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

¹ The Netherlands Cancer Institute; ² Academic Medical Center, Amsterdam, the Netherlands; ³ Pharma Mar Clinical R&D Sociedad Anónima Unipersonal, Madrid, Spain; and ⁴ Faculty of Pharmaceutical Sciences, Utrecht, the Netherlands

Requests for reprints: Jeany M. Rademaker-Lakhai, Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Louwesweg 6, 1066 EC Amsterdam, the Netherlands. Phone: 31-0-20-512-4481. E-mail: apjli{at}slz.nl.

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 m² 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 m² per day). The maximum tolerated dose on this schedule was 930 µg per m² 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 m² 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 m² 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 m² per day once every 3 weeks.

Key Words: Phase I study • marine antineoplastics • pharmacokinetics • PSA

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