Selumetinib (Sel) and cisplatin/gemcitabine (CisGem) for advanced biliary tract cancer (BTC): A randomized trial.
Bibliographic record
Abstract
4084 Background: Sel (AZD6244, ARR142886) is an oral MEK inhibitor, with preclinical evidence of synergy with Gem in BTC. CisGem is standard first-line treatment for advanced BTC. This trial assessed the efficacy of Sel in continuous or sequential combination with CisGem in first-line advanced BTC. Methods: This randomized multicentre phase II trial (NCT02151084) enrolled patients (pts) with advanced cholangiocarcinoma (CC) or gallbladder cancer (GBC). CisGem was given at standard doses. Sel started at 75mg BID, daily (continuous – Arm A) or day 1-5, 8-19 every 21 days (sequential – Arm B). Arm C was CisGem alone. Sel starting dose was reduced to 50mg BID for toxicity concerns after 32 enrolled pts (protocol amendment). Primary endpoint was % change in RECIST tumor size of 48 evaluable pts: Arm A or B vs Arm C at 10 wks. Secondary endpoints: PFS, OS, ORR, disease control rate (DCR) and toxicity. Results: 57 pts were enrolled: 29 female; 22 intrahepatic CC, 16 extrahepatic CC and 19 GBC. Baseline characteristics were similar across arms. Mean change in tumor size was not significantly different between either Sel arm and the control arm (Arm A p = 0.37, Arm B p = 0.53 [Table]). There were no significant differences in other efficacy endpoints. Toxicities appeared more frequent in Arm A; dose intensity of Gem and Sel were lower. More pts in Arms A and B stopped treatment due to toxicity than Arm C. Conclusions: Adding Sel to CisGem failed to improve tumor response at 10 wks, or prolong survival, but added toxicity and led to lower dose intensity. Exploration of biomarkers may identify a group deriving benefit, but it should not be studied further in unselected BTC. Clinical trial information: NCT02151084. Arm A (N = 19) Arm B (N = 19) Arm C (N = 19) overall p-value Mean % change in tumor size at 10 wks (95% CI) -7.3 (-24.3,+9.7) -16.3 (-26.2,-6.4) -13.2 (-25.2,-1.3) 0.80 ORR (%) 36 29 29 0.91 DCR (%) 86 88 88 0.95 Median PFS (months) 6.0 6.6 6.4 0.58 Median OS (months) 10.9 14.8 12.7 0.76 Treatment discontinuation reason Disease progression 7 7 13 Toxicity 4 6 0 Death 0 0 2 Withdrawn consent 1 3 1 Non-protocol surgery 0 1 0 Toxicity Events (Grade [G]) G 3 63 52 40 G 4 8 13 10 G 5 2 1 0 Non-hematologic G3-5 55 34 34 Relative Dose Intensity C1-3, % Cis 92.2 94.5 93.2 0.21 Gem 85.7 93.8 94.1 0.10 Sel 74.1 85.6 - 0.28
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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 | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.008 | 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".