| Author |
Courtney, Kevin D. Manola, Judith B. Elfiky, Aymen A. Ross, Robert Oh, William K. Yap, Jeffrey T. Van den Abbeele, Annick D. Ryan, Christopher W. Beer, Tomasz M. Loda, Massimo Priolo, Carmen Kantoff, Philip Taplin, Mary-Ellen |
| Description |
Country affiliation: Morocco Author Affiliation: Courtney KD ( Medical Oncology, Dana-Farber Cancer Institute and Internal Medicine, Harvard Medical School, Boston, MA.); Manola JB ( Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.); Elfiky AA ( Medical Oncology, Dana-Farber Cancer Institute and Internal Medicine, Harvard Medical School, Boston, MA.); Ross R ( Medical Oncology, Dana-Farber Cancer Institute and Internal Medicine, Harvard Medical School, Boston, MA.); Oh WK ( Medical Oncology, Dana-Farber Cancer Institute and Internal Medicine, Harvard Medical School, Boston, MA.); Yap JT ( Department of Imaging, Dana-Farber Cancer Institute, Department of Radiology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.); Van den Abbeele AD ( Department of Imaging, Dana-Farber Cancer Institute, Department of Radiology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.); Ryan CW ( Knight Cancer Institute at Oregon Health and Science University, Portland, OR.); Beer TM ( Knight Cancer Institute at Oregon Health and Science University, Portland, OR.); Loda M ( Medical Oncology, Dana-Farber Cancer Institute and Internal Medicine, Harvard Medical School, Boston, MA); Priolo C ( Medical Oncology, Dana-Farber Cancer Institute and Internal Medicine, Harvard Medical School, Boston, MA.); Kantoff P ( Medical Oncology, Dana-Farber Cancer Institute and Internal Medicine, Harvard Medical School, Boston, MA.); Taplin ME ( Medical Oncology, Dana-Farber Cancer Institute and Internal Medicine, Harvard Medical School, Boston, MA. Electronic address: Mary_Taplin@dfci.harvard.edu.) |
| 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. 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. |
