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

Abstract

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. 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. 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. 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.