Clusterin as an anti-apoptotic cytoprotective chaperone protein upregulated in an adaptive cell survival manner that confers resistance to various cell death triggers, including hormone-, radiation-, and chemotherapy. In pre-clinical models, inhibition of clusterin expression using the second generation antisense OGX-011 can enhance cell death following treatment with androgen ablation, radiotherapy, and chemotherapy. In phase I clinical trials, OGX-011 has been well tolerated and a biologically effective dose has been identified in humans.~Study Design~This is an open-label, non-blinded, phase II clinical, tissue pharmacokinetic and pharmacodynamic study of weekly OGX-011 and neoadjuvant hormone therapy prior to radical prostatectomy in patients with localized prostate carcinoma and high-risk features.~Study Objectives~Primary Objectives~To assess the effects of combined neoadjuvant hormone therapy (NHT) and OGX-011 prior to radical prostatectomy on pathologic complete response rates in men with high risk localized prostate cancer.~Secondary Objectives~To quantify changes in clusterin expression in residual prostate cancer after treatment with NHT and OGX-011.~To measure levels of full length OGX-011 in prostate tissues after 3 months of NHT.~To assess the safety and tolerability toxicity of 3 months of OGX-011 and NHT prior to radical prostatectomy.~To measure evidence of OGX-011's effect on clusterin expression in patient peripheral blood mononuclear cells (PBMNC).~To measure evidence of OGX-011's effect on patient clusterin serum levels.~To assess the effects of combined NHT and OGX-011 on time to PSA nadir.~To determine PSA recurrence rates after combined NHT and OGX-011.~Key Eligibility Criteria~Histologically confirmed adenocarcinoma of the prostate, previously untreated~Potential candidate for radical prostatectomy~Any one of the following criteria (minimum of 2 positive biopsies):~Clinical stage T3~Serum PSA > 10 ng/ml~Gleason score 7-10~Gleason score 6 and > 3 positive biopsies~ECOG performance status 0-1~WBC ≥ 3.0 x 10^9/L~Hemoglobin ≥ 100 g/L~Platelets ≥ 100 x 10^9/L~PTT, INR, AST, ALT, creatinine, total bilirubin within normal limits~Treatment Plan~Approximately 45 newly diagnosed, previously untreated patients with clinically localized, high-risk prostate carcinoma will be entered into this trial. These patients will receive neoadjuvant hormone therapy (buserelin 9.9 mg subcutaneously x 1 injection with flutamide 250 mg orally T.I.D. for the first 4 weeks only) for 12 weeks in combination with OGX-011 (a 2'MOE phosphorothioate clusterin antisense oligonucleotide) weekly on a 4 week cycle for 3 courses. For week one, cycle one only, OGX-011 will be given on Days 1, 3 and 5. OGX-011 is given at a dose of 640 mg by intravenous infusion over 2 hours. Radical prostatectomy will take place within 14 days of the last dose of OGX-011.
The purpose of this trial is to assess the effects of combined therapy with androgen ablation and OGX-011 (an antisense to clusterin) given prior to radical prostatectomy on pathologic complete response rates in men with localized prostate cancer and high risk features.