Pain palliation as an oncology label indication: Lessons learned in custirsen phase III development.
Bibliographic record
Abstract
222 Background: Durable pain palliation (dPP) in metastatic castrate-resistant prostate cancer (mCRPC) is a measure of clinical benefit suitable for a label indication. A randomized, double-blind, placebo-controlled, phase III study developed with FDA under a Special Protocol Assessment (SPA) compared custirsen/taxane (cust/tax) to placebo/taxane (plac/tax) as second-line chemotherapy for patients (pts) with mCRPC with disease progression during or after first-line docetaxel. Primary efficacy was 12-week or more dPP. Other endpoints included overall survival (OS), serious adverse events (AEs), and ≥Gr 3 AEs. Methods: Patients were randomized (1:1) to second-line taxane (docetaxel retreatment or cabazitaxel; based on prior docetaxel response, progression) + 640 mg custirsen or placebo. Eligible pts had to have baseline stable pain on consistent opioid-analgesic regimen. With a one-sided alpha of 0.025, power of 90%, and estimated difference in proportion of 25% vs. 10% dPP, the trial required 292 pts. Results: Trial was activated at a total of 62 sites and was stopped after 20 months (mo) with only 35 pts screened/14 pts enrolled. Requirements for baseline stable pain/analgesic use proved too restrictive to complete enrollment. Demographics were comparable. Prior response to first-line docetaxel occurred in 93% pts. Disease progression after first-line docetaxel based on bone scan (n=10) or prostate-specific antigen (n=4); median time from end of first-line to progression one mo. Treatment of a median thre cycles plac/tax arm compared to six cycles cust/tax arm. Three pts achieved dPP (n=1 [14%] plac/tax; n=2 [29%] cust/tax). Median OS (95% CI) was 7.8 (3.2, 11.5) mo plac/tax vs. 11.8 (9.8, 15.7) mo cust/tax. AEs greater than or equal to Gr 3 reported for two pts or more included: back pain (0 plac/tax; 2 cust/tax), hyperesthesia (0,2), asthenia (2,1). Serious AEs reported for nine subjects (4,5). Only serious AE reported in more than 1 pt was hyperesthesia, leading to study discontinuation (0, 2). Conclusions: Enrollment was not feasible due to restrictive trial criteria of stable baseline pain/consistent analgesia, which were too difficult to achieve. Thus, a survival based study has been launched and is recruiting, with monitoring of pain/analgesic use. Pragmatic criteria for oncology pain studies are needed. Clinical trial information: NCT01083615.
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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 | 0.021 | 0.011 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.002 | 0.001 |
| Open science | 0.002 | 0.001 |
| Research integrity | 0.002 | 0.005 |
| Insufficient payload (model declined to judge) | 0.006 | 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".