title: Randomized phase II study comparing two schedules of everolimus in patients with recurrent/metastatic breast cancer: NCIC Clinical Trials Group IND.163.
abstract: OBJECTIVE
  To evaluate the safety and efficacy of oral everolimus, a mammalian target of rapamycin (mTOR) inhibitor, in two different schedules in minimally pretreated patients with metastatic breast cancer and to explore for possible biologic correlates of response.
  
  
  METHODS
  Patients who received no or one prior chemotherapy regimen for metastatic breast cancer were entered onto this multicenter, noncomparative, randomized phase II study of everolimus 10 mg daily versus 70 mg weekly; the multinomial end points of response and progression were evaluated at 8 weeks. A two-stage accrual design was used, with 15 evaluable patients in each schedule in stage 1. Only daily therapy met criteria for continuing, and another 15 patients were added. pAKT, PTEN, carbonic anhydrase 9, estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) were evaluated for possible correlation with response.
  
  
  RESULTS
  The most common drug-related toxicities were fatigue, rash, anorexia, diarrhea, stomatitis, cough, and pneumonitis. Pneumonitis occurred at higher than expected rates and seemed to be schedule dependent, with the highest incidence on the daily schedule. Response rate with daily therapy was 12% (95% CI, 3.4% to 28.2%) compared with 0% (95% CI, 0.0% to 20.6%) for weekly therapy. Twenty-seven percent of patients on daily therapy discontinued treatment compared with 13% on weekly therapy (16% v 6% with pneumonitis, respectively). No biologic correlates of response could be identified, although there were trends favoring benefit in ER-positive and HER2-negative metastatic breast cancer.
  
  
  CONCLUSIONS
  Oral everolimus has activity in metastatic breast cancer that is schedule dependent. Daily therapy with 10 mg is worthy of further study in this patient population.
authors.affiliation: BC Cancer Agency-Southern Interior, 399 Royal Ave, Kelowna, British Columbia, Canada V1Y 5L3. sellard@bccancer.bc.ca
authors.forename: Susan L
authors.initials: SL
authors.lastname: Ellard
authors.forename: Mark
authors.initials: M
authors.lastname: Clemons
authors.forename: Karen A
authors.initials: KA
authors.lastname: Gelmon
authors.forename: Brian
authors.initials: B
authors.lastname: Norris
authors.forename: Hagen
authors.initials: H
authors.lastname: Kennecke
authors.forename: Stephen
authors.initials: S
authors.lastname: Chia
authors.forename: Kathleen
authors.initials: K
authors.lastname: Pritchard
authors.forename: Andrea
authors.initials: A
authors.lastname: Eisen
authors.forename: Ted
authors.initials: T
authors.lastname: Vandenberg
authors.forename: Marianne
authors.initials: M
authors.lastname: Taylor
authors.forename: Eric
authors.initials: E
authors.lastname: Sauerbrei
authors.forename: Moshe
authors.initials: M
authors.lastname: Mishaeli
authors.forename: David
authors.initials: D
authors.lastname: Huntsman
authors.forename: Wendy
authors.initials: W
authors.lastname: Walsh
authors.forename: Martin
authors.initials: M
authors.lastname: Olivo
authors.forename: Lynn
authors.initials: L
authors.lastname: McIntosh
authors.forename: Lesley
authors.initials: L
authors.lastname: Seymour
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D004305:Dose-Response Relationship, Drug; D000068338:Everolimus; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008875:Middle Aged; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives*
chemical_list: D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D000068338:Everolimus; D020123:Sirolimus