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


METHODS
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.
Rademaker-Lakhai
Jeany M
JM
Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Louwesweg 6, 1066 EC Amsterdam, the Netherlands. apjli@slz.nl
Horenblas
Simon
S
Meinhardt
Willem
W
Stokvis
Ellen
E
de Reijke
Theo M
TM
Jimeno
José M
JM
Lopez-Lazaro
Luis
L
Lopez Martin
José A
JA
Beijnen
Jos H
JH
Schellens
Jan H M
JH
D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D047630:Depsipeptides / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D008978:Mollusk Venoms; D017430:Prostate-Specific Antigen / Q000032:analysis; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology
D018931:Antineoplastic Agents, Hormonal; D047630:Depsipeptides; D008978:Mollusk Venoms; C097897:kahalalide F; D017430:Prostate-Specific Antigen