title: Phase I clinical and pharmacokinetic study of plitidepsin as a 1-hour weekly intravenous infusion in patients with advanced solid tumors.
abstract: OBJECTIVE
  Plitidepsin, given as a 1-hour weekly i.v. infusion for 3 consecutive weeks during a 4-week treatment cycle, was investigated in patients with solid tumors to determine the maximum tolerated dose and the recommended dose (RD) using this administration schedule.
  
  
  METHODS
  Consecutive cohorts of patients with metastatic solid tumors or non-Hodgkin's lymphomas were to be treated at escalating doses of plitidepsin in a conventional phase I study including pharmacokinetic analyses of plitidepsin in plasma, whole blood, and blood cell pellets.
  
  
  RESULTS
  Forty-nine patients with solid tumors were enrolled, and 48 were treated with plitidepsin (doses from 0.133 to 3.6 mg/m2/week). Dose-limiting toxicities (defining 3.6 mg/m2/week as the maximum tolerated dose) included myalgia, increased creatine phosphokinase levels, and sustained grade 3/4 increases of hepatic enzyme levels. The RD was established at 3.2 mg/m2/week. The most common toxicities were fatigue, vomiting/nausea, anorexia, injection site reaction, and pain, mostly of mild or moderate severity. Muscular toxicity manifested by mild-moderate myalgia, weakness, and/or creatine phosphokinase elevations occurred in approximately 25% of patients and seemed to be dose related. Transient transaminase elevations were frequent but achieved grade 3 or 4 in only approximately 10% of patients. Plitidepsin lacked significant hematologic toxicity. No complete or partial tumor responses were observed; however, five patients had disease stabilization (including one patient with medullary thyroid carcinoma with an unconfirmed partial response and one patient with renal carcinoma with major tumor shrinkage in lung metastases). Pharmacokinetic results for the RD indicated a long plasma half-life give value (16.8 +/- 7.7 hour) and a high volume of distribution value (525.2 +/- 219.3 L).
  
  
  CONCLUSIONS
  The recommended dose for plitidepsin given as a weekly 1-hour schedule was 3.2 mg/m2/week. Muscular and liver toxicity were dose limiting at 3.6 mg/m2/week. Additional evaluation of this dose dense schedule is warranted.
authors.affiliation: Department of Clinical Oncology, Catalan Institute of Oncology, Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Izquierdo
authors.forename: Angela
authors.initials: A
authors.lastname: Bowman
authors.forename: Margarita
authors.initials: M
authors.lastname: García
authors.forename: Duncan
authors.initials: D
authors.lastname: Jodrell
authors.forename: Marisa
authors.initials: M
authors.lastname: Martinez
authors.forename: Beatriz
authors.initials: B
authors.lastname: Pardo
authors.forename: Javier
authors.initials: J
authors.lastname: Gómez
authors.forename: José A
authors.initials: JA
authors.lastname: López-Martin
authors.forename: José
authors.initials: J
authors.lastname: Jimeno
authors.forename: José R
authors.initials: JR
authors.lastname: Germá
authors.forename: John F
authors.initials: JF
authors.lastname: Smyth
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D047630:Depsipeptides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D010456:Peptides, Cyclic
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; D010456:Peptides, Cyclic; C098980:plitidepsin