Sirolimus for Injection (Albumin-bound) Combined With Fulvestrant for HR+/HER2- Advanced/Metastatic Breast Cancer Patients Previously Treated With CDK4/6 Inhibitors

A Randomized, Double-blind, Multicenter Phase III Clinical Study to Evaluate the Efficacy and Safety of Sirolimus for Injection (Albumin-bound) Combined With Fulvestrant Versus Placebo Combined With Fulvestrant in HR-positive, HER2-negative Locally Advanced or Metastatic Breast Cancer Patients After Prior CDK4/6 Inhibitor Treatment.

A randomized, double-blind, multicenter phase III clinical study to evaluate the efficacy and safety of sirolimus for injection (albumin-bound) combined with fulvestrant in patients with HR+ and HER2- advanced breast cancer.

Inclusion Criteria:

• 1. Aged 18 or above, regardless of gender; female patients must be postmenopausal, or premenopausal/perimenopausal.
• 2. Pathologically confirmed HR+, HER2- breast cancer.
• 3. Locally advanced or metastatic breast cancer, not suitable for curative surgery or radiotherapy, and no current clinical indication for chemotherapy.
• 4. Previously received at least one, up to two lines of systemic therapy (including at least one line of endocrine therapy combined with CDK4/6 inhibitor therapy).
• 5. At least one measurable lesion according to RECIST 1.1 criteria.
• 6. Willing to provide tumor and/or blood samples for biomarker testing; if unable to provide, subject to investigator and sponsor evaluation for eligibility.
• 7. ECOG performance status score of 0-1.
• 8. Investigator-assessed life expectancy ≥6 months.
• 9. Adequate organ and bone marrow function.
• 10. Premenopausal female patients using LHRH agonists to suppress ovarian function must agree to use two acceptable forms of highly effective contraception during the study and for 2 years after stopping study treatment; female patients of childbearing potential must have a negative pregnancy blood test before starting study treatment and must not be breastfeeding.
• 11. Male patients must agree to use barrier contraception (i.e., condoms) during the study and for 2 years after stopping study treatment; for men with future fertility plans, sperm freezing is recommended before starting study treatment.
• 12. Participants must provide informed consent before the trial and voluntarily sign the written ICF.

Exclusion Criteria:

• 1. Previous pathological diagnosis of HER2-positive breast cancer.
• 2. Patients judged by the investigator to be unsuitable for endocrine therapy.
• 3. Patients who have previously received PI3K/AKT/mTOR inhibitors, fulvestrant, or other ER-targeted therapies (including oral SERDs, ER protein degraders PROTAC, etc.).
• 4. Received chemotherapy, radiotherapy, biological therapy, targeted therapy, immunotherapy, or other anti-tumor treatments within 4 weeks before randomization.
• 5. Received other unapproved investigational drugs within 4 weeks before randomization.
• 6. Underwent major surgery within 4 weeks before randomization or has not fully recovered from any previous invasive procedures.
• 7. Received systemic glucocorticoids (prednisone >10 mg/day or equivalent) or other immunosuppressive treatments within 2 weeks before randomization.
• 8. Had an infection within 2 weeks before randomization requiring systemic (oral or IV) anti-infective treatment (uncomplicated urinary tract infections or upper respiratory tract infections excluded).
• 9. Received inactivated or live attenuated vaccines or COVID-19 vaccines within 4 weeks before randomization.
• 10. Used strong inhibitors or inducers of CYP3A4 hepatic metabolic enzymes within 2 weeks before randomization or still need to continue using such drugs.
• 11. Diagnosed with other malignancies within 5 years before randomization.
• 12. Suffering from severe cardiovascular or cerebrovascular diseases.
• 13. Adverse reactions from previous anti-tumor treatments have not recovered to CTCAE 5.0 grade ≤1.
• 14. Active leptomeningeal disease or poorly controlled central nervous system metastases.
• 15. Presence of pleural/abdominal effusion or pericardial effusion with clinical symptoms or requiring symptomatic treatment.
• 16. Known bleeding tendency (constitution) or coagulation disorders.
• 17. History of severe lung diseases such as interstitial lung disease and/or pneumonia, pulmonary hypertension, or radiation pneumonitis requiring glucocorticoid treatment.
• 18. Known hypersensitivity or intolerance to any component of the study drug or its excipients, or LHRH agonists (if applicable).
• 19. History of autoimmune diseases (except tuberous sclerosis), immunodeficiency diseases, including HIV-positive, or other acquired or congenital immunodeficiency diseases, or organ transplant history.
• 20. Active HBV, HCV, syphilis, or tuberculosis infection.
• 21. Other conditions judged by the investigator to be unsuitable for participation in this study.