title: A phase I study of everolimus and docetaxel in patients with castration-resistant prostate cancer.
abstract: BACKGROUND
  The PTEN tumor suppressor is frequently lost in CRPC, with activation of Akt-mTOR signaling, driving growth. We conducted a phase I trial of the mTOR inhibitor, everolimus, and docetaxel in CRPC.
  
  
  METHODS
  Eligible patients had progressive, metastatic, chemotherapy-naive CRPC. Patients received everolimus 10 mg daily for 2 weeks and underwent a restaging FDG-PET/computed tomography scan. Patient cohorts were subsequently treated at 3 dose levels of everolimus with docetaxel: 5 mg to 60 mg/m(2), 10 mg to 60 mg/m(2), and 10 mg to 70 mg/m(2). The primary end point was the safety and tolerability of combination therapy.
  
  
  RESULTS
  Accrual was 4 patients at level 1, 3 patients at level 2, and 8 patients at level 3. Common toxicities were hematologic and fatigue. Serum concentrations of everolimus when administered with docetaxel were 1.5 to 14.8 ng/mL in patients receiving 5 mg everolimus and 4.5 to 55.4 ng/mL in patients receiving 10 mg everolimus. Four patients had partial metabolic response (PMR) using FDG-PET, 12 had stable metabolic disease, and 2 had progressive metabolic disease after a 2-week treatment with everolimus alone. Five of 12 evaluable patients experienced a prostate-specific antigen (PSA) reduction ≥ 50% during treatment with everolimus together with docetaxel. All 4 patients with a PMR according to PET imaging experienced a PSA reduction in response to everolimus with docetaxel, and 3 of 4 had PSA declines ≥ 50%.
  
  
  CONCLUSIONS
  Everolimus 10 mg daily and docetaxel 60 mg/m(2) was safe in CRPC patients and these were the recommended doses in combination. FDG-PET response might serve as a biomarker for target inhibition by mTOR inhibitors.
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute and Internal Medicine, Harvard Medical School, Boston, MA.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Courtney
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.
authors.forename: Judith B
authors.initials: JB
authors.lastname: Manola
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute and Internal Medicine, Harvard Medical School, Boston, MA.
authors.forename: Aymen A
authors.initials: AA
authors.lastname: Elfiky
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute and Internal Medicine, Harvard Medical School, Boston, MA.
authors.forename: Robert
authors.initials: R
authors.lastname: Ross
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute and Internal Medicine, Harvard Medical School, Boston, MA.
authors.forename: William K
authors.initials: WK
authors.lastname: Oh
authors.affiliation: Department of Imaging, Dana-Farber Cancer Institute, Department of Radiology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Yap
authors.affiliation: Department of Imaging, Dana-Farber Cancer Institute, Department of Radiology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Annick D
authors.initials: AD
authors.lastname: Van den Abbeele
authors.affiliation: Knight Cancer Institute at Oregon Health and Science University, Portland, OR.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Ryan
authors.affiliation: Knight Cancer Institute at Oregon Health and Science University, Portland, OR.
authors.forename: Tomasz M
authors.initials: TM
authors.lastname: Beer
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute and Internal Medicine, Harvard Medical School, Boston, MA; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute and Internal Medicine, Harvard Medical School, Boston, MA.
authors.forename: Carmen
authors.initials: C
authors.lastname: Priolo
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute and Internal Medicine, Harvard Medical School, Boston, MA.
authors.forename: Philip
authors.initials: P
authors.lastname: Kantoff
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute and Internal Medicine, Harvard Medical School, Boston, MA. Electronic address: Mary_Taplin@dfci.harvard.edu.
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Taplin
mesh_terms: D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D000077143:Docetaxel; D004334:Drug Administration Schedule; D000068338:Everolimus / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D049268:Positron-Emission Tomography / Q000379:methods; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D043823:Taxoids; D019788:Fluorodeoxyglucose F18; D000077143:Docetaxel; D000068338:Everolimus
keywords: PI3K; PTEN; Positron emission tomography; Prostatic adenocarcinoma; mTOR