A phase II study of the antisense oligonucleotide GTI-2040 plus docetaxel and prednisone as first line treatment in hormone refractory prostate cancer (HRPC)
Bibliographic record
Abstract
13015 Background: Despite initial responses to chemotherapy, median survival in HRPC remains a dismal 18 mos. Novel therapeutic approaches are clearly needed. The enzyme ribonucleotide reductase (RNR) composed of 2 subunits, R1 and R2 is essential for DNA synthesis and repair. The R2 subunit is often overexpressed in tumors increasing their malignant potential and promoting drug resistance. GTI-2040 (Lorus Therapeutics, Canada) is an antisense oligonucleotide to the R2 subunit downregulating its expression. In preclinical studies, GTI-2040 has shown antitumor activity in prostate cancer xenografts, synergy and non-overlapping toxicity with the taxanes. It is therefore a rational choice for combination with docetaxel in HRPC. Objectives: To determine efficacy of this regimen using PSA response rate. Secondary objectives include: duration of response, TTP, objective tumor response rate, safety and tolerability. Pharmacokinetic (PK) studies will be performed. PBMC will be used to determine RNR activity and R2 subunit quantitation. Methods: HRPC patients with PS 0–2, adequate organ function and no prior chemotherapy were treated with GTI-2040 5mg/kg/d continuous infusion for 14d, docetaxel 75 mg/m2 IV every 21d, and prednisone 5mg twice daily. Results: Twenty-two pts in 5 centers have been enrolled. Pts have received a total of 107 cycles to date. Median age 63 (52–77); median baseline PSA 140 (26–1256); ECOG 0:1:2: 14:7:1; prior radiotherapy in 14 pts. Pts received a median of 5 cycles (2–10). Grade 3/4 hematologic toxicities were lymphophenia (10pts), leukopenia (7pts), and neutropenia (7pts). Anemia (any grade) was seen in 19 pts across 92 cycles. Most frequent non-hematologic toxicities were fatigue and pain. PSA responses seen in 9/22 pts. Objective tumor response:1 PR, 9 SD, 3 PD, 3 off due to toxicity prior to objective response measurement, 3 no measureable lesions, 3 to be assessed. 19 pts off treatment: 9 PD, 4 toxicity (1 toxic death), 2 completed 10 cycles, 2 at investigator’s discretion and 2 withdrew consent. Three pts remain on study. Median TTP estimated at 17 wks. Accrual has been sufficient to meet stage 1 requirements. Final response, toxicity, pK, RNR and R2 subunit analysis will be available and presented. No significant financial relationships to disclose.
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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 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 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".