title: Phase I clinical and pharmacokinetic study of kahalalide F administered weekly as a 1-hour infusion to patients with advanced solid tumors.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 microg/m(2), 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 microg/m(2). 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 microg/m(2), and the recommended dose for phase II studies was 650 microg/m(2). 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 microg/m(2). Dose-limiting toxicities with weekly kahalalide F 1-h i.v. infusions were transient grade 3/4 increases in blood transaminase levels, and 650 microg/m(2) was declared the recommended dose for phase II studies. This schedule showed a favorable safety profile and hints of antitumor activity.
authors.affiliation: Institut Català d'Oncologia and Hospital Vall d'Hebron, Barcelona, Spain. bpardo@ico.scs.es
authors.forename: Beatriz
authors.initials: B
authors.lastname: Pardo
authors.forename: Luis
authors.initials: L
authors.lastname: Paz-Ares
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.forename: Eva
authors.initials: E
authors.lastname: Ciruelos
authors.forename: Margarita
authors.initials: M
authors.lastname: García
authors.forename: Ramón
authors.initials: R
authors.lastname: Salazar
authors.forename: Ana
authors.initials: A
authors.lastname: López
authors.forename: María
authors.initials: M
authors.lastname: Blanco
authors.forename: Antonio
authors.initials: A
authors.lastname: Nieto
authors.forename: José
authors.initials: J
authors.lastname: Jimeno
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Izquierdo
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Trigo
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D047630:Depsipeptides / Q000008:administration & dosage* / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; C097897:kahalalide F