Dabrafenib in pediatric patients with <i>BRAF</i> V600 mutation–positive high-grade glioma: Results from a phase 1/2a single-arm study
Bibliographic record
Abstract
Abstract Background BRAF V600E mutations occur in many pediatric malignancies, including ~5% to 10% of pediatric high-grade gliomas (HGGs). Despite efforts over the decades, the prognosis of pediatric HGG remains dismal, with low survival rates. Dabrafenib has shown efficacy in pediatric patients with BRAF V600 mutation–positive malignancies in a phase 1/2a study. This report combines data from all pediatric patients with HGG in both dose escalation (part 1) and tumor-specific dose expansion (part 2) parts of the study, including patients with HGG for the first time in phase 2a. Methods Patients aged 1 to &lt; 18 years with BRAF V600 mutation–positive HGG who had refractory or progressive disease after standard therapy received oral dabrafenib 3.0 to 5.25 mg/kg/day (part 1) or the recommended dose (part 2) of 5.25 mg/kg/day (age &lt; 12 years) or 4.5 mg/kg/day (age ≥ 12 years) as 2 equal doses twice daily. The primary objectives were safety and tolerability of dabrafenib (part 1; previously published) and clinical activity (part 2), defined as ORRs reported by investigator assessment and independent review using RANO 2010 criteria. Results Overall, 35 pediatric patients with HGG were treated. Histologic diagnosis included pleomorphic xanthoastrocytoma (n = 8), glioblastoma (n = 7), anaplastic astrocytoma (n = 6), anaplastic ganglioglioma (n = 4), and other gliomas (n = 10). The ORRs were 29% (95% CI, 14.6, 46.3) and 46% (28.8, 63.4) by investigator assessment and independent review, respectively. The 24-month PFS rates were 30% and 40%, respectively. The most common treatment-related adverse events were dry skin (31%), fatigue (29%), and pyrexia (26%). No treatment-related deaths were reported. Conclusions In pediatric patients with relapsed orrefractory BRAF V600–mutated HGG, dabrafenib exhibited sustained objective tumor responses and a manageable safety profile.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.003 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".