title: Phase 2 trial of everolimus and carboplatin combination in patients with triple negative metastatic breast cancer.
abstract: BACKGROUND
  Rapamycin acts synergistically with platinum agents to induce apoptosis and inhibit proliferation in breast cancer cell lines. Combination of everolimus also known as RAD001 (oral mammalian target of rapamycin (mTOR) inhibitor) and carboplatin may have activity in metastatic triple-negative breast cancer (TNBC).
  
  
  METHODS
  The primary objective of this study was to determine clinical benefit rate (CBR), that is (complete remission (CR) + partial remission (PR) + stable disease (SD) lasting ≥6 months) and the toxicity of everolimus/carboplatin in women with metastatic TNBC. Prior carboplatin was allowed. Treatment consisted of intravenous carboplatin area under the curve (AUC) 6 (later decreased to AUC 5 and subsequently to AUC 4) every 3 weeks with daily 5 mg everolimus.
  
  
  RESULTS
  We enrolled 25 patients in this study. Median age was 58 years. There were one CR, six PRs, seven SDs and eight PDs (progression of disease). CBR was 36% (95% confidence interval (CI) 21.1 to 57.4%). One SD was achieved in a patient progressing on single agent carboplatin. The median progression free survival (PFS) was 3 months (95% CI 1.6 to 4.6 months) and overall survival (OS) was 16.6 months (95% CI 7.3 months to not reached). There were seven patients (28%) with ≥ grade 3 thrombocytopenia; three (12%) with grade 3 neutropenia (no bleeding/febrile neutropenia) and one (4%) with grade 3 anemia. Greater hematological toxicity was seen in the first seven patients treated with carboplatin AUC5/6. After the amendment for starting dose of carboplatin to AUC 4, the regimen was well tolerated with only one out of 18 patients with grade 3 neutropenia and two patients with grade 3 thrombocytopenia. There was only one case of mucositis.
  
  
  CONCLUSIONS
  Everolimus-carboplatin was efficacious in metastatic TNBC. Dose limiting hematological toxicity was observed when AUC5/6 of carboplatin was combined with everolimus. However, carboplatin AUC 4 was well tolerated in combination with everolimus with continuing responses.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01127763.
authors.forename: Jasmeet
authors.initials: J
authors.lastname: Singh
authors.forename: Yelena
authors.initials: Y
authors.lastname: Novik
authors.forename: Stacey
authors.initials: S
authors.lastname: Stein
authors.forename: Matthew
authors.initials: M
authors.lastname: Volm
authors.forename: Marlene
authors.initials: M
authors.lastname: Meyers
authors.forename: Julia
authors.initials: J
authors.lastname: Smith
authors.forename: Coral
authors.initials: C
authors.lastname: Omene
authors.forename: James
authors.initials: J
authors.lastname: Speyer
authors.forename: Robert
authors.initials: R
authors.lastname: Schneider
authors.forename: Komal
authors.initials: K
authors.lastname: Jhaveri
authors.forename: Silvia
authors.initials: S
authors.lastname: Formenti
authors.forename: Victoria
authors.initials: V
authors.lastname: Kyriakou
authors.forename: Benson
authors.initials: B
authors.lastname: Joseph
authors.forename: Judith D
authors.initials: JD
authors.lastname: Goldberg
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Li
authors.forename: Sylvia
authors.initials: S
authors.lastname: Adams
authors.forename: Amy
authors.initials: A
authors.lastname: Tiersten
mesh_terms: D000740:Anemia / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D000068338:Everolimus; D005076:Exanthema / Q000139:chemically induced; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D012074:Remission Induction; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000097:blood / Q000188:drug therapy*
chemical_list: D000068338:Everolimus; D016190:Carboplatin; D020123:Sirolimus