Efficacy and Safety of Culmerciclib Plus Aromatase Inhibitors in a Response-Adapted Neoadjuvant Strategy for Highly Proliferative ER-Positive/HER2-Negative Breast Cancer

This is a prospective, response-adapted, phase II study designed to evaluate an individualized neoadjuvant treatment strategy based on culmerciclib in combination with aromatase inhibitors in patients with highly proliferative ER-positive/HER2-negative early breast cancer. The study incorporates an adaptive treatment algorithm guided by on-treatment assessment of tumor response, with the aim of optimizing therapeutic efficacy while minimizing unnecessary treatment exposure.

All eligible patients initially receive neoadjuvant treatment with culmerciclib plus endocrine therapy according to the study protocol. Following completion of a predefined initial treatment phase, tumor response is assessed using biological and clinical evaluation methods.

Patients who achieve an adequate response continue the same neoadjuvant regimen to complete the planned course of therapy. In contrast, patients demonstrating a suboptimal response are transitioned to alternative treatment strategies prior to surgery. Subsequent treatment selection and management are conducted according to protocol-defined principles and investigator assessment.

This response-adapted strategy is intended to address the clinical heterogeneity of endocrine sensitivity in ER-positive/HER2-negative breast cancer. By tailoring treatment intensity according to early response, the study seeks to maximize therapeutic benefit in responsive patients while facilitating timely treatment modification for those less likely to benefit from the initial regimen.

Primary and secondary objectives include evaluation of clinical efficacy, safety and tolerability of the response-adapted neoadjuvant strategy, and the feasibility of treatment modification based on early response assessment. Exploratory analyses will investigate potential biomarkers associated with treatment response and resistance, with the goal of informing future individualized treatment approaches.

Inclusion criteria

Female patients aged ≥18 and ≤75 years. Histologically confirmed estrogen receptor (ER)-positive (≥10%) and HER2-negative breast cancer, according to the 2018 ASCO/CAP guidelines. HER2-negative status is defined as immunohistochemistry (IHC) 0 or 1+, or IHC 2+ with negative in situ hybridization (ISH) (ISH ratio <2.0), as confirmed by a certified pathology laboratory.

Ki-67 ≥20% assessed on core needle biopsy samples. Newly diagnosed, treatment-naïve patients with stage I-IIIA disease according to the AJCC 8th edition.

Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

Adequate bone marrow function:

• Absolute neutrophil count ≥1.5 × 10⁹/L (without growth factor support within 14 days);
• Platelet count ≥100 × 10⁹/L (without transfusion or supportive therapy within 7 days);
• Hemoglobin ≥100 g/L (without transfusion within 7 days).

Adequate hepatic and renal function:

• Total bilirubin ≤1 × upper limit of normal (ULN);
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 × ULN (≤5 × ULN in patients with liver metastases);
• Blood urea nitrogen and serum creatinine ≤1.5 × ULN, and creatinine clearance ≥50 mL/min (calculated using the Cockcroft-Gault formula).

Left ventricular ejection fraction (LVEF) ≥50% as assessed by echocardiography. QT interval ≤480 ms on 12-lead electrocardiogram (ECG). Ability and willingness to undergo tumor biopsy. Provision of written informed consent. Exclusion Criteria Prior receipt of any anticancer therapy, including chemotherapy, radiotherapy, targeted therapy, or endocrine therapy.

Concurrent treatment with other anticancer agents. Bilateral breast cancer, inflammatory breast cancer, or occult breast cancer. Stage IV breast cancer. Breast cancer not confirmed by histopathology. History of other malignancies within the past 5 years, except for adequately treated carcinoma in situ of the cervix.

Severe dysfunction of major organs, including heart, liver, or kidneys. Conditions affecting oral drug administration or absorption, including inability to swallow, chronic diarrhea, or intestinal obstruction.

Participation in another interventional clinical trial within 4 weeks prior to enrollment.

Known hypersensitivity to any component of the study drugs; history of immunodeficiency, including HIV infection, active hepatitis B or C infection, other acquired or congenital immunodeficiency disorders, or history of organ transplantation.

History of significant cardiovascular disease, including but not limited to clinically significant arrhythmias requiring treatment, myocardial infarction, heart failure, or any other cardiac condition deemed unsuitable by the investigator.

Pregnant or breastfeeding women; women of childbearing potential with a positive pregnancy test at baseline, or unwilling to use effective contraception during the study period.

Any serious concomitant disease that, in the investigator's judgment, may compromise patient safety or compliance with the study, including but not limited to uncontrolled hypertension, severe diabetes, or active infection.

History of neurological or psychiatric disorders, including epilepsy or dementia.

Any other condition that, in the investigator's opinion, makes the patient unsuitable for participation in the study.