Study of Combination Neoadjuvant Hormone Therapy and Weekly OGX-011 (Clusterin Antisense Oligonulceotide) Prior to Radical Prostatectomy in Patients with Localized Prostate Cancer. Phase 1 and 2; Final rept. 1 Aug 2002-31 Jul 2007

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. The phase II component of this trial will assess the effects of combined NHT and OGX-011 on pathologic complete response. Progress: 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.