Culmerciclib in HR+/HER2+ Advanced Breast Cancer

Prior treatment

• Patients with extensive leptomeningeal metastases that are poorly controlled with corticosteroids or other dehydrating agents, or requiring urgent radiotherapy.
• Symptomatic active brain metastases requiring urgent cranial radiotherapy. Patients with asymptomatic CNS metastases are allowed.
• 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.
• Prior anti-tumor therapy with unresolved adverse events/reactions before study initiation.
• Concurrent receipt of other anti-tumor therapy.
• 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.

Other illness

• Disease progression after whole-brain radiotherapy or stereotactic radiosurgery to all intracranial lesions.
• History of grade 3 or 4 allergic reactions related to study drugs.
• History of clinically significant cardiovascular, hepatic, respiratory, renal, hematologic, endocrine, or neuropsychiatric disorders.
• Any severe underlying disease, comorbidity, or active infection.
• History of epilepsy or seizure predisposition.
• Known hypersensitivity to the study drugs.
• Other conditions judged by the investigator that may interfere with the conduct or outcome of the study.

Lab values

• 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.
• 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.

Other

• Pregnant or breastfeeding women.
• Poor compliance or inability to attend scheduled follow-up visits.

• Female patients aged 18 years and older with pathologically confirmed metastatic or locally advanced unresectable breast cancer.
• 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%.
• Patients must have available tumor tissue specimens for biomarker analyses including whole-exome sequencing.
• 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.
• 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.