Complete radiographic responses in pediatric patients with <i>BRAF</i><sup>V600</sup>-positive tumors including high-grade gliomas: Preliminary results of an ongoing phase 1/2a safety and pharmacokinetics (PK) study of dabrafenib.
Bibliographic record
Abstract
10056 Background: Dabrafenib is a selective inhibitor of V600 mutant BRAF kinase activity with a mechanism of action consistent with adenosine triphosphate-competitive inhibition. Dabrafenib has demonstrated anti-tumor efficacy in adult patients (pts) with BRAFV600 mutant tumors, including melanoma, papillary thyroid cancer (PTC), and non-small cell lung cancer. Methods: This 2-part study was designed to identify phase 2 recommended dose, safety, PK, and clinical activity in pediatric pts who have had ≥1 previous therapy. Part 1 is a PK-driven dose escalation. Part 2 is an expansion study to evaluate the safety and activity of dabrafenib in pediatric pts with 1 of 4 pre-specified tumor types. Pts are treated with dabrafenib orally twice daily, using capsules or a powder for oral suspension. Serial PK samples are obtained on days 1 and 15. Imaging is performed every 2 cycles, and responses require confirmation on a follow-up scan at least 4 weeks later. Results: From May 2013 to Jan 2014, 8 pts (median age, 11 y; range 3-17 y) with recurrent/refractory BRAFV600 mutant solid tumors including 6 high grade glioma (HGG), 1 each of Langerhans cell histiocytosis (LCH), and PTC were enrolled at dose levels 3mg/kg (n=3) and 3.75mg/kg (n=5). Radiographic responses for the HGG pts included 3 complete responses (2 confirmed and maintained at the 6 month assessment [both anaplastic astrocytoma], 1 unconfirmed [pleomorphic xanthoastrocytoma]), and 2 progressive disease. The LCH pt continues to exhibit stable disease at week 16. Data are not yet available for a PTC pt and 1 HGG pt. There were no DLTs or drug-related grade 3/4 toxicities in these 8 pts. No dose reductions have been required, and PK data analysis and dose escalation continues. Two pts (1 in each cohort) achieved plasma dabrafenib concentrations associated with clinical efficacy in adults. Conclusions: Dabrafenib shows encouraging initial clinical activity in this small number of evaluable pediatric pts with BRAFV600 mutant solid tumors, including primary brain tumors. The preliminary safety profile in pediatric pts is consistent with that in adults. Clinical trial information: NCT01677741.
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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 | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| 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) | 0.001 | 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 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".