title: Phase I-II study of plitidepsin and dacarbazine as first-line therapy for advanced melanoma.
abstract: BACKGROUND
  This phase I-II trial compared plitidepsin 1-h infusion alone or combined with dacarbazine (DTIC) 1-h infusion as front-line therapy for advanced melanoma.
  
  
  METHODS
  The recommended dose (RD) for plitidepsin/DTIC was defined in the first stage. In the second stage, patients were randomised to receive single-agent plitidepsin 3.2 mg m(-2) (n = 20) on days 1, 8 and 15 every 4 weeks (q4wk) or plitidepsin 2.4 mg m(-2) on days 1, 8 and 15 q4wk combined with DTIC 800 mg m(-2) q4wk (n = 38).
  
  
  RESULTS
  The overall response rate with plitidepsin/DTIC was 21.4%; all responders had normal serum lactate dehydrogenase (LDH) levels and performance status ≤ 1 at baseline. Median progression-free survival (PFS) with plitidepsin/DTIC was 3.3 months in all patients, and 4.3 months in those with baseline normal LDH. No responses occurred with single-agent plitidepsin and median PFS was 1.5 months. Both regimens were well tolerated. Haematological abnormalities were more common and transaminase increases more severe with plitidepsin/DTIC. Treatment-related transaminase increases leading to infusion omission on day 8 were relatively common. No drug-drug pharmacokinetic interactions were found.
  
  
  CONCLUSIONS
  This plitidepsin/DTIC schedule has antitumour activity and manageable toxicity in advanced melanoma. Further evaluation of plitidepsin 2.4 mg m(-2) fortnightly and DTIC 800 mg m(-2) q4wk is recommended.
authors.affiliation: Northern Centre for Cancer Care, Freeman Hospital, Newcastle upon Tyne, NE7 7DN, UK.
authors.forename: R
authors.initials: R
authors.lastname: Plummer
authors.forename: P
authors.initials: P
authors.lastname: Lorigan
authors.forename: E
authors.initials: E
authors.lastname: Brown
authors.forename: R
authors.initials: R
authors.lastname: Zaucha
authors.forename: V
authors.initials: V
authors.lastname: Moiseyenko
authors.forename: L
authors.initials: L
authors.lastname: Demidov
authors.forename: V
authors.initials: V
authors.lastname: Soriano
authors.forename: E
authors.initials: E
authors.lastname: Chmielowska
authors.forename: R
authors.initials: R
authors.lastname: Andrés
authors.forename: G
authors.initials: G
authors.lastname: Kudryavtseva
authors.forename: C
authors.initials: C
authors.lastname: Kahatt
authors.forename: S
authors.initials: S
authors.lastname: Szyldergemajn
authors.forename: S
authors.initials: S
authors.lastname: Extremera
authors.forename: B
authors.initials: B
authors.lastname: de Miguel
authors.forename: M
authors.initials: M
authors.lastname: Cullell-Young
authors.forename: H
authors.initials: H
authors.lastname: Calvert
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D047630:Depsipeptides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D010456:Peptides, Cyclic; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D047630:Depsipeptides; D010456:Peptides, Cyclic; D003606:Dacarbazine; C098980:plitidepsin