title: Results of a phase I trial of sorafenib (BAY 43-9006) in combination with oxaliplatin in patients with refractory solid tumors, including colorectal cancer.
abstract: BACKGROUND
  Sorafenib (BAY 43-9006), a multiple kinase inhibitor, has been shown to inhibit tumor growth and tumor angiogenesis by targeting Raf kinase, vascular endothelial growth factor receptor, and platelet-derived growth factor receptor. In phase I studies, sorafenib demonstrated single-agent activity in patients with advanced solid tumors and was successfully combined with oxaliplatin in preclinical studies. This phase I study investigated the safety, pharmacokinetics, and efficacy of sorafenib in combination with oxaliplatin.
  
  
  METHODS
  Twenty-seven patients with refractory solid tumors were enrolled in the initial dose-escalation part (cohorts 1, 2A, and 2B) and 10 additional patients with oxaliplatin-refractory colorectal cancer were subsequently enrolled in an extension part (cohort 3). Oxaliplatin 130 mg/m2 was given on day 1 of a 3-week cycle and oral sorafenib was administered continuously from day 4 of cycle 1 at 200 mg twice daily (cohort 1) or 400 mg twice daily (cohorts 2A, 2B, and 3).
  
  
  RESULTS
  Adverse events were generally mild to moderate and the maximum tolerated dose was not reached. Common adverse events were diarrhea (52% of patients in the dose-escalation part and 20% in the extension part), sensory neuropathy (44% and 20%), and dermatologic toxicities (41% and 80%). No pharmacokinetic interaction between sorafenib and oxaliplatin was detectable. Two patients with gastric cancer had a partial response. Forty-three percent of patients in cohorts 1 and 2A/B and 78% of patients in cohort 3 exhibited stable disease for >or=10 weeks.
  
  
  CONCLUSIONS
  Continuous oral sorafenib 400 mg twice daily was safely combined with oxaliplatin without detectable drug interactions and showed preliminary antitumor activity in this phase I study. This dose is recommended for phase II studies.
authors.affiliation: West German Cancer Center, University of Essen, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Kupsch
authors.forename: Bernhard F
authors.initials: BF
authors.lastname: Henning
authors.forename: Katrin
authors.initials: K
authors.lastname: Passarge
authors.forename: Heike
authors.initials: H
authors.lastname: Richly
authors.forename: Katrin
authors.initials: K
authors.lastname: Wiesemann
authors.forename: Ralf A
authors.initials: RA
authors.lastname: Hilger
authors.forename: Max E
authors.initials: ME
authors.lastname: Scheulen
authors.forename: Olaf
authors.initials: O
authors.lastname: Christensen
authors.forename: Erich
authors.initials: E
authors.lastname: Brendel
authors.forename: Brian
authors.initials: B
authors.lastname: Schwartz
authors.forename: Elke
authors.initials: E
authors.lastname: Hofstra
authors.forename: Rudolf
authors.initials: R
authors.lastname: Voigtmann
authors.forename: Siegfried
authors.initials: S
authors.lastname: Seeber
authors.forename: Dirk
authors.initials: D
authors.lastname: Strumberg
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000008:administration & dosage; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D010671:Phenylurea Compounds; D011725:Pyridines / Q000008:administration & dosage; D000077157:Sorafenib
chemical_list: D001557:Benzenesulfonates; D009944:Organoplatinum Compounds; D010671:Phenylurea Compounds; D011725:Pyridines; D000077150:Oxaliplatin; D009536:Niacinamide; D000077157:Sorafenib