title: Phase I study of elisidepsin (Irvalec®) in combination with carboplatin or gemcitabine in patients with advanced malignancies.
abstract: OBJECTIVE
  To determine the maximum tolerated dose and the recommended dose (RD) for phase II trials of elisidepsin (Irvalec®) in combination with carboplatin or gemcitabine.
  
  
  METHODS
  Open-label, dose-escalating, two-arm, uncontrolled, phase I study. Patients received carboplatin on Day (D) 1, followed by elisidepsin on D1 and D8, every 3 weeks, or gemcitabine on D1 and D15, followed by elisidepsin on D1 and D15, every 4 weeks. A pharmacokinetic analysis was done from blood samples collected during the first treatment infusion.
  
  
  RESULTS
  Fifteen patients were treated with carboplatin/elisidepsin at doses from 4 AUC/1.0 mg flat dose (FD) to 5 AUC/2.5 mg FD. Two patients had dose-limiting toxicities (DLTs) at 5 AUC/2.0 mg, a dose delay >2 weeks due to grade-2 ALT increase and grade-3 thrombocytopenia, and a D8 infusion omission due to grade-3 ALT increase. The RD was established at 4 AUC/1.0 mg. Toxicity consisted mainly of mild-moderate anorexia, fatigue, and nausea. Twenty-two patients were treated with gemcitabine/elisidepsin at doses from 1,000 mg*m(2)/1.0 mg FD to 1,250 mg*m(2)/7.5 mg FD. Two patients had DLTs at 1,250 mg*m(2)/7.5 mg, both a D15 dose omission due to grade-2 ALT increase. The RD was defined at 1,250 mg*m(2)/5.0 mg. Toxicity consisted mainly of mild-moderate fatigue, pruritus, erythema, and myalgia. No objective response was observed. No relevant pharmacokinetic interaction was detected.
  
  
  CONCLUSIONS
  Infra-optimal doses of elisidepsin and carboplatin and a lack of antitumor activity despite using active drug concentrations in combination with gemcitabine do not warrant further clinical development for these two combinations.
authors.affiliation: AP-HP, Faculté de Medicine Paris Descartes, Hôpital Cochin, Paris, France.
authors.forename: Francois
authors.initials: F
authors.lastname: Goldwasser
authors.forename: Sandrine
authors.initials: S
authors.lastname: Faivre
authors.forename: Jerome
authors.initials: J
authors.lastname: Alexandre
authors.forename: Cinthya
authors.initials: C
authors.lastname: Coronado
authors.forename: Eva M
authors.initials: EM
authors.lastname: Fernández-García
authors.forename: Carmen M
authors.initials: CM
authors.lastname: Kahatt
authors.forename: Pilar García
authors.initials: PG
authors.lastname: Paramio
authors.forename: Jorge Luis Iglesias
authors.initials: JL
authors.lastname: Dios
authors.forename: Bernardo
authors.initials: B
authors.lastname: Miguel-Lillo
authors.forename: Eric
authors.initials: E
authors.lastname: Raymond
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics; D047630:Depsipeptides / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D000093542:Gemcitabine
chemical_list: D047630:Depsipeptides; C522358:elisidepsin; D003841:Deoxycytidine; D016190:Carboplatin; D000093542:Gemcitabine