TWT-203: Phase 1b/2 dose-confirming study of CFI-402257 as a single agent in advanced solid tumors and in combination with fulvestrant in patients with ER+/HER2- advanced breast cancer after disease progression on prior CDK4/6 and endocrine therapy.
Bibliographic record
Abstract
TPS1123 Background: TTK (Threonine Tyrosine Kinase also known as Monopolar spindle 1 [Mps1]), is a dual-specificity serine-threonine kinase critical for anaphase promoting complex/cyclosome inhibition at the spindle assembly checkpoint, and is required for chromosome alignment and error correction. Inhibition of TTK causes cells to prematurely exit mitosis with unattached chromosomes, resulting in aneuploidy and cell death. Higher TTK tumor levels correlate with worse prognosis and may contribute to the survival and proliferation of aneuploid cells. CFI-402257, a potent and selective inhibitor of TTK inhibits the growth of a variety of human cancer-derived cell lines with IC50 of 8-40 nM. A first-in-human phase 1 study of CFI-402257 administered orally as a single agent, demonstrated a tolerable safety profile and evidence of clinical activity in patients with advanced solid tumors. The MTD was 168 mg daily, and the study expanded to 3 cohorts: solid tumors, HER2-negative breast cancer, and hormone receptor positive (HR+/HER2-) breast cancer in combination with fulvestrant. The dose limiting toxicity was manageable and reversible dose-dependent neutropenia. Investigator-confirmed partial responses (cPR) were observed in 5 patients (10.6%) with 25 (53.2%) exhibiting disease control. In the HR+/HER2- breast cancer population previously treated with cyclin dependent kinase 4/6 inhibitors (CDK4/6i) and aromatase inhibitors, there were 4 cPR’s with a median duration of response of 256 days, with responses emerging after 2 cycles of therapy. Responses were observed with CFI-402257 as a single agent and in combination with fulvestrant. Based on these data, study TWT-203 will focus on advanced solid tumors and advanced HR+/HER2- breast cancers in combination with an approved endocrine therapy. Methods: Safety and clinical activity of CFI-402257 monotherapy will be evaluated in patients with advanced solid tumors (Part A) or in combination with fulvestrant in patients with HR+/HER2- advanced breast cancer (Part B). Part A will confirm the RP2D using a 3+3 design with a starting dose of 126 mg daily. Part B evaluates CFI-402257 in combination with fulvestrant in patients with HR+/HER2- advanced breast cancer following progression on prior CDK4/6i and endocrine therapy. Initially 6 patients will be treated with CFI-402257 and fulvestrant, and safety, tolerability, and PK evaluated, with further expansion to confirm the RP2D and characterize CFI-402257 activity. Efficacy endpoints include overall response rate and disease control rate. Safety endpoints include incidence of treatment emergent adverse events. Exploratory objectives include characterization of protein and molecular alterations relevant to the cell cycle and CFI-402257 response.
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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 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.004 |
| 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".