Phase I Clinical and Pharmacokinetic Study of Kahalalide F in Patients with Advanced Androgen Refractory Prostate Cancer

• Published in: Clinical cancer research Vol. 11; no. 5; pp. 1854 - 1862
• Main Authors: RADEMAKER-LAKHAI, Jeany M, HORENBLAS, Simon, MEINHARDT, Willem, STOKVIS, Ellen, DE REIJKE, Theo M, JIMENO, José M, LOPEZ-LAZARO, Luis, LOPEZ MARTIN, José A, BEIJNEN, Jos H, SCHELLENS, Jan H. M
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.03.2005
• Subjects: Aged; Aged, 80 and over; Antineoplastic agents; Antineoplastic Agents, Hormonal - pharmacology; Biological and medical sciences; Depsipeptides - administration & dosage; Depsipeptides - adverse effects; Depsipeptides - pharmacokinetics; Drug Resistance, Neoplasm; Elysia rufescens; Humans; Infusions, Intravenous; Male; marine antineoplastics; Maximum Tolerated Dose; Medical sciences; Middle Aged; Mollusk Venoms; Nephrology. Urinary tract diseases; pharmacokinetics; Pharmacology. Drug treatments; Phase I study; Prostate-Specific Antigen - analysis; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - pathology; PSA; Tumors of the urinary system; Urinary tract. Prostate gland; Human; Treatment resistance; Urinary system disease; Prostate disease; Androgen; Advanced stage; Malignant tumor; Sex steroid hormone; Pharmacokinetics; Male genital diseases; Prostate cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-04-1534

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 μg 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 μg per m 2 per day). The maximum tolerated dose on this schedule was 930 μg 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 μg 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 μg per m 2 per day had a partial response with a prostate-specific antigen decline by at least 50% for ≥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 μg per m 2 per day once every 3 weeks.