title: Randomized, placebo-controlled, double-blind, phase II study of axitinib plus docetaxel versus docetaxel plus placebo in patients with metastatic breast cancer.
abstract: OBJECTIVE
  This multicenter, randomized, double-blind, phase II study assessed safety and efficacy of axitinib plus docetaxel in metastatic breast cancer (MBC).
  
  
  METHODS
  Women with MBC were randomly assigned 2:1 to receive docetaxel 80 mg/m2 once every 3 weeks plus axitinib 5 mg twice per day (combination arm) or placebo (placebo arm), following a lead-in phase I trial. The primary end point was time to progression (TTP).
  
  
  RESULTS
  In all, 168 patients were enrolled; 112 were randomly assigned to axitinib and 56 to placebo. Median TTP was numerically longer in the combination arm than in the placebo arm (8.1 v 7.1 months), but this difference was not statistically significant (hazard ratio, 1.24; 95% CI, 0.82 to 1.87; one-sided P = .156). The difference in median TTP was greatest among patients who had received prior adjuvant chemotherapy (9.2 v 7.0 months; P = .043, prespecified subgroup analysis). Objective response rate was higher in the combination arm (41.1% v 23.6%; P = .011). The most common grades 3 to 4 treatment-related adverse events (combination/placebo) included diarrhea (10.8%/0%), fatigue (10.8%/5.4%), stomatitis (12.6%/1.8%), mucositis (9.0%/0%), asthenia (7.2%/0%), and hypertension (4.5%/0%). Three patients in the combination arm experienced serious thromboembolic events (one death). Febrile neutropenia was more frequent in the combination arm (15.3% v 7.1%); rates of other hematologic toxicities were comparable. Increased toxicity with axitinib was generally managed by dose reduction and/or growth factor support.
  
  
  CONCLUSIONS
  The addition of axitinib to docetaxel did not improve TTP in first-line MBC treatment. Combination therapy may be more effective in patients previously exposed to adjuvant chemotherapy.
authors.affiliation: University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, 1600 Divisadero Ave, Second Floor, Box 1710, San Francisco, CA 94115, USA. hrugo@medicine.ucsf.edu
authors.forename: Hope S
authors.initials: HS
authors.lastname: Rugo
authors.forename: Alison T
authors.initials: AT
authors.lastname: Stopeck
authors.forename: Anil A
authors.initials: AA
authors.lastname: Joy
authors.forename: Stephen
authors.initials: S
authors.lastname: Chan
authors.forename: Shailendra
authors.initials: S
authors.lastname: Verma
authors.forename: Anna
authors.initials: A
authors.lastname: Lluch
authors.forename: Katherine F
authors.initials: KF
authors.lastname: Liau
authors.forename: Sinil
authors.initials: S
authors.lastname: Kim
authors.forename: Paul
authors.initials: P
authors.lastname: Bycott
authors.forename: Brad
authors.initials: B
authors.lastname: Rosbrook
authors.forename: Angel H
authors.initials: AH
authors.lastname: Bair
authors.forename: Denis
authors.initials: D
authors.lastname: Soulieres
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000077784:Axitinib; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000628:therapy; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000473:pathology / Q000556:secondary*; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D000077143:Docetaxel; D004311:Double-Blind Method; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D007191:Indazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D008875:Middle Aged; D052016:Mucositis / Q000139:chemically induced; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009503:Neutropenia / Q000139:chemically induced; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects; D019851:Thrombophilia / Q000139:chemically induced
chemical_list: D020533:Angiogenesis Inhibitors; D007093:Imidazoles; D007191:Indazoles; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D043823:Taxoids; D000077143:Docetaxel; D000077784:Axitinib; D040262:Receptors, Vascular Endothelial Growth Factor