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 acidcontaining 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 Ag 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 Ag per m 2 per day). The maximum tolerated dose on this schedule was 930 Ag per m 2 per day. The doselimiting toxicity was reversible and asymptomatic Common Toxicity Criteria grade 3 and 4 increases in transaminases. The recommended dose for phase II studies is 560 Ag 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 Ag 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 Ag per m 2 per day once every 3 weeks.

Phase I Clinical and Pharmacokinetic Study of Kahalalide F Administered Weekly as a 1-Hour Infusion to Patients with Advanced Solid Tumors

“…infusion overall agrees with that reported for the other kahalalide F schedule tested to date (12). Both infusion schedules were characterized by linear kinetics for C max and AUC values (at doses up to the recommended dose for phase II studies), a narrow volume of distribution (5.55 liters at the recommended dose with the once-weekly schedule versus 7.16 liters at the recommended dose with the daily schedule), and a short terminal half-life (0.52 h versus 0.47 h, respectively).…”

“…infusion. The starting dose (266 Ag/m per week) was chosen after the finding that kahalalide F total doses of up to 1,600 Ag/m 2 given every 3 weeks (in a fractionated daily  5 schedule) were not associated with dose-limiting or drug-related toxicities in a previous phase I study (12). Initially, three patients were treated in each cohort.…”

“…The dose-limiting toxicities (DLT) were reversible, and asymptomatic grade 3/4 increases in blood levels of transaminases. No other relevant toxicities, including severe hematologic toxicity, were observed, and the recommended dose was 560 Ag/m 2 (12). The aim of this phase I study was to establish the MTD, and the recommended dose of kahalalide F administered as a weekly i.v.…”

Seaweeds as Source of New Bioactive Prototypes

“…The study concluded that the peptide can be given safely as a onehour i.v. infusion during five days at a dose of 560 µg/m 2 per day once every three weeks [12]. Also in the Phase I clinical stage, another group found that the maximum tolerated dose was 800 µg/m 2 to patients with advanced solid tumors [13].…”

ErbB3 expression predicts sensitivity to elisidepsin treatment: in�vitro synergism with cisplatin, paclitaxel and gemcitabine in lung, breast and colon cancer cell lines

“…Based on these observations, and in view of its acceptable low clinical toxicity profile, elisidepsin has been selected for clinical development (6). In phase I trials Irvalec was shown to be safe, well tolerated and with evidence of activity in patients with solid tumors (7)(8)(9).…”