A phase I/II study of LDE225, a smoothened (Smo) antagonist, in pediatric patients with recurrent medulloblastoma (MB) or other solid tumors.
Bibliographic record
Abstract
9519 Background: Hedgehog (Hh) signaling is crucial in the development and homeostasis of many human organs and tissues. Aberrant Hh signaling is involved in tumorigenesis through promotion of cell proliferation, survival, and differentiation in wide range of human cancers, including approximately 30% of MBs. LDE225 is a potent and selective inhibitor of Smo, a key positive regulator of Hh signaling. The phase I is exploring the safety and pharmacokinetics of LDE225 in pediatric patients with advanced solid tumors that are potentially dependent on Hh signaling. Preliminary data from the ongoing phase I are presented. Methods: Dose-escalation was performed according to a Bayesian design starting at 372 mg/m2 of continuous once daily oral LDE225. Safety and preliminary efficacy of LDE225 at the maximum tolerated dose will be assessed in pediatric and adult patients with recurrent MB in a phase II expansion part. Pharmacokinetic profiles were performed at Day 1 and 21. Tumor samples were analyzed for Hh pathway activation status using a 5-gene Hh signature assay. Results: Thirty-three patients (24 MB, 3 rhabdomyoscarcoma [RMS], 3 osteosarcoma, and 1 each of neuroblastoma, gliomatosis and oligoastrocytoma) with a median age of 13 years (range, 4–17 y) have enrolled. Dose-limiting toxicity of Grade 4 creatine phosphokinase elevation occurred in 1 RMS patient out of 7 patients treated at 372 mg/m2. No dose-limiting toxicity was observed at 233 and 425 mg /m2. LDE225 at 233 and 372 mg/m2 was absorbed with a median Tmax of 2 h (range, 1–24 h). Systemic exposures were comparable with adults. Two MB patients achieved a confirmed complete response (CR) at doses of 372 and 425 mg/m2. Analysis of 14 available MB tumor samples using the 5-gene Hh signature assay showed that the 2 CR patients have Hh‑activated tumor. The remaining 12 tumor samples were from patients who did not achieve response and were determined to be Hh pathway non-activated. Conclusions: LDE225 is well tolerated in pediatric patients with advanced malignancies. Preliminary data show promising efficacy in medulloblastoma patients and support the use of the 5-gene Hh signature assay as a pre-selection tool in future trials.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.002 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 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".