title: Phase I combination study of trabectedin and capecitabine in patients with advanced malignancies.
abstract: BACKGROUND
  To determine the maximum tolerated dose (MTD), safety and pharmacokinetics of trabectedin with capecitabine in patients with advanced malignancies.
  
  
  METHODS
  In this Phase I, open-label, dose-finding study, patients refractory to standard therapy received trabectedin (3-h intravenous infusion, 0.4-1.3 mg/m(2), day 1) and capecitabine (2,000 or 1,600 mg/m(2)/day orally, days 2-15) every 3 weeks. Standard "3 + 3" dose escalation was used to define the MTD. Antitumor response was assessed every two cycles; adverse events (AEs) were recorded throughout.
  
  
  RESULTS
  Forty patients received 149 cycles of treatment (median 2; range 1-11) at nine dose levels. Gastrointestinal dose-limiting toxicities in two patients at two dose levels with capecitabine at 2,000 mg/m(2)/day prompted dose reduction to 1,600 mg/m(2)/day and initiation of new trabectedin dose escalation at 0.6 mg/m(2). The MTD was capecitabine 1,600 mg/m(2)/day + trabectedin 1.1 mg/m(2). Common grade 3-4 drug-related AEs were neutropenia (20%), nausea (18%), diarrhea (15%) and palmar-plantar erythrodysesthesia (15%). One patient with cholangiocarcinoma achieved a sustained partial response, and 18 patients maintained stable disease (six for ≥6 months).
  
  
  CONCLUSIONS
  The combination of trabectedin and capecitabine is generally well tolerated, without pharmacokinetic interactions, and shows some activity in patients with advanced cancers.
authors.affiliation: University of Colorado Cancer Center, Aurora, CO 80045, USA. lia.gore@ucdenver.edu
authors.forename: Lia
authors.initials: L
authors.lastname: Gore
authors.forename: E
authors.initials: E
authors.lastname: Rivera
authors.forename: M
authors.initials: M
authors.lastname: Basche
authors.forename: S L
authors.initials: SL
authors.lastname: Moulder-Thompson
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: S
authors.initials: S
authors.lastname: Eppers
authors.forename: S
authors.initials: S
authors.lastname: Grolnic
authors.forename: C
authors.initials: C
authors.lastname: O'Bryant
authors.forename: D
authors.initials: D
authors.lastname: Cleere
authors.forename: Y A
authors.initials: YA
authors.lastname: Elsayed
authors.forename: S G
authors.initials: SG
authors.lastname: Eckhardt
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D000069287:Capecitabine; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004149:Dioxoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000077606:Trabectedin; D055815:Young Adult
chemical_list: D004149:Dioxoles; D044005:Tetrahydroisoquinolines; D003841:Deoxycytidine; D000069287:Capecitabine; D000077606:Trabectedin; D005472:Fluorouracil