title: Phase I trial of sorafenib and gemcitabine in advanced solid tumors with an expanded cohort in advanced pancreatic cancer.
abstract: BACKGROUND
  With its potent inhibitory effects against Raf-1 kinase and vascular endothelial growth factor receptor-2, sorafenib is a novel oral anticancer agent targeting signal transduction and angiogenic pathways. This study is designed to combine sorafenib and gemcitabine due to their compatibility in preclinical models and nonoverlapping clinical toxicities.
  
  
  METHODS
  An initial dose-escalation part of the study enrolled patients with advanced solid tumors, followed by an expanded cohort at the recommended dose for patients with advanced unresectable or metastatic pancreatic cancer. Sorafenib is administered continuously, whereas gemcitabine is given at 1,000 mg/m2 weekly x 7 followed by 1 rest week, then weekly x 3 every 4 weeks.
  
  
  RESULTS
  Forty-two patients have been enrolled overall, including 19 in the dose-escalation part and 23 in the extended pancreatic cancer cohort. Demographics were as follows: male-to-female ratio = 26:16; median age = 61 years (range 39-83 years); Eastern Cooperative Oncology Group performance status 0:1:2 ratio = 16:21:5. The recommended dose of this combination is sorafenib 400 mg twice daily and gemcitabine 1,000 mg/m2. The most frequent grade 3 or 4 adverse events of all causalities were thrombocytopenia (28.6%), lymphopenia (21.4%), lipase elevation (19%), neutropenia (16.7%), and fatigue (14.3%). Antitumor activity was observed in both groups, with 2 (10.5%) confirmed partial responses in ovarian cancer and 12 patients (63.2%) with disease stabilization in the dose-escalation part; 13 patients (56.5%) achieved disease stabilization in the pancreatic cohort. There was no consistent pharmacokinetic drug-to-drug interaction between sorafenib and gemcitabine.
  
  
  CONCLUSIONS
  Sorafenib and gemcitabine are well tolerated in combination; further evaluations in pancreatic and ovarian cancers are warranted.
authors.affiliation: Department of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada M5G 2M9. lillian.siu@uhn.on.ca
authors.forename: Lillian L
authors.initials: LL
authors.lastname: Siu
authors.forename: Ahmad
authors.initials: A
authors.lastname: Awada
authors.forename: Chris H
authors.initials: CH
authors.lastname: Takimoto
authors.forename: Martine
authors.initials: M
authors.lastname: Piccart
authors.forename: Brian
authors.initials: B
authors.lastname: Schwartz
authors.forename: Tom
authors.initials: T
authors.lastname: Giannaris
authors.forename: Chetan
authors.initials: C
authors.lastname: Lathia
authors.forename: Oana
authors.initials: O
authors.lastname: Petrenciuc
authors.forename: Malcolm J
authors.initials: MJ
authors.lastname: Moore
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001557:Benzenesulfonates / Q000493:pharmacokinetics / Q000627:therapeutic use; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D009536:Niacinamide / Q000031:analogs & derivatives; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D010671:Phenylurea Compounds; D011725:Pyridines / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077157:Sorafenib; D000093542:Gemcitabine
chemical_list: D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D003841:Deoxycytidine; D009536:Niacinamide; D000077157:Sorafenib; D000093542:Gemcitabine