Randomized comparisons of bevacizumab (B) and irinotecan (I), added to temozolomide (T), in children with relapsed or refractory high-risk neuroblastoma (RR-HRNB): First survival results of the ITCC-SIOPEN BEACON-Neuroblastoma phase II trial.
Bibliographic record
Abstract
10501 Background: BEACON is a randomized phase 2 trial assessing whether inhibiting angiogenesis with bevacizumab adds to the activity of chemotherapy and evaluating chemotherapy regimens for children with RR-HRNB. Methods: Patients with RR-HRNB were eligible. There were randomizations (rand), in a 3x2 factorial design, to: T, IT or topotecan (To)-T, +/- B. Toxicity and response were reported in 2019 (ASCO, ESMO). Survival outcomes – progression-free (PFS) and overall (OS) – for the I and B rands are reported here (To rand is still open). The B rand used a relaxed alpha (1-sided p=0.2) for PFS as its phase 2 success criterion; the I rand was Bayesian. Cox model hazard ratios (HR) <1.0 indicate benefit for I or B. Heterogeneity tests (HT) assessed interactions between B and I. Analysis was intention-to-treat. Results: From 2013-19, 160 patients were randomized to B v. no B, including 121 to I v. no I, with: median age 5.8 years; 113 and 47 measurable and evaluable disease; 67 and 93 refractory and relapsed disease; 35 had MYCN amplification. Median follow-up was 15.4 months. PFS and OS are shown in the table. In the main comparisons (I v. no I, B v. no B), I improved PFS and OS (98% probability that true HR<1.0 for both) and B just met its success criterion (PFS: 1p=0.20; OS: 1p=0.19). However, there was some, but not conclusive, evidence of a positive interaction between B and I for both PFS (HT: p=0.06) and OS (HT: p=0.12). If real, this would suggest that adding either I (IT) or B (BT) to T does not improve outcome, but adding both (BIT) does. Twice as many patients had serious adverse events with BIT (57%) than with T (26%) or IT (27%), with BT at 40%. Conclusions: The BEACON results show that single agent T is suboptimal. Statistical uncertainty about an interaction between I and B means two further interpretations are possible: 1) IT and possibly BT are better than T; 2) IT and BT are not better than T, but I and B together (BIT) are better. Hence, a definitive conclusion on the best combination(s) to take forward is not currently possible and further randomized evaluation is needed. Clinical trial information: ISRCTN40708286. [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 | 0.003 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 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 | 0.003 |
| 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".