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

Authors' Affiliations: ¹ Institut Català d'Oncologia and ² Hospital Vall d'Hebron, Barcelona, Spain; and ³ Hospital Universitario 12 de Octubre and ⁴ PharmaMar R&D, Colmenar Viejo, Madrid, Spain

Requests for reprints: Beatriz Pardo, Institut Català d'Oncologia, Av. Gran Via s/n, km. 2.7, 08907-L'Hospitalet de Llobregat, Barcelona, Spain. Phone: 34932607744; Fax: 34932607741; E-mail: bpardo{at}ico.scs.es.

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.