title: A phase 3 tRial comparing capecitabinE in combination with SorafenIb or pLacebo for treatment of locally advanced or metastatIc HER2-Negative breast CancEr (the RESILIENCE study): study protocol for a randomized controlled trial.
abstract: BACKGROUND
  Sorafenib is an oral multikinase inhibitor with antiangiogenic/antiproliferative activity. A randomized phase 2b screening trial in human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer demonstrated a significant improvement in progression-free survival (PFS) when sorafenib was added to capecitabine versus placebo (median 6.4 versus 4.1 months; hazard ratio = 0.58; P = 0.001). Most drug-related adverse events were Grade 1/2 in severity with the exception of Grade 3 hand-foot skin reaction/syndrome (44% versus 14%, respectively). These results suggest a role for the combination of sorafenib and capecitabine in breast cancer and supported a phase 3 confirmatory trial. Here we describe RESILIENCE - a multinational, double-blind, randomized, placebo-controlled, phase 3 trial - assessing the addition of sorafenib to first- or second-line capecitabine in advanced HER2-negative breast cancer.
  
  
  METHODS
  Eligibility criteria include ≥18 years of age, ≤1 prior chemotherapy regimen for metastatic disease, and resistant to/failed taxane and anthracycline or no indication for further anthracycline. Prior treatment with a vascular endothelial growth factor inhibitor is not allowed. Patients with significant cardiovascular disease or active brain metastases are not eligible. Patients are stratified by hormone-receptor status, geographic region, and prior metastatic chemotherapy status and randomized (1:1) to capecitabine (1000 mg/m2 orally twice daily (BID), days 1 to 14 of 21) in combination with sorafenib (orally BID, days 1 to 21, total dose 600 mg/day) or matching placebo. Capecitabine and sorafenib/placebo doses can be escalated to 1250 mg/m2 BID and 400 mg BID, respectively, as tolerated, or reduced to manage toxicity. Dose re-escalation after a reduction is allowed for sorafenib/placebo but not for capecitabine. This dosing algorithm was designed to mitigate dermatologic and other toxicity, in addition to detailed guidelines for prophylactic and symptomatic treatment. Radiographic assessment is every 6 weeks for 36 weeks, and every 9 weeks thereafter. The primary endpoint is PFS by blinded independent central review (Response Evaluation Criteria in Solid Tumors 1.1 criteria). Secondary endpoints include overall survival, time to progression, overall response rate, duration of response, and safety. Enrollment began in November 2010 with a target of approximately 519 patients.
  
  
  CONCLUSIONS
  RESILIENCE will provide definitive PFS data for the combination of sorafenib and capecitabine in advanced HER2-negative breast cancer and better characterize the benefit-to-risk profile.
  
  
  BACKGROUND
  Clinicaltrials.gov, NCT01234337.
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. baselgaj@MSKCC.ORG
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.forename: Frederico
authors.initials: F
authors.lastname: Costa
authors.forename: Henry
authors.initials: H
authors.lastname: Gomez
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Hudis
authors.forename: Bernardo
authors.initials: B
authors.lastname: Rapoport
authors.forename: Henri
authors.initials: H
authors.lastname: Roche
authors.forename: Lee S
authors.initials: LS
authors.lastname: Schwartzberg
authors.forename: Oana
authors.initials: O
authors.lastname: Petrenciuc
authors.forename: Minghua
authors.initials: M
authors.lastname: Shan
authors.forename: William J
authors.initials: WJ
authors.lastname: Gradishar
mesh_terms: D000284:Administration, Oral; D000465:Algorithms; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D000069287:Capecitabine; D002985:Clinical Protocols; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D009361:Neoplasm Invasiveness; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D018579:Patient Selection; D010671:Phenylurea Compounds / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D012107:Research Design; D000077157:Sorafenib; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D000069287:Capecitabine; D003841:Deoxycytidine; D005472:Fluorouracil; D009536:Niacinamide; D010671:Phenylurea Compounds; D018719:Erb-b2 Receptor Tyrosine Kinases; D000077157:Sorafenib; C508053:ERBB2 protein, human