A Phase I/II Study of Combination Neoadjuvant Hormone Therapy and Weekly OGX-011 Prior to Radical Prostatecomy 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 in pre-clinical models confers a resistant phenotype. OGX-011-is a 2nd generation antisense complimentary to cluster in mRNA that inhibits expression of cluster 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 1 study was to determine phase II dose based on target regulation effect in addition to standard toxicity parameters. 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. There were no dose-limiting toxicities. Plasma PK analysis showed linear 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%) compared with 2-15% for lower dose levels and historical controls.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2004
- Accession Number
- ADA428552
Entities
People
- Kim N. Chi
Organizations
- University of British Columbia