A Study of BEBT-209 Plus Chemotherapy in Patients With Locally Advanced or Metastatic Triple-Negative Breast Cancer

1. Study Overview This is a randomized, controlled, open-label, multi-center, Phase IIb/III study designed to systematically evaluate the efficacy and safety of BEBT-209 (a selective cyclin-dependent kinase 4/6 \[CDK4/6\] inhibitor) in combination with carboplatin and gemcitabine (CG) compared to CG alone. The study is conducted in patients with locally advanced or metastatic triple-negative breast cancer (TNBC). 2. The trial is structured into two stages: Phase IIb (Proof of Concept): Primarily focused on assessing the objective response rate (ORR) in approximately 60 participants. Phase III (Confirmatory): A pivotal stage focused on overall survival (OS) in approximately 386 participants. 3. Scientific Rationale: Triple-negative breast cancer remains a highly aggressive subtype with limited treatment options once initial therapies fail. BEBT-209 acts as a highly selective CDK4/6 inhibitor. By arresting the cell cycle at the G1 phase, BEBT-209 synchronizes tumor cells, making them more susceptible to chemotherapy-induced DNA damage. Preclinical and early-phase clinical data suggest that BEBT-209 not only enhances the sensitivity of TNBC cells to carboplatin and gemcitabine but also provides a myeloprotective effect, reducing chemotherapy-induced bone marrow suppression. 4. Study Design and Intervention: Eligible participants are randomly assigned in a 1:1 ratio to either the experimental group or the control group via a central randomization system. Experimental Group: Participants receive BEBT-209 (150 mg, four times per cycle on Day 1 \[D1\], Day 2 \[D2\], Day 8 \[D8\], and Day 9 \[D9\]) combined with carboplatin (area under the curve \[AUC\] × \[creatinine clearance {CrCl} + 25\]) and gemcitabine (1000 mg/m²). The AUC value is set to 2 mg/mL/min in this study. Control Group: Participants receive carboplatin (2 \[mg/mL/min\] × \[CrCl {mL/min} + 25\]) and gemcitabine (1000 mg/m²) on Day 1 (D1) and Day 8 (D8) of each 21-day cycle. 5. Stratification Factors: Phase IIb: Lines of prior therapy (1st-line vs. 2nd-line). Phase III: (1) Lines of prior systemic therapy; (2) Prior programmed cell death-1/programmed death-ligand 1 (PD-1/PD-L1, or PD-\[L\]1) inhibitor therapy (yes vs. no); (3) Prior TROP2 antibody-drug conjugate (ADC) therapy (yes vs. no). 6. Assessment and Follow-up: Tumor response is evaluated every 6 weeks for the first three assessments, then every 9 weeks, and eventually every 12 weeks after one year, based on Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 criteria. Independent Review: An independent review committee (IRC) will perform a blinded central review of all imaging data to provide a baseline-independent assessment of ORR and progression-free survival (PFS). Safety Monitoring: Safety is assessed through adverse events (AE), graded by Common Terminology Criteria for Adverse Events version 6.0 of the National Cancer Institute (NCI-CTCAE v6.0), physical exams, and laboratory monitoring. Special focus is placed on hematological toxicities (e.g., duration of severe neutropenia \[DSN\]). Pharmacokinetics and Biomarkers: A subset of participants in Phase IIb will undergo pharmacokinetics (PK) sampling. Exploratory analyses will investigate the relationship between biomarkers (e.g., PD-L1, BRCA1/2) and clinical outcomes.