Phase I clinical and pharmacokinetic study of kahalalide F in patients with advanced androgen refractory prostate cancer.

Abstract

PURPOSE:

The purpose is to determine the maximum tolerated dose, profile of adverse events, and dose-limiting toxicity of Kahalalide F (KF) in patients with androgen refractory prostate cancer. Furthermore, the pharmacokinetics after KF administration and preliminary antitumor activity were evaluated. KF is a dehydroaminobutyric acid-containing peptide isolated from the marine herbivorous mollusk, Elysia rufescens.

EXPERIMENTAL DESIGN:

Adult patients with advanced or metastatic androgen refractory prostate cancer received KF as an i.v. infusion over 1 hour, during five consecutive days every 3 weeks. The starting dose was 20 microg per m(2) per day. Clinical pharmacokinetics studies were done in all patients using noncompartmental analysis. Prostate-specific antigen levels were evaluated as a surrogate marker for activity against prostate cancer.

RESULTS:

Thirty-two patients were treated at nine dose levels (20-930 microg per m(2) per day). The maximum tolerated dose on this schedule was 930 microg per m(2) per day. The dose-limiting toxicity was reversible and asymptomatic Common Toxicity Criteria grade 3 and 4 increases in transaminases. The recommended dose for phase II studies is 560 microg per m(2) per day. Pharmacokinetics analysis revealed dose linearity up to the recommended dose. Thereafter, a more than proportional increase was observed. Elimination was rapid with a mean (SD) terminal half-life (t(1/2)) of 0.47 hour (0.11 hour). One patient at dose level 80 microg per m(2) per day had a partial response with a prostate-specific antigen decline by at least 50% for > or =4 weeks. Five patients showed stable disease.

CONCLUSIONS:

KF can be given safely as a 1-hour i.v. infusion during five consecutive days at a dose of 560 microg per m(2) per day once every 3 weeks.

• Authors: Jeany M Rademaker-Lakhai, Simon Horenblas, Willem Meinhardt, Ellen Stokvis, Theo M de Reijke, José M Jimeno, Luis Lopez-Lazaro, José A Lopez Martin, Jos H Beijnen, Jan H M Schellens
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 11 Issue 5 Pg. 1854-62 (Mar 01 2005) ISSN: 1078-0432 [Print] United States
• PMID: 15756010 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Hormonal
• Depsipeptides
• Mollusk Venoms
• kahalalide F
• Prostate-Specific Antigen

Topics

• Aged
• Aged, 80 and over
• Antineoplastic Agents, Hormonal (pharmacology)
• Depsipeptides (administration & dosage, adverse effects, pharmacokinetics)
• Drug Resistance, Neoplasm
• Humans
• Infusions, Intravenous
• Male
• Maximum Tolerated Dose
• Middle Aged
• Mollusk Venoms
• Prostate-Specific Antigen (analysis)
• Prostatic Neoplasms (drug therapy, pathology)