ADORE: an open platform study of ruxolitinib in combination with other novel therapies in patients with myelofibrosis
Bibliographic record
Abstract
ABSTRACT: Ruxolitinib, a Janus kinase (JAK)1/JAK2 inhibitor, is the standard of care for symptomatic patients with myelofibrosis (MF). However, ∼70% of patients discontinue ruxolitinib after ∼5 years, a third of whom report suboptimal splenic response. ADORE was a phase 1b/2 study with an innovative open platform design that assessed the safety, efficacy, and pharmacokinetics of novel compounds in combination with ruxolitinib in patients with MF who had a suboptimal response to ruxolitinib alone. A total of 44 patients were enrolled in part 1 of the study of ruxolitinib in combination with siremadlin, rineterkib, sabatolimab, crizanlizumab, or NIS793. Most patients were allocated to receive ruxolitinib plus siremadlin (N = 23). The most frequent adverse events with siremadlin were gastrointestinal (nausea and diarrhea) and hematological (thrombocytopenia, anemia, and neutropenia). Siremadlin 30 mg orally once daily on days 1 to 5 of a 28-day cycle was selected as the recommended phase 2 dose. The most robust spleen volume reduction (SVR) at 24 weeks was observed with ruxolitinib plus siremadlin 30 mg. Reductions in percent JAK2V617F allele burden at week 24 were observed, notably in several patients with SVR. An increase in growth differentiation factor 15 protein levels in patients receiving siremadlin demonstrated the on-target modulation of downstream p53 targets. Overall, available data from ADORE suggest the feasibility and benefits of combining novel agents with ruxolitinib in patients with suboptimal response to ruxolitinib alone. This trial was registered at www.clinicaltrials.gov as #NCT04097821.
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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 | 0.003 | 0.001 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.003 | 0.002 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.002 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.003 | 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".