A phase 1 study of E7386, a CREB-binding protein (CBP)/β-catenin interaction inhibitor, in patients (pts) with advanced solid tumors including colorectal cancer: Updated dose-escalation part.
Bibliographic record
Abstract
106 Background: E7386 is a novel oral anticancer agent that inhibits the binding of β-catenin to its transcriptional co-activator, CBP, thereby modulating Wnt/β-catenin signaling. In preclinical studies, E7386 showed promising activity (eg, modulation of tumor angiogenesis, alteration of the immune microenvironment, and inhibition of tumor growth). At a prior cutoff point for the dose-escalation part of a phase 1 study of E7386 in pts with advanced solid tumors, we reported 2 dose-limiting toxicities (DLTs; both grade 3 decreased appetite) with E7386 160 mg twice daily (BID). Here we describe an update of the dose-escalation part of this phase 1 study—we mainly report updated safety, tolerability, and preliminary efficacy and biomarker results, which led to the inclusion of an additional dose level for investigation in the expansion part of this study. Methods: E7386 was administered orally in escalating doses on a BID continuous schedule in 28-day cycles. Adverse events (AEs) were graded using CTCAE v5.0. Tolerability was judged by DLTs during cycle 1 (C1). Tumor response was assessed every 8 weeks from C1 day (D) 1, or sooner if clinically indicated, and at the end of treatment by investigators using RECIST v1.1. Samples for pharmacokinetic analyses were collected on C1D1 and C1D8; samples for biomarker analyses were collected at protocol-defined time points. To determine the appropriate dose(s) for the expansion part of this study, additional investigation of the dose-escalation part was conducted. Results: As of the data cutoff (DCO) date (30 June 2022), 36 pts (24 men, 12 women; median age, 61.5 y) were enrolled in E7386 dose cohorts (10 to 160 mg BID). Doses were tolerable up to 120 mg BID. The most common treatment-related AEs (all grades; > 10%) were nausea (80.6%), vomiting (58.3%), aspartate aminotransferase increased (16.7%), and alanine aminotransferase increased, decreased appetite, and diarrhea (13.9% each). Nausea and vomiting were well-controlled with antiemetics such as 5HT3 antagonists, except in the 160 mg BID cohort. Two pts with a Wnt-related adenomatous polyposis coli (APC)- mutation (small bowel adenocarcinoma and desmoid tumor) showed a partial response. As of the DCO date, 2 pts (who continued on-treatment as of that date) had received over 1.5 y of E7386 treatment. The preliminary PK analysis showed plasma exposure of E7386 generally increased with an increasing dose over the assessed dose range. FGF21 levels in plasma increased following E7386 administration. Conclusions: E7386 120 mg BID was tolerated and determined as the recommended dose for the expansion part. Based on additional analyses of the dose-escalation part of this study, further investigation of safety, preliminary efficacy, PK, and biomarker analyses of E7386 is ongoing using 2 dose levels (100 and 120 mg BID) in the expansion part. Clinical trial information: NCT03833700 .
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| 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".