Trametinib in pediatric patients with neurofibromatosis type 1 (NF-1)–associated plexiform neurofibroma: A phase I/IIa study.
Bibliographic record
Abstract
10504 Background: NF-1 loss-of-function alterations are associated with development of plexiform neurofibromas (PNs). NF-1–associated PNs can arise early in life in different locations, with variable and significant morbidity. Many patients (pts) progress following surgery, and currently there are no approved systemic therapies. The MEK inhibitor trametinib is being evaluated in pediatric pts across a spectrum of tumor types in a dose-escalation cohort of a phase I/IIa study (NCT02124772) to determine a recommended dose; disease-expansion cohorts include pts with NF-1 PN. Here we present an interim analysis of safety and clinical benefit of trametinib in pediatric pts with NF-1–associated PN. Methods: Pts aged 1 mo to < 18 y with medically significant, unresectable NF-1–associated PN were treated with trametinib 0.025 to 0.040 mg/kg/d. The primary objective was safety, and secondary objectives included tumor response assessed by independent review (IR) using published MRI volumetric criteria. Results: Twenty-six pts received trametinib (0.025 mg/kg/d, n = 21; 0.032 mg/kg/d, n = 1; 0.040 mg/kg/d, n = 4). Presented here are results from the disease-expansion cohort (n = 10). Median duration of exposure was 408 d (range, 360-429 d), and 8 pts (80%) had treatment ongoing at the data cutoff (September 2017). Median age was 5.5 y (range, 1-16 y), and prior therapies included surgery (n = 5), biologics (n = 1), and targeted therapy (n = 1). Treatment-related AEs (TRAEs) were reported in 9 of 10 pts (90%), and 1 pt discontinued due to a TRAE. The most frequent TRAEs were paronychia (50%) and rash (40%). No deaths occurred on treatment. Analysis of the full NF-1 PN cohort (n = 26) is ongoing; across this cohort, 12 of 26 pts (46%) had a PR (≥ 20% volume reduction) by IR, and 10 of the 12 responses (83%) were ongoing. Conclusions: Trametinib demonstrated a manageable safety profile in pediatric pts with NF-1–associated PN. Using volumetric criteria for response determination, the objective responses observed with trametinib support continued investigation in this pt population. Clinical trial information: NCT02124772.
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 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".