Breast Cancer Clinical Trials

‣ Subjects must meet all of the following criteria to be eligible for enrollment in this clinical study:

• Voluntarily participate in the clinical trial and sign the informed consent form.

• Female, aged ≥18 years.

• Able to provide blood samples for central laboratory testing of ESR1 mutation status and other biomarker assessments. Phase I Study: ESR1 mutation status will be tested retrospectively. Phase II Study: Only subjects with confirmed ESR1 mutations will be enrolled (see Appendix 5 for details).

• Histologically or cytologically confirmed locally advanced or metastatic breast cancer that is ER-positive and HER2-negative.

• Criteria for ER positivity: Immunohistochemistry staining shows nuclear staining in ≥10% of tumor cells.

• Criteria for HER2 negativity: Immunohistochemistry staining intensity is 0 or 1+; if the intensity is 2+, it must be confirmed negative by in situ hybridization.

• Confirmed in menopause and not caused by ovarian function suppression drugs, must meet one of the following criteria:

• Previous bilateral oophorectomy. Age ≥ 60 years.

• Age \< 60 years (subdivided into the following conditions):

‣ Never received chemotherapy, ovarian function inhibitors, or SERM drugs (tamoxifen, toremifene), with amenorrhea ≥12 months, and E2 and FSH levels in the postmenopausal range.

‣ Received chemotherapy resulting in chemotherapy-induced amenorrhea ≥12 months, with E2 and FSH levels in the postmenopausal range.

‣ Using SERM drugs (tamoxifen, toremifene), with E2 and FSH levels in the postmenopausal range.

• Premenopausal or perimenopausal female subjects must agree to receive and maintain treatment with ovarian function suppression (LHRH agonists) during the study treatment period (ovarian function suppression treatment must be initiated at least 14 days before the first dose of study drug).

• Prior treatment history must meet the following requirements:

∙ Disease progression during or intolerance to standard therapy, or unsuitability for standard therapy.

‣ Previous adjuvant endocrine therapy for at least 2 years, with recurrence during treatment or within 1 year after completion; OR at least one line of endocrine therapy for the advanced stage, with progression after at least 6 months of maintenance therapy on any line of advanced endocrine therapy (no limit on the number of endocrine therapy lines).

‣ Previous chemotherapy for the advanced stage is ≤ 2 lines.

‣ Prior use of fulvestrant, with an interval of at least 6 weeks between the last dose of fulvestrant and the first dose in this study.

‣ An interval of at least 6 weeks is required between the last dose of prior tamoxifen and the first dose in this study.

‣ Previous treatment with CDK4/6 inhibitors is ≤ 1 line.

• Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 (see Appendix 1 for details).

• At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Tumor lesions that have previously received radiotherapy or other local-regional treatment can only be considered measurable lesions if disease progression is confirmed.

⁃ Expected survival ≥ 3 months.

⁃ Subjects must have adequate organ and bone marrow function at screening (no blood transfusion, human albumin administration, or use of hematopoietic growth factors within 7 days prior to screening tests), defined as follows:

• Complete Blood Count:

• Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L. White blood cell count (WBC) ≥ 3.0 × 10⁹/L and ≤ 15 × 10⁹/L. Platelet count (PLT) ≥ 100 × 10⁹/L. Hemoglobin (HGB) ≥ 100 g/L.

∙ Liver Function:

• Serum total bilirubin (TBIL) ≤ 1.5 × ULN. For subjects without liver metastases: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN.

• For subjects with liver metastases: ALT and AST ≤ 5 × ULN.

∙ Renal Function:

• Serum creatinine (Scr) ≤ 1.5 × ULN OR creatinine clearance (Clcr) calculated by the Cockcroft-Gault method ≥ 50 mL/min.

∙ Coagulation Function:

• Activated partial thromboplastin time (APTT) ≤ 1.5 × ULN.

• International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN (for subjects on anticoagulant therapy, values should be within the therapeutic range):

⁃ For patients receiving warfarin, INR must be stable between 2.0 and 3.0.

⁃ For patients receiving heparin, APTT should be between 1.5 and 2.5 × ULN (or returned to the value prior to starting heparin therapy).

⁃ For prosthetic heart valves requiring anticoagulation, a stable INR between 2.5 and 3.5 is allowed.

∙ Cardiac Function:

⁃ Left ventricular ejection fraction (LVEF) \> 50% as shown by echocardiography.

⁃ Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to the first dose and must be non-lactating. Women of childbearing potential must agree to use effective contraceptive methods from the time of signing the informed consent form until 6 months after the last dose of the study drug. Effective methods include double barrier methods, condoms, oral or injectable contraceptives, intrauterine devices, etc. All female subjects will be considered of childbearing potential unless they are naturally postmenopausal, have undergone artificial menopause, or have undergone sterilization (e.g., hysterectomy, bilateral salpingo-oophorectomy).