A Phase I/II Study of Combination Neoadjuvant Hormone Therapy and Weekly OGX-011 Prior to Radical Prostatectomy in Patients with Localized Prostate Cancer
Annual rept. 1 Aug 2005-31 Jul 2006
BRITISH COLUMBIA UNIV VANCOUVER
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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 III 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-01 1 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 12 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 112 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 SD4 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 SD24. Dose-dependent changes in serum clusterin were also apparent.
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