A Phase I/II Study of Combination Neoadjuvant Hormone Therapy and Weekly OGX-011 Prior to Radical to Prostatectomy in Patients With Localized Prostate Cancer
Abstract
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-O ii 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 1/11 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. 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2005
- Accession Number
- ADA443706
Entities
People
- Kim N. Chi
Organizations
- University of British Columbia