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

Abstract

Purpose: A dose-escalation, phase I study evaluated the safety, pharmacokinetics, and efficacy of a weekly 1-h regimen of kahalalide F, a cyclic depsipeptide isolated from the marine mollusk Elysia rufescens, in adult patients with advanced solid tumors and no standard treatment available. Experimental Design: Patients received an i.v. 1-h infusion of kahalalide F once weekly until disease progression or unacceptable toxicity. The starting kahalalide F dose was 266 μg/m2, and dose escalation proceeded based on the worst toxicity found in the previous cohort. Results: Thirty-eight patients were enrolled at three Spanish institutions and received once-weekly kahalalide F 1-h infusions at doses between 266 and 1,200 μg/m2. Dose-limiting toxicities consisted of transient grade 3/4 increases in transaminase blood levels. The maximum tolerated dose for this kahalalide F schedule was 800 μg/m2, and the recommended dose for phase II studies was 650 μg/m2. No accumulated toxicity was found. One patient with malignant melanoma had unconfirmed partial response, one patient with metastatic lung adenocarcinoma had minor response, and six patients with different types of metastatic solid tumors had stable disease for 2.8 to 12.7 months. The noncompartmental pharmacokinetics of this kahalalide F schedule was linear and showed a narrow distribution and short body residence. The transaminitis associated with kahalalide F was dose dependent. Conclusions: The maximum tolerated dose was 800 μg/m2. Dose-limiting toxicities with weekly kahalalide F 1-h i.v. infusions were transient grade 3/4 increases in blood transaminase levels, and 650 μg/m2 was declared the recommended dose for phase II studies. This schedule showed a favorable safety profile and hints of antitumor activity.

First-in-human, phase I study of elisidepsin (PM02734) administered as a 30-min or as a 3-hour intravenous infusion every three weeks in patients with advanced solid tumors

“…Transaminase increases were also reported in phase I trials with the related compound kahalalide F [24][25][26]. An evaluation done with data from the entire clinical development program of elisidepsin, including phase I and II data, showed no serious liver dysfunction as related to elisidepsin; no patients qualified for Hy's law criteria [23].…”

Seaweeds as Source of New Bioactive Prototypes

“…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]. Recently, a group evaluated the effect of demographics and pathophysiologically relevant factors on KF pharmacokinetic parameters, however, no clinically relevant covariates were identified [14].…”

Antitumour Effect of Cyclodepsipeptides from Marine Sponges

“…[10]. In phase I and II clinical trials, kahalalide F provided a benefit to patients with advanced androgen-refractory prostate cancer and other advanced tumours [11][12][13][14]. Thus, marine natural compounds with cyclodepsipeptidic structure are of great interest in drug discovery.…”