OGX-427, a 2'methoxyethyl antisense oligonucleotide (ASO), against HSP27: Results of a first-in-human trial
Bibliographic record
Abstract
3506 Background: Heat shock protein 27 (Hsp27) is a chaperone protein expressed in many cancers and implicated as a therapeutic “hyper-node” affecting multiple pathways in cancer progression. Overexpression of Hsp27 confers a resistant phenotype. OGX-427 is a second generation ASO that inhibits Hsp27 expression which in preclinical models inhibited cell growth, induced apoptosis, and enhanced chemotherapy efficacy. The purpose of this phase 1 study was to determine the recommended phase 2 dose of OGX-427 alone and in combination with docetaxel. Methods: Eligible patients (pts) had to have metastatic breast, ovarian, prostate, NSCLC, or bladder cancer. OGX-427 was administered IV weekly on a 21-day cycle after 3 loading doses (LD) within 9 days. OGX-427 was escalated over 5 planned dose levels (DL) (200, 400, 600, 800, 1,000 mg), with 6 pts/DL. Plasma PK and serial ECGs were performed in cycle 1. Circulating tumor cells (CTC), Hsp27+ CTC and serum Hsp27 levels were evaluated serially. Results: 34 pts have been accrued and single agent dose escalation is complete. Median age was 62 (range: 33–86) yrs; 16 pts had prostate, 10 breast, 5 ovary and 3 lung ca. Median cycles administered were 2 (0–8) with 2 pts remaining on treatment. Most common related AEs: chills (53%), pruritis (29%), flushing (21%), elevated creatinine (18%), fatigue (15%), arthralgia (15%). More than 80% of pts had grade (Gr) 1/2 infusion reactions during the LDs or C1. One pt on 1,000 mg DL was hospitalized with Gr 3 infusion reaction. Gr 3 elevations of PTT (with normal INR) were seen in >50% of pts on 800 and 1,000 mg DL. At 600 mg DL, one pt had a Gr 3 epistaxis and one pt had a DLT with a Gr 3 cerebral bleed into a metastasis. No significant QTcF changes were observed. Three pts with prostate ca had PSA declines of 43%, 58%, 62% and 3 pts with ovarian cancer had CA-125 declines of 27%, 28%, and 41%. Five pts have had stable disease for >3 months. Preliminary mean PK data for 200–600 mg DLs: T1/2 = 2.8–3.1 hrs, peak concentration = 21,756 - 102,591 ng/mL and AUCinf ranged from 63,552 - 328,153 ng.h/mL, increasing with dose. Declines in CTC and Hsp27+ CTC have been observed at all DL. Conclusions: OGX-427 was well tolerated. Toxicity consisted mainly of infusion reactions and transient PTT changes. Changes in tumor markers suggest single-agent activity. [Table: see text]
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".