A phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of OGX-011, a 2'methoxyethyl phosphorothioate antisense to <i>clusterin</i>, in patients with prostate cancer prior to radical prostatectomy
Bibliographic record
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
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".