title: Phase I and pharmacokinetic study of aplidine, a new marine cyclodepsipeptide in patients with advanced malignancies.
abstract: OBJECTIVE
  To establish the safety, pharmacokinetic parameters, maximum-tolerated dose, and recommended dose of aplidine, a novel marine cyclodepsipeptide, in patients with advanced cancer.
  
  
  METHODS
  Using a modified Fibonacci method, we performed a phase I and pharmacokinetic study of aplidine administered as a 24-hour intravenous infusion every 2 weeks.
  
  
  RESULTS
  Sixty-seven patients received aplidine at a dose ranging from 0.2 to 8 mg/m(2). Dose-limiting myotoxicity corresponding to grade 2 to 3 creatine phosphokinase elevation and grade 1 to 2 myalgia and muscle weakness occurred in two of six patients at 6 mg/m(2). No cardiac toxicity was observed. Electron microscopy analysis showed the disappearance of thick filaments of myosin. Grade 3 muscle toxicity occurred in three of 14 patients at the recommended dose of 5 mg/m(2) and seemed to be more readily reversible with oral carnitine (1 g/10 kg). Therefore, dose escalation was resumed using carnitine prophylactically, allowing an increase in the recommended dose to 7 mg/m(2). Other toxicities were nausea and vomiting, diarrhea, asthenia, and transaminase elevation with mild hematologic toxicity. Aplidine displayed a long half-life (21 to 44 hours), low clearance (45 to 49 L/h), and a high volume of distribution (1,036 to 1,124 L) with high interpatient variability in plasma, whereas in whole blood, clearance ranged from 3.0 to 6.2 L/h. Minor responses and prolonged tumor stabilizations were observed in patients with medullary thyroid carcinoma.
  
  
  CONCLUSIONS
  Muscle toxicity was dose limiting in this study. Recommended doses of aplidine were 5 and 7 mg/m(2) without and with carnitine, respectively. The role of carnitine will be further explored in phase II studies.
authors.affiliation: Department of Medicine, Institute Gustave-Roussy, Villejuif, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Faivre
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Chièze
authors.forename: Catherine
authors.initials: C
authors.lastname: Delbaldo
authors.forename: Nora
authors.initials: N
authors.lastname: Ady-Vago
authors.forename: Cecilia
authors.initials: C
authors.lastname: Guzman
authors.forename: Luis
authors.initials: L
authors.lastname: Lopez-Lazaro
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Lozahic
authors.forename: José
authors.initials: J
authors.lastname: Jimeno
authors.forename: Fernando
authors.initials: F
authors.lastname: Pico
authors.forename: Jean Pierre
authors.initials: JP
authors.lastname: Armand
authors.forename: José Antonio Lopez
authors.initials: JA
authors.lastname: Martin
authors.forename: Eric
authors.initials: E
authors.lastname: Raymond
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics*; D002331:Carnitine / Q000627:therapeutic use; D047630:Depsipeptides / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D010456:Peptides, Cyclic; D014803:Vitamin B Complex / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; D010456:Peptides, Cyclic; D014803:Vitamin B Complex; D002331:Carnitine; C098980:plitidepsin