Dasatinib plus SMO antagonist versus dasatinib alone for treating patients (pts) with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP): Design of CA180-363, a phase II, open-label randomized trial.
Bibliographic record
Abstract
TPS6634 Background: Dasatinib 100 mg once daily (QD) is approved as first-line therapy for pts with newly diagnosed Ph+ CML-CP and those who are resistant or intolerant to prior therapy, including imatinib, based on demonstrated efficacy and tolerability. BMS-833923 (SMO antagonist), selectively blocks hedgehog (Hh) pathway signaling by binding to and antagonizing Smoothened (SMO), preventing downstream signaling and activation of target genes. In preclinical studies, SMO loss or inhibition reduces hematopoietic stem cell renewal, induces CML stem cell depletion, and inhibits imatinib-resistant CML cell growth (Dierks, Cancer Cell 2008; Zhao, Nature 2009). In pts with CML, Hh signaling genes (Sonic hedgehog, SMO, and Gli1) are significantly upregulated compared with control pts (Long, J Exp Clin Cancer Res 2011), suggesting that drug resistance and disease recurrence may be overcome by targeting the Hh signaling pathway. Methods: CA180-363 is a phase 2 trial to assess dasatinib activity with or without SMO antagonist in pts with newly diagnosed Ph+ CML-CP. Pts receive dasatinib 100 mg QD for 12 months and are then randomized 1:1 to continuing dasatinib 100 mg QD with or without SMO antagonist up to 24 months, followed by dasatinib 100 mg QD alone until end of study (60 months). Randomization is stratified by Sokal score at diagnosis and major molecular response (MMR) at 12 months (yes/no). Eligible pts are aged ≥18 years, have an Eastern Cooperative Group (ECOG) performance status of 0-2, and previously untreated Ph+ CML-CP diagnosed within 6 months of enrollment. Primary endpoint (evaluated in pts who do not achieve MMR prior to randomization) is comparison of MMR rates for dasatinib alone vs dasatinib plus SMO antagonist. Other endpoints (evaluated in all pts) are complete molecular response, progression-free survival, event-free survival, transformation-free survival, and safety of the combination regimen. Recruitment started in September 2011 (14 pts enrolled to date); estimated primary completion date is November 2014. ClinicalTrials.gov ID: NCT01357655.
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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) | 0.003 | 0.001 |
| Meta-epidemiology (broad) | 0.003 | 0.002 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.002 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.004 |
| Insufficient payload (model declined to judge) | 0.010 | 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".