A Study of SHR-A1811 and Fulvestrant, With or Without HS-10352, in Locally Advanced or Metastatic Breast Cancer Patients

A Phase Ib/II Study of SHR-A1811 and Fulvestrant in Combination With or Without HS-10352 in Locally Advanced or Metastatic Breast Cancer Patients Who Progressed After Adjuvant Therapy

This study is being conducted to evaluate the efficacy and safety of SHR-A1811 and Fulvestrant in Combination with or without HS-10352 in locally advanced or metastatic breast cancer patients. Subjects will receive SHR-A1811 and Fulvestrant in Combination with or without HS-10352.

This study plans to enroll breast cancer patients whose disease progressed during treatment or within 12 months of completing adjuvant therapy and who have not received prior systemic therapy. SHR-A1811 + fulvestrant group will receive treatment with SHR-A1811 and fulvestrant. HS-10352 group will receive treatment with SHR-A1811, fulvestrant, and HS-10352. Treatment will continue until disease progression or the occurrence of intolerable toxicity.

Inclusion Criteria:

1. Female patients aged ≥18 years and ≤75 years;
2. ECOG Performance Status of 0 -2;
3. Locally advanced/metastatic breast cancer not amenable to curative therapy
4. Disease progression during treatment or within 12 months of completing adjuvant therapy ;
5. No prior anti-cancer systemic therapy has been administered;
6. Fasting blood glucose < 126 mg/dL, and HbA1C < 6.0%;
7. Life expectancy of ≥3 months;
8. Patients have at least one target lesion according to RECEST 1.1;
9. Adequate function of major organs;
10. Female patients who are either premenopausal or have not undergone surgical sterilization: during the treatment period and for at least 7 months after the final dose of study medication, agree to abstain from sexual activity or utilize effective contraceptive methods.
11. Sign Informed Consent Form.

Exclusion Criteria:

1. Breast cancer that has not been histologically confirmed;
2. Inflammatory breast cancer;
3. Participants ineligible for endocrine therapy due to any disease burden, as judged by the investigator;
4. Meningeal metastasis or active parenchymal brain metastasis;
5. Presence of diabetes symptoms, history of primary diabetes, gestational diabetes, steroid-induced diabetes, or other secondary diabetes;
6. Prior anti-cancer systemic therapy has been administered;
7. Use of investigational drugs within 4 weeks；
8. Received immunotherapy, macromolecular targeted therapy, or other antitumor biologics within 4 weeks; or received endocrine therapy, chemotherapy, small molecule targeted drug therapy, or traditional Chinese medicine treatment with antitumor indications within 2 weeks;
9. Received radical radiotherapy within 4 weeks, or received palliative radiotherapy within 2 weeks;
10. Previously received antitumor treatment or radiotherapy for any malignancy, excluding malignancies such as cured cervical carcinoma in situ, basal cell carcinoma, or squamous cell carcinoma;
11. A history of other malignancies within the past 5 years, excluding cured cases of skin basal cell carcinoma and cervical carcinoma in situ;
12. Prior anti-tumor treatment toxicities have not yet recovered to NCI CTCAE V5.0 grade ≤1 or baseline levels;
13. A history of immunodeficiency, including HIV positivity, other acquired or congenital immunodeficiency diseases, or a history of organ transplantation;
14. Interstitial pneumonia/interstitial lung disease, or presence of moderate to severe pulmonary disease that may interfere with the detection or management of drug-related pulmonary toxicity within 3 months prior to the first administration of the study drug, as well as any autoimmune, connective tissue, or inflammatory diseases involving the lungs, or a history of total pulmonary resection surgery
15. Presence of active hepatitis B, hepatitis C, liver cirrhosis, or severe infections requiring control with antibiotics, antiviral drugs, or antifungal medications;
16. History of hereditary or acquired bleeding and thrombotic tendencies (such as haemophilia, coagulation disorders, etc.);
17. Inability to swallow, intestinal obstruction, or the presence of other factors affecting drug intake and absorption;
18. Patients with known allergies or contraindications to the study drug and its excipient components;
19. Female patients who are pregnant or lactating, those of reproductive potential with a positive baseline pregnancy test, or those of reproductive age who are unwilling to use effective contraceptive measures throughout the entire study period;
20. According to the investigator's judgment, patients with severe concomitant diseases that pose a risk to their safety or prevent them from completing the study, a history of definite neurological or psychiatric disorders, including epilepsy or dementia, or any other condition deemed by the investigator to make the patient unsuitable for participation in this study.