Abstract PO2-20-04: TACTIVE-U: phase 1b/2 umbrella study of vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, combined with other anticancer treatments in ER–positive advanced or metastatic breast cancer
Bibliographic record
Abstract
Abstract Background: Vepdegestrant (ARV-471), an oral PROTAC ER degrader, was well tolerated and showed evidence of clinical activity in the first-in-human phase 1/2 study in heavily pretreated patients with ER+/human epidermal growth factor receptor 2–negative (HER2-) advanced breast cancer (NCT04072952). The cyclin-dependent kinase (CDK)4/6 inhibitors abemaciclib and ribociclib are approved in combination with an aromatase inhibitor or fulvestrant, or as monotherapy (abemaciclib), for ER+/HER2- advanced or metastatic breast cancer. In preclinical studies, vepdegestrant combined with abemaciclib or ribociclib showed evidence of synergistic interactions in ER+ breast cancer cells and greater tumor growth inhibition in a xenograft breast cancer model compared with fulvestrant in combination with these agents. Inhibitors targeting different CDKs, such as samuraciclib (oral CDK7 inhibitor), are in clinical development for solid tumors. The open-label, phase 1b/2 TACTIVE-U umbrella study will evaluate the safety, efficacy, and pharmacokinetics of vepdegestrant in combination with other anticancer treatments in patients with ER+ advanced or metastatic breast cancer. Vepdegestrant is being evaluated in combination with abemaciclib (sub-study A; NCT05548127), ribociclib (sub-study B; NCT05573555), and samuraciclib (sub-study C). Trial Design: Patients eligible for current sub-studies of TACTIVE-U are aged ≥18 years, have histologically or cytologically confirmed ER+/HER2- advanced or metastatic breast cancer not amenable to surgical resection, and have received prior therapy for advanced or metastatic disease, including any CDK4/6 inhibitor–based regimen in any setting. In each sub-study, patients will receive vepdegestrant orally once daily (QD) continuously in a dose escalation/de-escalation approach. Abemaciclib will be given orally twice daily continuously in sub-study A, ribociclib will be given orally QD for 21 days followed by 7 days off treatment in sub-study B, and samuraciclib will be given orally QD continuously in sub-study C. For all sub-studies, the primary endpoint of the phase 1b portion is dose-limiting toxicities to determine the recommended phase 2 dose of vepdegestrant in combination with the other anticancer treatment. Secondary endpoints of phase 1b are antitumor activity (objective response, clinical benefit rate [CBR], and duration of response [DOR]), progression-free survival (PFS), safety (type, frequency, and severity of adverse events and laboratory abnormalities), and plasma concentrations of study drugs. The phase 2 portion of each sub-study will further evaluate the antitumor activity of the combinations; the primary endpoint is objective response and secondary endpoints include antitumor activity (CBR and DOR), PFS, overall survival, safety, plasma concentration of study drugs, and changes in circulating tumor DNA. Future combination sub-studies will be included in TACTIVE-U. Citation Format: Claudine Isaacs, Katarzyna Jerzak, John Hilton, José Luiz Miranda Guimarães, Rachel Layman, Dongrui Lu, Gary Mo, Anna Maria Calella, Olga Valota, Sibyl Anderson, Cynthia Ma. TACTIVE-U: phase 1b/2 umbrella study of vepdegestrant, a PROteolysis TArgeting Chimera (PROTAC) estrogen receptor (ER) degrader, combined with other anticancer treatments in ER–positive advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-20-04.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.002 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.002 | 0.004 |
| Insufficient payload (model declined to judge) | 0.006 | 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".