This study adopts multicenter/randomized trial design. It plans to enroll patients with HR- positive, HER2- negative advanced breast cancer who are resistant to (neo)adjuvant endocrine therapy. Dose-escalation and dose-expansion studies will be carried out to evaluate the safety, tolerability, and preliminary efficacy of sirolimus (albumin-bound) in combination with palbociclib and fulvestrant in this patient population.
1. Subjects should be over 18 years old, regardless of gender.
2. Histologically or cytologically confirmed HR - positive, HER2 - negative advanced breast cancer.
3. For patients in the dose escalation stage, there are no limitation on previous treatments. The investigator must assess whether the patients are currently suitable for enrollment and eligible to receive the study drug treatment. For patients in the dose expansion stage need to meet the following criteria: The patient has received (neo)adjuvant endocrine therapy and has evidence of radiographic recurrence or progression during the treatment or within 12 months after the end of the treatment. The patient is allowed to receive no more than one line of systemic chemotherapy at the recurrence and metastasis setting. The patient has not received CDK4/6 inhibitor treatment at the recurrence and metastasis setting.
4. At least one measurable lesion meeting RECIST V1.1 criteria (patients with bone-only metastases may be enrolled in the dose escalation stage).
1. Previously diagnosed with HER2 - positive breast cancer through pathological examination.
2. Patients deemed by the investigator as unsuitable for endocrine therapy (e.g., those with visceral crisis posing immediate life-threatening risks in the short term, including: uncontrolled massive effusions [pleural, pericardial, or peritoneal], pulmonary lymphangitic carcinomatosis, or hepatic involvement >50%).
3. Patients who have previously received treatment with fulvestrant or inhibitors such as PI3K/AKT/mTOR.
4. Patients with uncontrolled third-space fluid accumulation (e.g., pericardial effusion, pleural effusion, or ascites) requiring repeated drainage or other therapeutic interventions, and deemed ineligible for enrollment by investigators.