TACTIVE-U: Phase 1b/2 umbrella study of ARV-471, a proteolysis targeting chimera (PROTAC) estrogen receptor (ER) degrader, combined with other anticancer treatments in ER+ advanced or metastatic breast cancer.
Bibliographic record
Abstract
TPS1121 Background: ARV-471, an oral PROTAC ER degrader, was well tolerated and showed evidence of clinical activity in a phase 1/2 study in heavily pretreated patients with ER+/human epidermal growth factor receptor 2 (HER2)- advanced breast cancer. The CDK4/6 inhibitors abemaciclib and ribociclib are approved in combination with endocrine therapy as first- and second-line treatment for ER+/HER2- advanced or metastatic breast cancer; abemaciclib is also approved as monotherapy and in combination with other agents in additional breast cancer settings. ARV-471 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. Here we describe the first sub-studies of the open-label, phase 1b/2 TACTIVE-U umbrella study, which evaluate the safety and clinical activity of ARV-471 plus abemaciclib (sub-study A; NCT05548127) and ribociclib (sub-study B; NCT05573555) in patients with ER+/HER2- advanced or metastatic breast cancer. Future combination sub-studies will be included in TACTIVE-U. Methods: Patients eligible for sub-studies A and B are aged ≥18 years, have histologically or cytologically confirmed ER+/HER2- advanced or metastatic breast cancer not amenable to surgical resection with ≥1 measurable lesion by RECIST 1.1, and have received ≤2 lines of prior therapy for advanced or metastatic disease and 1 line of any CDK4/6 inhibitor–based regimen in any setting. In sub-studies A and B, patients will receive ARV-471 orally once daily (QD) continuously in a dose escalation/de-escalation approach. In sub-study A, abemaciclib will be given orally twice daily continuously, and in sub-study B, ribociclib will be given orally QD for 21 days followed by 7 days off treatment. For both sub-studies, the primary endpoint of the phase 1b portion is dose-limiting toxicities to determine the recommended phase 2 dose of ARV-471 in combination with abemaciclib or ribociclib. Secondary endpoints of phase 1b are antitumor activity (overall response rate [ORR], 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. Phase 2 further evaluates the antitumor activity of the combinations; the primary endpoint is ORR and secondary endpoints include antitumor activity (CBR and DOR), PFS, overall survival, safety, plasma concentration of study drugs, and changes in circulating tumor DNA. Clinical trial information: NCT05548127 , NCT05573555 .
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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) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.002 | 0.003 |
| 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".