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.

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.

Copyright © 2015 Elsevier Inc. All rights reserved.

Figures

Figure 1

Treatment Schema and Patient Flow for the Study Abbreviations: DLT = Dose-Limiting Toxicity; E/D = Everolimus With Docetaxel Treatment; PET = Positron Emission Tomography; pts = Patients.

Figure 2

Metabolic Response to Everolimus Treatment and Prostate-Specific Antigen (PSA) Response to Everolimus With Docetaxel (E/D) Treatment. Patients Underwent Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography Imaging Before Treatment and Again After 10 to 14 Days of Treatment With Everolimus Alone to Assess for Metabolic Response. (A) Representative Images Before and After Everolimus Treatment Are Shown for Patient 005. (B) The Percent Change in Summed Maximum Standardized Uptake Value (SUVmax) Was Calculated for Bone, Soft Tissue, and Total Lesions. (C) After Everolimus Treatment, 4 Patients Had a Partial Metabolic Response (PMR), 12 Had Stable Metabolic Disease (SMD), and 2 Had Progressive Metabolic Disease (PMD)

Figure 3

(A) The Percent Change in Prostate-Specific Antigen (PSA) After Treatment With Everolimus and Docetaxel (E/D) Is Shown. Color Coding Matches That for Figure 2C to Permit Comparison With Metabolic Response to Treatment With Everolimus. Best PSA Response for All Patients Is Shown Ranked According to the Change in Summed Maximum Standardized Uptake Value (SUVmax) Using Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) Corresponding to Figure 2C. (B) A Waterfall Plot of Maximal Change in PSA for All Patients Treated With E/D for at Least 2 Cycles. Patients 2, 9, 10, 17, 18, and 19 Were Not Evaluable for Change in PSA. (C) The Percent Change in PSA at 12 Weeks Is Shown for the 6 Patients Who Continued Treatment

Figure 4

Histologic and Immunohistochemical Response to Everolimus Treatment. Image-Guided Bone Biopsy Was Performed on Patient 3 Before and After Everolimus Treatment. Tissue Sections Were Stained With (A and B) Hematoxylin and Eosin (H & E) or (C and D) Antibody Against Serine-Phosphorylated Ribosomal Protein S6 (Phospho-S6)