones
  • Topoisomerase II Inhibitors
  • Teniposide
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • fostriecin