title: A phase 1 study of weekly everolimus (RAD001) in combination with docetaxel in patients with metastatic breast cancer.
abstract: BACKGROUND
  Inhibition of mammalian target of rapamycin with everolimus may improve the efficacy of taxanes. Everolimus and docetaxel are both metabolized by CYP3A4, which could result in a pharmacokinetic (PK) interaction.
  
  
  METHODS
  Fifteen patients with metastatic breast cancer were treated with docetaxel (doses of 40-75 mg/m(2) intravenously on day 1 of a 21-day cycle) in combination with everolimus (doses ranging from 20 to 50 mg orally on days 1 and 8 of a 21-day cycle) in a phase 1 trial using the continuous reassessment method to determine maximum tolerated dose. The first 2 patients developed a dose-limiting toxicity (neutropenic infection), prompting a mandatory dose reduction and PK evaluation of both everolimus and docetaxel for patients enrolled in subsequent dosing cohorts.
  
  
  RESULTS
  Fifteen patients were treated. Dose-limiting toxicity included grade 3 mucositis (n = 1), prolonged grade 4 neutropenia (n = 1), and grade 3 infection/febrile neutropenia (n = 3). Day 8 of everolimus was commonly held for neutropenia despite a dose reduction in docetaxel to 40 mg/m(2). Eleven patients underwent complete PK evaluation for everolimus, and 9 patients underwent complete PK evaluation for both everolimus and docetaxel. Widely variable changes in clearance were seen for both drugs, and the study was terminated because of lack of efficacy and concerns regarding toxicity seen with the combination.
  
  
  CONCLUSIONS
  Weekly everolimus in combination with docetaxel every 3 weeks was associated with excessive neutropenia and variable clearance of both drugs, making combination therapy unpredictable, even at low doses of both drugs.
authors: Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. smoulder@mdanderson.org
authors: Stacy
authors: S
authors: Moulder
authors: Gregory
authors: G
authors: Gladish
authors: Joe
authors: J
authors: Ensor
authors: Ana Maria
authors: AM
authors: Gonzalez-Angulo
authors: Massimo
authors: M
authors: Cristofanilli
authors: James L
authors: JL
authors: Murray
authors: Daniel
authors: D
authors: Booser
authors: Sharon H
authors: SH
authors: Giordano
authors: Abeena
authors: A
authors: Brewster
authors: Julia
authors: J
authors: Moore
authors: Edgardo
authors: E
authors: Rivera
authors: Gabriel N
authors: GN
authors: Hortobagyi
authors: Hai T
authors: HT
authors: Tran
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D000077143:Docetaxel; D004334:Drug Administration Schedule; D057239:Early Termination of Clinical Trials; D000068338:Everolimus; D005260:Female; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D043823:Taxoids / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D043823:Taxoids; D000077143:Docetaxel; D000068338:Everolimus; D020123:Sirolimus