A phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of OGX-011, a 2'methoxyethyl phosphorothioate antisense to clusterin, in patients with prostate cancer prior to radical prostatectomy

Abstract

3033 Background: The clusterin gene encodes a chaperone protein that promotes cell survival. Clusterin is expressed in a variety of cancers including prostate, increases in response to after androgen abaltion and other apoptotic stimuli, and confers a resistant phenotype in pre-clinical models . OGX-011 (Oncogenex Technologies Inc) is a 2nd generation antisense complimentary to clusterin mRNA that inhibits expression of clusterin in xenograft models and thereby increases sensitivity to therapy. The objective of this first-in-man study was to determine phase II dose based on optimal target regulation effect in addition to standard toxicity parameters. Methods: Patients having localized prostate cancer with high-risk features and candidates for prostatectomy were enrolled to this dose escalation trial. OGX-011 was given by IV infusion over 2 hrs at a starting dose of 40mg on days 1, 3, 5, 8, 15, 22, and 29. Buserelin and flutamide were started on day 1. Prostatectomy was performed day 30–36. OGX-011 plasma PK and prostate tissue concentrations were determined. Prostate tissues, serial samples of peripheral blood mononuclear cells, and serum were assessed for clusterinexpression. Results: 20 patients have been enrolled to 6 cohorts with doses of OGX-011 up to 640mg. Toxicity has been limited to grade 1 or 2, including fevers, rigors, fatigue and transient AST and ALT elevations. Plasma PK analysis showed linear increases in AUC with a t1/2 of approximately 2 hrs. OGX-011 prostate tissue concentrations increased with dose to a mean of 2.30 ug/g (∼300nM) at 480mg dosing. Dose dependent decreases in prostate tumor clusterin expression were observed by immunohistochemistry (IHC) and in situ hybridization. By IHC, mean % cancer cells staining for 0 intensity at 480mg was 49.2% (SE 9.0) compared with 3.3–14.5% for lower dose levels. Conclusions: OGX-011 is well tolerated and can inhibit clusterin expression in prostate cancers. Dose escalation and additional PD assessments continue. Supported by a grant from the U.S. Department of Defense and coordinated by the NCIC-CTG. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration OncoGenex Technologies OncoGenex Technologies OncoGenex Technologies Abbott; Aventis OncoGenex Technologies