title: Phase I study of the safety and pharmacokinetics of trabectedin with docetaxel in patients with advanced malignancies.
abstract: OBJECTIVE
  Combination therapy with trabectedin and docetaxel was evaluated in patients with advanced malignancies.
  
  
  METHODS
  In this open-label phase 1 study, docetaxel (60 or 75 mg/m(2); 1-h intravenous infusion) was given on day 1 of a 21-day cycle in combination with escalating doses of trabectedin (0.4-1.3 mg/m(2) by 3-h intravenous infusion, 1 h after docetaxel) and prophylactic granulocyte colony-stimulating factor (G-CSF). Maximum tolerated dose (MTD) as primary objective and safety, plasma pharmacokinetics, and antitumor activity as secondary objectives were assessed.
  
  
  RESULTS
  Patients (N = 49) received a median of four cycles of treatment. MTD was 1.3 mg/m(2) trabectedin and 60 mg/m(2) docetaxel for patients with limited and 1.1 mg/m(2) trabectedin and 60 mg/m(2) docetaxel for patients with unlimited prior chemotherapy. Dose-limiting toxicities (during cycle 1) included elevated alanine aminotransferase (ALT) and fatigue in patients with limited prior chemotherapy and elevated ALT and febrile neutropenia in those with unlimited prior chemotherapy. The most common drug-related adverse events were nausea (65 %), fatigue (63 %), and neutropenia (53 %). One patient achieved a complete response. Thirty patients had stable disease, and 11 had stable disease for ≥6 months. Pharmacokinetic results for trabectedin plus docetaxel were similar to those previously reported for the single agents.
  
  
  CONCLUSIONS
  In patients with previously treated, advanced malignancies, the combination of therapeutic doses of trabectedin and docetaxel showed clinical activity and was tolerable with prophylactic G-CSF, with no evidence of clinically important drug interactions.
authors: Department of Medical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA, margaret.vonmehren@fccc.edu.
authors: Margaret
authors: M
authors: von Mehren
authors: Michael
authors: M
authors: Bookman
authors: Neal J
authors: NJ
authors: Meropol
authors: Louis M
authors: LM
authors: Weiner
authors: Eric
authors: E
authors: Sherman
authors: Jinhui
authors: J
authors: Li
authors: Roland
authors: R
authors: Knoblauch
authors: Trilok
authors: T
authors: Parekh
authors: Roger B
authors: RB
authors: Cohen
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D004149:Dioxoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000077606:Trabectedin
chemical_list: D004149:Dioxoles; D043823:Taxoids; D044005:Tetrahydroisoquinolines; D016179:Granulocyte Colony-Stimulating Factor; D000077143:Docetaxel; D000077606:Trabectedin