A randomized phase I clinical and biologic study of two schedules of BAY 43–9006 in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML): A National Cancer Institute of Cancer Clinical Trials Group Study
Bibliographic record
Abstract
6611 Background: Components of the Ras pathway are becoming important targets in AML therapy. BAY 43–9006 (BAY) is a small molecule inhibitor of CRAF and BRAF kinases and the receptor tyrosine kinases VEGFR-2, PDGFR-β and flt-3 and is currently in phase II and III testing in solid tumors. This randomized phase I trial was initiated to establish optimal dose and schedule in patients (pts) with AML or MDS. Methods: Pts with AML or MDS (1 prior regimen or elderly or secondary high risk AML) were randomized to BAY for 28 days (continuous) or 14 days followed by a 14-day rest period, escalated at 100, 200 and 400 mg bid orally. Phospho-ERK levels were assessed in bone marrow (BM) blasts at baseline, day 15 and 28 by immunohistochemistry and in stem cell factor (SCF) stimulated peripheral blood (PB) blasts by a flow cytometry assay. Results: 36 pts have been enrolled (4 MDS, 32 AML; median age 70 range 50–82; prior chemotherapy: 17 pts) and received 100 mg bid (7 pts); 200 mg bid (12 pts); 400 mg bid (17 pts). Dose-limiting toxicity was seen in 0/7 pts at 100 mg bid, 2/12 pts at 200 mg bid and 1/17 pts at 400 mg bid. At 400 mg bid, 6 pts received <14 days of treatment due to gr 1 and 2 toxicity (abdominal pain, nausea, vomiting, rash, stroke, thrombocytopenia), indicating this dose was above tolerability. Accrual to an intermediate dose of 300 mg bid for 28 days is ongoing. Clinical effects (reduction in PB and BM blasts) have been seen in 4/27 evaluable pts: 2 at 200 mg bid (one 28 d, one 14 d schedule) and 2 at 400 mg bid (both on 28 d schedule). One pt at 400 mg bid with AML and a 30 bp internal tandem duplication in flt-3 had a confirmed CRp lasting 3 cycles. Biologic activity (inhibition of pERK in SCF stimulated PB blasts) has been assessed in 14 pts and shows drug-related inhibition in 5/14, all at 400 mg bid. Assessment of flt-3 mutational status, BM pERK staining and gene expression by 19K microarray will be presented. Conclusions: BAY appears to be well-tolerated when given continuously at 100–300 mg bid to pts with relapsed or high risk AML/MDS. Early clinical and biological activity is evident. No significant financial relationships to disclose.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.002 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.003 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.002 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.004 |
| Insufficient payload (model declined to judge) | 0.007 | 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".