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

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

Author information

1
Medical Oncology, Dana-Farber Cancer Institute and Internal Medicine, Harvard Medical School, Boston, MA.
2
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA.
3
Department of Imaging, Dana-Farber Cancer Institute, Department of Radiology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
4
Knight Cancer Institute at Oregon Health and Science University, Portland, OR.
5
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.
6
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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00459186.

KEYWORDS:

PI3K; PTEN; Positron emission tomography; Prostatic adenocarcinoma; mTOR

PMID:
25450031
PMCID:
PMC4418946
DOI:
10.1016/j.clgc.2014.08.007
[Indexed for MEDLINE]
Free PMC Article

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