A phase Ia/Ib, open label, multicenter, dose-escalation study of BI 907828 (MDM2-p53 antagonist) in adult patients with advanced or metastatic solid tumors.
Bibliographic record
Abstract
TPS3166 Background: Inactivation of tumor protein 53 (TP53) is a central mechanism of tumors to promote survival and proliferation. The murine double minute 2 ( MDM2) oncogene is the primary cellular negative regulator of TP53. Small molecule inhibitors of the MDM2-p53 interaction are currently being evaluated in clinical trials as new anti-cancer drugs, and clinical data published to date support the rationale to target MDM2-amplified tumors. BI 907828 is a potent MDM2-p53 antagonist that has shown efficacy in mouse models of human cancer. Methods: NCT03449381 is a Phase 1a/1b, open-label, multicenter, dose-escalation trial of BI 907828 in patients aged ≥18 years with advanced/metastatic solid tumors. Primary objectives of the Phase 1a (dose-escalation) part are to determine: the maximum tolerated dose (MTD) of BI 907828 based on dose-limiting toxicities (DLTs) during the first treatment cycle; the recommended dose for expansion (RDE); safety and tolerability. Patients in Arm A will receive one dose of BI 907828 every 21 days, and patients in Arm B one dose on Days 1 and 8, every 28 days. Secondary objectives include pharmacokinetics (PK), pharmacodynamics (PD) [GDF-15 induction in plasma], and preliminary anti-tumor activity. Primary endpoints are the number of patients with DLTs during the first treatment cycle, and the MTD. Phase 1a will include ≈50 evaluable patients with locally advanced or metastatic solid tumors with either a known TP53 wild type (wt) status or unknown TP53 status, regardless of MDM2 amplification status at the time of study entry. The main objectives of Phase 1b (expansion cohorts) are to assess efficacy, safety, and PK profiles at the RDE, and to determine the recommended dose for Phase 2. The primary endpoint is objective response, where best response is determined according to RECIST v1.1, or RANO criteria for patients with glioblastoma. Phase 1b will include up to 150 evaluable patients with TP53 wt tumors, assigned to four different cohorts, including non-squamous NSCLC, soft tissue sarcoma, glioblastoma, urothelial carcinoma, and solid tumors with brain metastases. As of 8th February 2019, 11 patients have been enrolled. Clinical trial information: NCT03449381.
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| 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 | 0.001 | 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".