Oral EPI-7386 in patients with metastatic castration-resistant prostate cancer.
Bibliographic record
Abstract
177 Background: EPI-7386 is a next generation aniten, a novel class of compounds designed to inhibit androgen receptor (AR) activity by binding to the N-terminal domain. Preclinical data supports disruption of AR regulated gene transcription even in the presence of resistance mechanisms including ligand-binding domain point mutations and truncated splice variants. Here we report results of the Part 1a first-in-human trial of EPI-7386 in mCRPC (NCT04421222). Methods: This Phase 1, open-label, multicenter, dose escalation (Part 1a) and expansion (Part 1b) trial was designed to evaluate the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of EPI-7386 in mCRPC patients (pts) progressing on standard of care treatment, including next generation antiandrogen(s) and chemotherapy. Originally designed to assess up to 5 doses of EPI-7386 (200, 400, 600, 800, and 1000 mg QD), two additional cohorts were added examining 400 and 600 mg BID due to 600 mg QD showing exposure saturation while demonstrating a favorable safety profile. Results: 31 pts were enrolled in the QD cohorts and 8 in the BID cohorts. Pts had a median of 4 lines of prior therapy for mCRPC: 83% received abiraterone and at least one next generation AR inhibitor, and 58% had at least one line of prior chemotherapy. No DLTs were observed; EPI-7386 was safe and well tolerated at all doses/schedules evaluated. All related adverse events (AEs) were Grade 1 and 2 and consistent with AEs associated with second-generation antiandrogens. For doses above 400 mg QD, exposures were at or above those associated with antitumor activity in animal models. Evidence of antitumor activity (including significant and durable PSA responses and/or decreases in ctDNA, and/or radiographically documented tumor shrinkage) were observed in pts with fewer than 3 lines of treatment for mCRPC, no visceral metastases and no prior chemotherapy (9/31 pts). Conclusions: Part 1a treatment with EPI-7386 monotherapy was safe, well tolerated up to a daily dose of 1200 mg (600 mg BID), achieved target clinical exposures and showed preliminary signals of antitumor activity in heavily-pretreated mCRPC. Part 1b is open with enrollment focused on pre-chemotherapy, post-second generation antiandrogen treated mCRPC pts in one cohort, and treatment-naïve non-mCRPC pts in a window of opportunity proof-of-concept second cohort. Two doses will be evaluated (600 mg BID and QD) based on FDA Project Optimus recommendations. Clinical trial information: NCT04421222 .
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
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".