A Clinical Trial Comparing the Efficacy and Safety of Different Doses of BL0175 Injection in Treating Postmenopausal Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Locally Advanced or Metastatic Breast Cancer

A Randomized, Open-Label, Multicenter Phase II Clinical Trial: Comparing the Efficacy and Safety of Different Doses of BL0175 Injection in Treating Postmenopausal Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Locally Advanced or Metastatic Breast Cancer Patients

The goal of this clinical trial is to compare the objective response rates (ORR) of different doses of BL0175 in patients with postmenopausal hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer. The main questions it aims to answer are:

1. Which dose level of BL0175 demonstrates the optimal ORR?
2. What is the recommended phase 3 dose (RP3D) based on efficacy and safety data across the tested dose levels?

Inclusion Criteria:

1. Voluntary participation in the trial, understanding the specific procedures of the trial, and willing to sign a written informed consent form.
2. Age ≥ 18 years.
3. HR positive, HER2 negative, with locally advanced or metastatic breast cancer in postmenopausal patients during or after endocrine therapy.
4. The blood pregnancy test result during the screening period must be negative (if the postmenopausal state is caused by GnRH agonists).
5. If the postmenopausal state is caused by GnRH agonists, the trial participants must agree to take effective contraceptive measures from the time of enrollment until at least 2 years after the last administration of the study treatment. For patients with breast cancer, the use of estrogen-based hormonal contraceptive methods (including hormone-type intrauterine devices) is not allowed, while the efficacy of progestin-based hormonal contraceptive methods is currently unclear. Effective contraceptive measures include: a. Complete abstinence (if it is their preferred regular lifestyle); b. Intrauterine device; c. Bilateral tubal ligation; d. The partner has undergone vasectomy and confirmed no sperm; e. Dual barrier method (male condom combined with cervical cap, vaginal diaphragm, or contraceptive sponge in combination with spermicidal agent).
6. At least one measurable lesion exists.
7. The Eastern Cooperative Oncology Group (ECOG) status score at screening must be ≤ 1.
8. Life expectancy ≥ 12 weeks.

Exclusion Criteria:

1. Participants with symptomatic central nervous system (CNS) metastases or cancerous meningitis;

2. Have a history of other primary malignant tumors (except for participants who have been cured of skin basal cell carcinoma, skin squamous cell carcinoma, or cervical carcinoma in situ, and participants with other primary tumors that have no evidence of disease for 2 years or more and do not require treatment).

3. Patients whose pericardial effusion, pleural effusion or ascites remain uncontrollable after intervention.

4. Participants who have a history of allogeneic transplantation (including but not limited to allogeneic organ, bone marrow, or stem cell transplantation).

5. A history of allergic to fulvestrant, or prone to allergic reactions (such as prone to angioedema, urticaria, asthma, rash, etc.).

6. Severe cardiovascular or cerebrovascular diseases, including: Heart failure classified as New York Heart Association (NYHA) functional class III-IV (assessment only for patients with a history of heart disease), or left ventricular ejection fraction (LVEF) <50% (if LVEF data are available); Uncontrolled ventricular arrhythmias: baseline QT interval corrected by Fridericia method (QTcF) > 480 ms, or congenital long QT syndrome; Myocardial infarction, severe or unstable angina, congestive heart failure, cerebrovascular accident (including transient ischemic attack), symptomatic pulmonary embolism, or other clinically significant thromboembolic events occurring within 6 months prior to the first administration of the investigational drug, or coronary artery bypass graft surgery performed within 6 months prior to the first administration of the investigational drug; Clinically symptomatic bradycardia as assessed by the investigator; Other clinically significant cardiovascular diseases that, in the opinion of the investigator, make the patient unsuitable for participation in the trial.

7. Human immunodeficiency virus (HIV) infection or positive HIV antibody test at screening.

8. Active hepatitis B (HBV DNA ≥2000 IU/mL) or active hepatitis C (HCV RNA ≥200 IU/mL). Additionally, eligible participants with hepatitis B or C must agree to receive antiviral treatment according to established guidelines; otherwise, they will not be enrolled.

9. Active infection requiring intravenous antibiotic therapy within 1 week prior to the first administration of the investigational drug.

10. Moderate or severe hepatic impairment, defined as meeting Child-Pugh classification criteria B or C.

11. Insufficient organ function reserve at baseline, as defined by any of the following criteria (no blood products [including platelets or red blood cells] or colony-stimulating factors [including granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, or recombinant erythropoietin] administered within 7 days prior to testing): Absolute neutrophil count (ANC) <1.5×10⁹/L; Total bilirubin >1.5×ULN; ALT or AST >3×ULN if no liver metastasis is present; ALT or AST >5×ULN if liver metastasis is present; Hemoglobin (Hb) <90 g/L; Platelet count (PLT) <100×10⁹/L; International Normalized Ratio (INR) >1.5 (for patients on anticoagulant therapy, values within therapeutic range are acceptable); Creatinine clearance <30 mL/min.

12. Receipt of anti-tumor drugs or investigational agents within the following time intervals prior to the first administration of the investigational drug: Anti-tumor endocrine therapy, targeted small-molecule therapy, or radiotherapy (except palliative radiotherapy or radiotherapy not involving the planned target lesion) ≤14 days or 5 half-lives (whichever is shorter); Chemotherapy ≤28 days or 5 half-lives (whichever is shorter); Immunotherapy or cell therapy (e.g., chimeric antigen receptor T-cell therapy) ≤28 days; other forms of cell therapy must be discussed with the investigator to determine eligibility; Monoclonal antibodies used for anti-tumor treatment ≤28 days; Traditional Chinese medicine with a clearly defined anti-tumor indication ≤14 days; Immunosuppressive therapy for any reason ≤7 days; All other investigational drugs or devices ≤28 days or 5 half-lives (whichever is shorter).

13. Bleeding disorders (e.g., disseminated intravascular coagulation, deficiency of coagulation factors), or requiring long-term anticoagulant therapy (excluding antiplatelet therapy and low-dose warfarin or low-molecular-weight heparin).

14. Severe vascular embolic events requiring medical or surgical intervention.

15. Active autoimmune diseases requiring systemic treatment (including use of immunomodulatory agents, corticosteroids, or immunosuppressive drugs).

    Note: Patients with hyperthyroidism/hypothyroidism are eligible for enrollment. Hormonal replacement therapy and symptomatic treatments (e.g., levothyroxine for adrenal or pituitary insufficiency, insulin, or physiologic corticosteroid replacement) are not considered forms of systemic therapy and are permitted.

16. Received systemic corticosteroids within 4 weeks prior to the first administration of the investigational medicinal product (except low-dose corticosteroids, such as ≤20 mg prednisone per day or equivalent).

17. Underwent major surgery within 4 weeks prior to the first administration of the investigational medicinal product, or planned to undergo major surgery during the study period.

18. Currently pregnant or breastfeeding, or expected to become pregnant during the study period (from screening visit through 2 years after the last dose of study treatment).

19. Not recovered from toxicity related to prior treatment (including prior immunotherapy) and/or complications from surgical interventions to a CTCAE v6.0 grade ≤1.

    Note: Participants with stable chronic adverse events (≤grade 2) that are not expected to resolve spontaneously (e.g., peripheral neuropathy and alopecia) are allowed.

20. Any other condition deemed unsuitable for participation in this trial by the investigator.