A phase I study of everolimus and docetaxel in patients with castration-resistant prostate cancer

Clin Genitourin Cancer. 2015 Apr;13(2):113-23. doi: 10.1016/j.clgc.2014.08.007. Epub 2014 Oct 22.


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.

Patients and 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%.

Conclusion: 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.

Trial registration: ClinicalTrials.gov NCT00459186.

Keywords: PI3K; PTEN; Positron emission tomography; Prostatic adenocarcinoma; mTOR.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Biomarkers, Tumor / metabolism
  • Docetaxel
  • Drug Administration Schedule
  • Everolimus / administration & dosage*
  • Everolimus / adverse effects
  • Everolimus / pharmacokinetics
  • Fluorodeoxyglucose F18 / metabolism*
  • Humans
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Positron-Emission Tomography / methods
  • Prostatic Neoplasms, Castration-Resistant / drug therapy*
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • Taxoids / administration & dosage*
  • Taxoids / adverse effects
  • Taxoids / pharmacokinetics
  • Treatment Outcome


  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Taxoids
  • Fluorodeoxyglucose F18
  • Docetaxel
  • Everolimus

Associated data

  • ClinicalTrials.gov/NCT00459186