title: Phase I Trial of Everolimus and Capecitabine in Metastatic HER2-Breast Cancer.
abstract: The mammalian target of rapamycin (mTOR) pathway is a driver of breast tumorigenesis. The mTOR inhibitor everolimus reverses antihormonal therapy resistance and is an approved therapy for metastatic breast cancer. A synergistic effect with fluoropyrimidine has been suggested. The present study evaluated the safety and tolerability of an all-oral combination of everolimus and capecitabine for metastatic breast cancer (MBC).
  
  
  
  MBC patients naive to capecitabine and mTOR inhibitors who had received ≤ 3 previous chemotherapy regimens in the metastatic setting were eligible for the present study. The patients were scheduled to receive capecitabine 825 mg/m2twice daily for 14 days in a 21-day cycle, combined with everolimus in 5 separate dose cohorts: 2.5 mg every other day, 2.5 mg daily, 5 mg daily, 7.5 mg daily, and 10 mg daily. A 3+3 design was used. The maximum tolerated dose was based on the dose-limiting toxicity of everolimus plus capecitabine.
  
  
  
  A total of 18 patients were enrolled in the present trial. The median age was 58 years. Most had received previous anthracycline (83%) and taxane (94%) therapy. The maximum tolerated dose was everolimus 7.5 mg daily and capecitabine 825 mg/m2. The incidence of grade 3 events was low and mainly hematologic in nature. One incident each of grade 4 neutropenia, thrombocytopenia, hyperglycemia, and mucositis occurred. No grade 5 events occurred. The clinical benefit rate was 50%. The median progression-free survival was 196 days, and the median overall survival was 569 days.
  
  
  
  The all-oral regimen of everolimus with capecitabine is active and well tolerated, with encouraging results for progression-free survival, overall survival, and clinical benefit rate in patients with MBC.
authors.affiliation: Division of Oncology, Department of Internal Medicine, University of Tennessee West Cancer Center, Germantown, TN. Electronic address: gvidal@westclinic.com.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Vidal
authors.affiliation: Division of Oncology, Stanford University School of Medicine, Stanford, CA.
authors.forename: Mary
authors.initials: M
authors.lastname: Chen
authors.affiliation: Division of Oncology, Stanford University School of Medicine, Stanford, CA.
authors.forename: Shruti
authors.initials: S
authors.lastname: Sheth
authors.affiliation: Diablo Valley Oncology and Hematology Medical Group, Pleasant Hill, CA.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Svahn
authors.affiliation: Division of Oncology, Stanford University School of Medicine, Stanford, CA.
authors.forename: Ellie
authors.initials: E
authors.lastname: Guardino
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality; D000069287:Capecitabine / Q000008:administration & dosage / Q000009:adverse effects; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D016896:Treatment Outcome
chemical_list: D000069287:Capecitabine; D000068338:Everolimus
keywords: 5-FU; Metastatic breast cancer; Phase 1; Tolerable; mTOR inhibitor