Abstract
3085 Background: The clusterin gene encodes a cytoprotective chaperone protein that promotes cell survival, is expressed in a variety of cancers, and increases in response to apoptotic stimuli. OGX-011 (OGX, Oncogenex Technologies Inc) is a 2’methoxyethyl antisense complimentary to clusterin mRNA that inhibits expression with a tissue t1/2 >7 days in pre-clinical studies. A phase I trial of OGX in men prior to prostatectomy identified biologically active doses of 480 and 640mg as determined by clusterin suppression effects. The objective of this phase I study was to define a phase II dose of OGX in combination with docetaxel. Methods: The study was conducted at 3 centers in Canada. Patients (pts) with cancers known from the literature to express clusterin were eligible. OGX was given by 2 hr IV infusion at fixed doses starting at 40mg weekly after loading on days 1, 3, and 5. Docetaxel was given IV 30 mg/m2/week (w) for 5 out of 6w or 75 mg/m2 every 3w. Serial samples of peripheral blood mononuclear cells and serum were assessed for clusterin as were accessible malignant tissues. Results: 26 pts (9 prostate, 8 ovary, 3 NSCLC, 4 renal, 1 breast and other) have been enrolled to 6 cohorts with doses of OGX up to 640mg delivered with weekly docetaxel. 24 pts are evaluable for toxicity. Toxicity was typical for docetaxel with 3 pts having grade 3 treatment related toxicity (allergic, gastrointestinal, fatigue). OGX attributable adverse events were grade 1/2, including fevers, rigors, fatigue and transient AST and ALT elevations. OGX AUC and CMAX increased linearly with dose with no apparent effect on docetaxel pharmacokinetics. Serial baseline serum clusterin levels were consistent, but by treatment day 8 decreased in 3/3 pts by a mean of 52% (SD=26%) at the 640 mg dose level. Of 18 pts with measurable disease, there has been 1 partial response and 5 patients with stable disease. Conclusions: OGX can be given at biologically active doses with standard doses of weekly docetaxel. Accrual continues and additional cohorts are evaluating OGX with docetaxel q3w. Phase II trials of this combination are planned in pts with breast and prostate cancer. Supported by a grant from the NCIC and a grant in aid from Aventis Pharma. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration OncoGeneX Technologies OncoGeneX Technologies
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