A phase I trial of depsipeptide (FR901228) in patients with advanced cancer

J Exp Ther Oncol. Nov-Dec 2002;2(6):325-32. doi: 10.1046/j.1359-4117.2002.01039.x.

Abstract

Depsipeptide (FR901228) is a bicyclic peptide isolated from Chromobacterium violaceum that has demonstrated potent in vitro cytotoxic activity against human tumor cell lines and in vivo efficacy against human tumor xenografts. The primary mechanism of action is through inhibition of histone deacetylase. Initial development was halted due to significant cardiac toxicity. Subsequent studies performed at the National Cancer Institute demonstrated administration without cardiotoxicity was possible by varying the schedule of administration. A phase I trial was designed to determine the maximum tolerated dose and toxicity profile when administered as a 4-hour infusion weekly x 3 with one week rest. 33 Patients with advanced, incurable cancers were enrolled into this trial and treated with doses of Depsipeptide ranging from 1 mg/m2 to 17.7 mg/m2. At doses above 5 mg/m2, we observed common symptoms of nausea, vomiting, fatigue, and anorexia. Subtle changes in ECGs were seen in several patients. However, no cardiac enzyme abnormalities or reduction in ejection fraction were observed. The MTD was defined as 13.3 mg/m2 with dose limiting toxicities being grade 3 thrombocytopenia and fatigue. Depsipeptide can be safely administered when given as a 4-hour infusion and further clinical trials are warranted.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Antibiotics, Antineoplastic / administration & dosage*
  • Antibiotics, Antineoplastic / adverse effects
  • Antibiotics, Antineoplastic / pharmacokinetics
  • Depsipeptides*
  • Electrocardiography
  • Enzyme Inhibitors / administration & dosage*
  • Enzyme Inhibitors / adverse effects
  • Enzyme Inhibitors / pharmacokinetics
  • Fatigue / chemically induced
  • Female
  • Histone Deacetylase Inhibitors
  • Humans
  • Infusions, Intravenous
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Peptides, Cyclic / administration & dosage*
  • Peptides, Cyclic / adverse effects
  • Peptides, Cyclic / pharmacokinetics
  • Therapeutics
  • Thrombocytopenia / chemically induced

Substances

  • Antibiotics, Antineoplastic
  • Depsipeptides
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Peptides, Cyclic
  • romidepsin