title: A phase I and pharmacokinetic study of elisidepsin (PM02734) in patients with advanced solid tumors.
abstract: OBJECTIVE
  To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and recommended phase II dose (RD) of elisidepsin.
  
  
  METHODS
  Eligible patients with refractory, advanced solid tumors received elisidepsin as 24-h intravenous infusion every 3 weeks. Pharmacokinetic profiles were analyzed during cycles 1 and 2.
  
  
  RESULTS
  Forty-two patients received elisidepsin at doses from 0.5 to 6.8 mg/m(2). The MTD was 6.8 mg/m(2), and the RD was 5.5 mg/m(2). Cohort expansion at the RD was done at a fixed dose (FD) of 10 mg, considered equivalent to 5.5 mg/m(2). DLTs (reversible grade 3 transaminase increases) occurred at 6.8 mg/m(2) (n = 2 patients), 5.5 mg/m(2) (n = 1), and 10 mg FD (n = 1). One patient with esophageal adenocarcinoma achieved complete response for >38 months, and 12 patients had disease stabilization (8 for ≥3 months). Median time-to-progression for these 12 patients was 4.8 months. Plasma elisidepsin concentrations increased with dose. No drug accumulation between cycles was found. No correlation was observed between body surface area (BSA) and plasma clearance; therefore, elisidepsin was given as flat dose (in mg) in the expansion cohort at the RD and in ongoing clinical trials.
  
  
  CONCLUSIONS
  Elisidepsin is well tolerated with predictable reversible transaminase increases. Encouraging preliminary evidence of antitumor activity was observed.
authors.affiliation: Instituto Catalán de Oncología, L'Hospitalet de Llobregat, Avda. Gran Via 199-203, Barcelona, Spain. ramonsalazar@iconcologia.net
authors.forename: R
authors.initials: R
authors.lastname: Salazar
authors.forename: R J
authors.initials: RJ
authors.lastname: Jones
authors.forename: A
authors.initials: A
authors.lastname: Oaknin
authors.forename: D
authors.initials: D
authors.lastname: Crawford
authors.forename: C
authors.initials: C
authors.lastname: Cuadra
authors.forename: C
authors.initials: C
authors.lastname: Hopkins
authors.forename: M
authors.initials: M
authors.lastname: Gil
authors.forename: C
authors.initials: C
authors.lastname: Coronado
authors.forename: A
authors.initials: A
authors.lastname: Soto-Matos
authors.forename: M
authors.initials: M
authors.lastname: Cullell-Young
authors.forename: J L
authors.initials: JL
authors.lastname: Iglesias Dios
authors.forename: T R J
authors.initials: TR
authors.lastname: Evans
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; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000637:Transaminases / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; C522358:elisidepsin; D000637:Transaminases