Phase I/II Study of Combination Neoadjuvant Hormone Therapy and Weekly OGX-011 (Clusterin Antisense Oligonulceotide) Prior to Radical Prostatectomy in Patients with Localized Prostate Cancer

摘要

The clusterin gene encodes a cytoprotective chaperone protein that promotes cell survival. Clusterin is expressed in a variety of cancers including prostate, increases in response to apoptotic stimuli, and confers a resistant phenotype. OGX-011 is a 2nd generation antisense complimentary to clusterin mRNA that inhibits expression of clusterin in xenograft models and thereby increases sensitivity to therapy. To evaluate OGX-011 as a potential treatment in humans, we have undertaken this Phase I/II study to evaluate the clinical, pathologic and biologic effects of OGX-011, in combination with neoadjuvant hormone therapy (NHT) in patients with prostate cancer and high risk features prior to radical prostatectomy. The primary objective of the phase I study was to determine phase II dose based on target regulation effect and the phase II primary objective was to assess the effects on pathologic complete response. 25 patients were enrolled to 6 cohorts with doses of OGX-011 up to 640mg delivered. Toxicity was limited to grade 1/2, including fevers, rigors, fatigue and transient AST and ALT elevations and no dose-limiting toxicities. Plasma PK analysis showed dose proportional increases in AUC and Cmax with a t1/2 of approximately 2h. Prostate tissue concentrations of OGX-011 increased with dose, and tissue concentrations associated with preclinical effect could be achieved. Dose dependent decreases in prostate cancer cell clusterin expression were observed by QRT-PCR and immunohistochemistry (IHC). At 640mg dosing, clusterin mRNA was decreased to a mean of 8% (SD=4%) compared with lower dose levels and historical controls as assessed by QRT-PCR on laser captured microdissected cancer cells. By IHC, mean % cancer cells staining 0 intensity for clusterin protein at 640mg dosing was 54% (SD=24%). Dose- dependent changes in serum clusterin were also apparent.