Overview

This is a phase II, multicenter, open-label, single-arm clinical study. The purpose of this study is to evaluate the efficacy and safety of culmerciclib combined with anti-HER2 targeted therapy and endocrine therapy as maintenance treatment in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer.

Culmerciclib is a novel oral cyclin-dependent kinase 2/4/6 (CDK2/4/6) inhibitor. It has been approved in China for use in combination with fulvestrant in patients with HR-positive, HER2-negative advanced breast cancer who have progressed on prior endocrine therapy.

Patients enrolled in this study will receive culmerciclib at a stepwise escalating dose of 120 mg, 150 mg, and 180 mg once daily, in combination with anti-HER2 therapy (trastuzumab with or without pertuzumab) and physician-selected endocrine therapy. Treatment will continue until disease progression, unacceptable toxicity, death, withdrawal of consent, or loss to follow-up.

The primary endpoint is progression-free survival. Secondary endpoints include objective response rate, disease control rate, clinical benefit rate, overall survival, and safety.

Eligibility

Inclusion Criteria:

1. Female patients aged 18 years and older with pathologically confirmed metastatic or locally advanced unresectable breast cancer.
2. Hormone receptor-positive and HER2-positive disease. HER2 positivity is defined as immunohistochemistry (IHC) 3+ or IHC 2+ with HER2 gene amplification confirmed by fluorescence in situ hybridization (FISH). If multiple tumor specimens have been tested, the most recent test result shall be used. Hormone receptor positivity is defined as estrogen receptor (ER) expression of at least 10%.
3. Patients must have available tumor tissue specimens for biomarker analyses including whole-exome sequencing.
4. Patients with brain metastases are eligible if they have asymptomatic central nervous system (CNS) metastases, defined as no CNS symptoms or symptoms are controlled and do not require urgent radiotherapy.
5. Prior radiotherapy, chemotherapy, or anti-HER2 targeted therapy received in the neoadjuvant or adjuvant setting is permitted.

5、Patients must have achieved a response to first-line systemic anti-tumor therapy for locally recurrent or metastatic disease, with at least 4 cycles of chemotherapy completed and no evidence of radiographic progression.

6、Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 1. 7、Life expectancy of at least 12 weeks. 8、Adequate major organ function as defined by the following criteria: Hematologic function: absolute neutrophil count (ANC) ≥1.5×10⁹/L, platelet count ≥75×10⁹/L, hemoglobin ≥85 g/L (without transfusion or use of G-CSF or other hematopoietic growth factors within 14 days prior to screening).

Biochemical function: total bilirubin (TBIL) \<1.5×upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \<2.5×ULN (or \<5×ULN in patients with liver metastases); blood urea nitrogen (BUN) and creatinine ≤1×ULN or calculated creatinine clearance ≥50 mL/min (Cockcroft-Gault formula).

9、Women of childbearing potential must have practiced reliable contraception or have a negative pregnancy test (serum or urine) within 7 days prior to enrollment, and must be willing to use appropriate contraception during the study and for 8 weeks after the last dose of study drug.

10、Patients must voluntarily sign informed consent, be willing and able to comply with the study protocol and follow-up visits.

Exclusion Criteria:

1. Patients with extensive leptomeningeal metastases that are poorly controlled with corticosteroids or other dehydrating agents, or requiring urgent radiotherapy.
2. Symptomatic active brain metastases requiring urgent cranial radiotherapy. Patients with asymptomatic CNS metastases are allowed.
3. Disease progression after whole-brain radiotherapy or stereotactic radiosurgery to all intracranial lesions.
4. Known spinal cord compression or active CNS metastases that have not been treated with surgery or radiotherapy, unless the condition has been stable for at least 1 month and corticosteroids have been discontinued for \>2 weeks.
5. History of grade 3 or 4 allergic reactions related to study drugs.
6. History of clinically significant cardiovascular, hepatic, respiratory, renal, hematologic, endocrine, or neuropsychiatric disorders.
7. Acute or chronic active hepatitis B (defined as hepatitis B surface antigen and/or hepatitis B core antibody positive with HBV DNA ≥1×10³ copies/mL or ≥200 IU/mL) or acute or chronic active hepatitis C antibody positive; patients with positive hepatitis C antibody but negative RNA test are eligible.
8. Prior anti-tumor therapy with unresolved adverse events/reactions before study initiation.
9. History or evidence of any condition, therapy, or laboratory abnormality that might interfere with the study results or preclude the patient's full participation, or other conditions deemed unsuitable for enrollment by the investigator.
10. Any severe underlying disease, comorbidity, or active infection.
11. Concurrent receipt of other anti-tumor therapy.
12. History of epilepsy or seizure predisposition.
13. Pregnant or breastfeeding women.
14. Poor compliance or inability to attend scheduled follow-up visits.
15. Known hypersensitivity to the study drugs.
16. Diagnosis of another malignancy within 3 years, except for the following: surgically resected non-melanoma skin cancer, adequately treated cervical carcinoma in situ, localized prostate cancer treated with curative intent, ductal carcinoma in situ treated with curative surgery, or malignancy diagnosed \>2 years prior with no evidence of disease and not treated within ≤2 years before randomization.
17. Other conditions judged by the investigator that may interfere with the conduct or outcome of the study.