title: Sorafenib Plus Ixabepilone as First-Line Treatment of Metastatic HER2-Negative Breast Cancer: A Sarah Cannon Research Institute Phase I/II Trial.
abstract: The purposes of the present phase I/II trial were (1) to define tolerable doses of ixabepilone and sorafenib when used in combination and (2) to evaluate the efficacy and toxicity of this combination in the treatment of patients with human epidermal growth factor receptor-negative metastatic breast cancer (MBC).
  
  
  
  The eligible patients had human epidermal growth factor receptor-negative MBC and had not received previous chemotherapy in the metastatic setting. All patients received ixabepilone intravenously on day 1 of each 21-day treatment cycle; sorafenib was administered orally twice daily. Patients in phase II received the maximum doses identified in phase I. The patients were reevaluated after the completion of 3 treatment cycles; treatment continued until disease progression or intolerable toxicity. A total of 67 patients were required in phase II to demonstrate increased median progression-free survival from 4.2 to 6.2 months (90% power, α = 0.05).
  
  
  
  Ten patients entered the phase I portion; the maximum tolerated doses were ixabepilone 32 mg/m(2) and sorafenib 400 mg orally twice daily. A total of 76 patients were treated at the phase II dose. The median progression-free survival was 4.8 months (95% confidence interval, 3.5-6.3 months). The overall response rate was 37%. The regimen was difficult to tolerate for many patients; 20 patients discontinued because of toxicity, and dose reductions were frequent. The common toxicities included neutropenia, fatigue, rash, and neuropathy.
  
  
  
  The combination of ixabepilone and sorafenib was poorly tolerated as first-line treatment of patients with MBC. The activity of the combination was similar to the activity previously reported with single-agent ixabepilone or taxanes. Further development of this combination is not recommended.
authors.affiliation: Sarah Cannon Research Institute, Nashville, TN; Tennessee Oncology, PLLC, Nashville, TN. Electronic address: dyardley@tnonc.com.
authors.forename: Denise A
authors.initials: DA
authors.lastname: Yardley
authors.affiliation: Tennessee Oncology, PLLC, Nashville, TN.
authors.forename: Natalie
authors.initials: N
authors.lastname: Dickson
authors.affiliation: Oncology Hematology Care, Cincinnati, OH.
authors.forename: David
authors.initials: D
authors.lastname: Drosick
authors.affiliation: Sarah Cannon Research Institute, Nashville, TN.
authors.forename: Chris
authors.initials: C
authors.lastname: Earwood
authors.affiliation: Mercy Hospital, Portland, ME.
authors.forename: Roger
authors.initials: R
authors.lastname: Inhorn
authors.affiliation: Tennessee Oncology, PLLC, Nashville, TN.
authors.forename: Patrick
authors.initials: P
authors.lastname: Murphy
authors.affiliation: Sarah Cannon Research Institute, Nashville, TN; Tennessee Oncology, PLLC, Nashville, TN.
authors.forename: John D
authors.initials: JD
authors.lastname: Hainsworth
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality; D018572:Disease-Free Survival; D034261:Epothilones / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage* / Q000009:adverse effects; D018719:Erb-b2 Receptor Tyrosine Kinases; D000077157:Sorafenib; D016896:Treatment Outcome
chemical_list: D034261:Epothilones; D009536:Niacinamide; D010671:Phenylurea Compounds; D018719:Erb-b2 Receptor Tyrosine Kinases; D000077157:Sorafenib; C508053:ERBB2 protein, human; C430592:ixabepilone
keywords: First line treatment for breast cancer; HER2-negative breast cancer; Metastatic breast cancer; Phase I; Phase II