Paediatric strategy forum for medicinal product development in diffuse midline gliomas in children and adolescents ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration
Bibliographic record
Abstract
Fewer than 10 % of children with diffuse midline glioma (DMG) survive 2 years from diagnosis. Radiation therapy remains the cornerstone of treatment and there are no medicinal products with regulatory approval. Although the biology of DMG is better characterized, this has not yet translated into effective treatments. H3K27-alterations initiate the disease but additional drivers are required for malignant growth. Hence, there is an urgent unmet need to develop new multi-modality therapeutic strategies, including alternative methods of drug delivery. ONC201 (DRD2 antagonist and mitochondrial ClpP agonist) is the most widely evaluated investigational drug. Encouraging early data is emerging for CAR T-cells and oncolytic viruses. GD2, B7-H3 and PI3K signalling are ubiquitous targets across all subtypes and therapeutics directed to these targets would potentially benefit the largest number of children. PI3K, ACVR1, MAPK and PDGFRA pathways should be targeted in rational biological combinations. Drug discovery is a very high priority. New specific and potent epigenetic modifiers (PROTACS e.g. SMARCA4 degraders), with blood-brain penetrance are needed. Cancer neuroscience therapeutics are in early development. Overall survival is the preferred regulatory endpoint. However, the evaluation of this can be influenced by the use of re-irradiation at the time of progression. An efficient clinical trial design fit for regulatory purposes for the evaluation of new therapeutics would aid industry and facilitate more efficient therapy development. Challenges in conducting clinical trials such as the need for comparator data and defining endpoints, could be addressed through an international, first-in-child, randomised, complex innovative design trial. To achieve progress: i) drug discovery; ii) new multi-modality, efficient, collaborative, pre-clinical approaches, possibly including artificial intelligence and, iii) efficient clinical trial designs fit for regulatory purposes are required.
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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 | 0.006 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.003 | 0.002 |
| Open science | 0.001 | 0.003 |
| Research integrity | 0.005 | 0.003 |
| Insufficient payload (model declined to judge) | 0.095 | 0.040 |
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".