title: Phase I, dose-escalating study of elisidepsin (Irvalec(®)), a plasma membrane-disrupting marine antitumor agent, in combination with erlotinib in patients with advanced malignant solid tumors.
abstract: OBJECTIVE
  To determine the recommended dose for phase II trials of elisidepsin (PM02734, Irvalec®) in combination with erlotinib in patients with advanced malignant solid tumors.
  
  
  METHODS
  Open-label, dose-escalating, phase I study of intravenous elisidepsin administered weekly (days 1, 8 and 15) over 3 h as a flat dose (FD) and daily oral erlotinib, every 3 weeks. A pharmacokinetic analysis was done on blood samples collected around the first elisidepsin infusion.
  
  
  RESULTS
  Thirty patients were treated across six different dose levels (DLs) ranging from elisidepsin 0.33-2.25 mg/erlotinib 100-150 mg. Two patients had dose-limiting toxicities: grade 3 bilirubin increase (DL3: 0.75 mg/150 mg) and a dose omission for > 2 weeks due to grade 3 alanine aminotransferase increase (DL6: 2.25 mg/100 mg). The daily erlotinib dose was escalated to 150 mg at DL2-DL5, but decreased to 100 mg at DL6, as most grade 3 toxicities were related to this agent only. The most frequent toxicities were transaminase increases (related to elisidepsin), and rash, pruritus and diarrhea (related to erlotinib). No objective responses were observed. Despite no overlapping toxicities, the combination was declared unfeasible due to frequent elisidepsin dose delays. The pharmacokinetics of elisidepsin/erlotinib was not significantly different from that of each agent alone.
  
  
  CONCLUSIONS
  The difficulty in combining elisidepsin with the standard dose of erlotinib (150 mg), together with the lack of antitumor activity, made the combination unattractive for further development. The trial was closed without having determined a recommended dose.
authors.affiliation: Montefiore Medical Center, 1695 Eastchester Road, Bronx, NY, 10461, USA. sgoel@montefiore.org.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Goel
authors.affiliation: Instituto Universitario Dexeus, Barcelona, Spain.
authors.forename: Santiago
authors.initials: S
authors.lastname: Viteri
authors.affiliation: Catalan Institute of Oncology, Hospital Germans Trias I Pujol, Badalona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Morán
authors.affiliation: Pharma Mar, S.A., Madrid, Spain.
authors.forename: Cinthya
authors.initials: C
authors.lastname: Coronado
authors.affiliation: Pharma Mar, S.A., Madrid, Spain.
authors.forename: Jorge Luis Iglesias
authors.initials: JL
authors.lastname: Dios
authors.affiliation: Pharma Mar, S.A., Madrid, Spain.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Miguel-Lillo
authors.affiliation: Pharma Mar, S.A., Madrid, Spain.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Fernández-García
authors.affiliation: Catalan Institute of Oncology, Hospital Germans Trias I Pujol, Badalona, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Rosell
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D047630:Depsipeptides / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D047630:Depsipeptides; C522358:elisidepsin; D000069347:Erlotinib Hydrochloride
keywords: Combination; Dose-limiting toxicities; Erlotinib; PM02734; Phase I