title: Combination therapy: intermittent sorafenib with bevacizumab yields activity and decreased toxicity.
abstract: BACKGROUND
  We previously reported preliminary results of our phase I study of continuous daily sorafenib with bevacizumab every other week for solid tumours. Toxicity was moderate, leading to additional dose levels (DL) testing intermittent sorafenib dosing.
  
  
  METHODS
  Seventeen patients with advanced solid tumours were treated on three additional DLs testing sorafenib days 1-5 per week. Dose level 4 was sorafenib 200 mg twice daily (b.i.d.) and bevacizumab 5 mg kg(-1). DL5 alternated between bevacizumab 10 mg kg(-1)-sorafenib 200 mg b.i.d. (A) and sorafenib 400 mg b.i.d. with bevacizumab 5 mg kg(-1) (B). Outcome and toxicity data from 19 epithelial ovarian cancer (EOC) patients from DL 1-5 were analysed.
  
  
  RESULTS
  Fewer patients required sorafenib dose reduction with the intermittent schedule (41 vs 74% daily, P=0.01). Hand-foot skin reaction (HFSR) remained the primary cause of dose reduction (n=5). Partial responses (12%) or disease stabilisation > or =4 months (53%; median 6 (4-26)) occurred in most patients on the intermittent schedule. Partial response occurred in 47% EOC patients treated in pooled analysis of duration 4-37 months.
  
  
  CONCLUSIONS
  Intermittent sorafenib dosing with bevacizumab has promising clinical activity and less sorafenib dose reduction and side effects, but does not ameliorate HFSR. We are conducting a phase II clinical trial with intermittent sorafenib and bevacizumab in patients with EOC.
authors.affiliation: Medical Ovarian Cancer Team, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
authors.forename: J-M
authors.initials: JM
authors.lastname: Lee
authors.forename: G A
authors.initials: GA
authors.lastname: Sarosy
authors.forename: C M
authors.initials: CM
authors.lastname: Annunziata
authors.forename: N
authors.initials: N
authors.lastname: Azad
authors.forename: L
authors.initials: L
authors.lastname: Minasian
authors.forename: H
authors.initials: H
authors.lastname: Kotz
authors.forename: J
authors.initials: J
authors.lastname: Squires
authors.forename: N
authors.initials: N
authors.lastname: Houston
authors.forename: E C
authors.initials: EC
authors.lastname: Kohn
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000008:administration & dosage / Q000009:adverse effects; D000068258:Bevacizumab; D005260:Female; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy*; D009536:Niacinamide / Q000031:analogs & derivatives; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D010671:Phenylurea Compounds; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects; D000077157:Sorafenib
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000068258:Bevacizumab; D000077157:Sorafenib