TRLS-08. ROVER: A PHASE 1/2 TRIAL IN PROGRESS OF AVAPRITINIB IN PEDIATRIC PATIENTS WITH SOLID TUMORS DEPENDENT ON KIT OR PDGFRA SIGNALING
Bibliographic record
Abstract
Abstract BACKGROUND Advanced pediatric solid tumors, including central nervous system (CNS) tumors with PDGFRA and/or KIT mutations/amplifications are aggressive diseases with limited treatment options. KIT alterations occur in germ cell tumors and high-grade glioma (HGG); platelet-derived growth factor receptor alpha (PDGFRA) alterations are common in sarcoma and HGG. No KIT-/PDGFRA-targeted therapies are currently approved for pediatric patients. The selective KIT and PDGFRA inhibitor avapritinib has demonstrated potent activity against KIT activation-loop (exon 17) and juxtamembrane (exon 11) mutants (IC50<2 nM), and PDGFRA activation-loop (D842V) mutants (half-maximal inhibitory concentration [IC50]=0.24 nM). Cellular IC50 of wild-type PDGFRA was 95 nM. CNS penetration in preclinical models (steady-state brain-to-plasma ratios, 0.74–1.00) indicates potential for CNS antitumor activity. Avapritinib is approved in the USA and Europe to treat adults with indolent systemic mastocytosis, in the USA for adults with advanced systemic mastocytosis (AdvSM), and in Europe for adults with AdvSM after ≥1 prior systemic therapy. Avapritinib is also approved to treat adults with unresectable/metastatic gastrointestinal stromal tumors harboring PDGFRA exon 18 mutations (including D842V) in the USA and PDGFRA D842V mutations in Europe. METHODS ROVER, a 2-part phase 1/2, multicenter, open-label study (NCT04773782), is investigating avapritinib (once daily, administered in continuous 28-day cycles) in pediatric patients aged 2 to <18 years with relapsed/refractory solid tumors that harbor PDGFRA and/or KIT mutations/amplifications or patients with diffuse midline glioma H3K27-altered (DMG-H3K27a). Objectives include safety, efficacy, and pharmacokinetics. Part 1 will enroll ≥12 patients; primary endpoint is to determine the recommended Part 2 dose (RP2D). Part 2 will enroll ≥25 patients at the RP2D; primary endpoint is objective response rate per RECIST v1.1 for solid tumors and Response Assessment in Neuro-Oncology for CNS tumors. Study enrollment is planned at 26 sites in 9 countries, including North America, Europe, and Asia/Pacific.
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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 | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.002 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.003 |
| Insufficient payload (model declined to judge) | 0.005 | 0.002 |
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".