Neoadjuvant Culmerciclib Combined With Endocrine Therapy for Hormone Receptor-Positive， Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer

Neoadjuvant Culmerciclib Combined With Endocrine Therapy Versus Endocrine Therapy Alone for Hormone Receptor-positive, Human Epidermal Growth Factor Receptor 2-negative Breast Cancer: a Single-center, Open-label, Randomized-controlled Phase II Clinical Trial

This is a single-center, open-label, randomized phase II clinical trial designed to evaluate the efficacy and safety of neoadjuvant Culmerciclib combined with aromatase inhibitor versus aromatase-inhibitor monotherapy in patients with Hormone Receptor-positive, Human Epidermal Growth Factor Receptor 2-negative early-stage breast cancer.

Inclusion Criteria:

• Able to understand study procedures, voluntarily participate in the study, and provide written informed consent.

• Female patients aged ≥18 and ≤70 years with histopathologically confirmed untreated unilateral primary invasive breast cancer.

• Hormone-receptor positive (estrogen receptor immunohistochemical expression ≥10%), and HER2-negative (IHC 0-1+, or IHC 2+ with negative FISH test).

• Tumor size >2 cm or positive regional lymph nodes (TNM stage II-IIIA).

• At least one measurable target lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

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

• Adequate cardiac function meeting all of the following criteria:

  i. 12-lead electrocardiogram shows no abnormality or clinically insignificant changes requiring no medical intervention; ii. QTc interval ≤480 ms; iii. No history of torsades de pointes or other symptomatic QTc abnormalities; iv. Left-ventricular ejection fraction (LVEF) ≥50%.

• Adequate bone-marrow reserve: white blood cell count ≥3.0×10⁹/L; absolute neutrophil count ≥1.5×10⁹/L; platelet count ≥100×10⁹/L; hemoglobin ≥90 g/L.

• Adequate hepatic and renal function: AST and ALT ≤2.5 × upper limit of normal (ULN); alkaline phosphatase ≤2.5 × ULN; total bilirubin ≤1.5 × ULN; serum creatinine ≤1.5 × ULN.

• For pre-menopausal females or females without surgical sterilization: agree to use effective contraception during study treatment and for at least 6 months after the last dose of study treatment.

Exclusion Criteria:

• Occult breast cancer, inflammatory breast cancer, Paget's disease of the breast, stage IV (metastatic) breast cancer, or bilateral breast cancer.

• Known hypersensitivity to active ingredients or other excipients of study drugs.

• Requirement for additional anti-tumor therapy (excluding ovarian function suppression) during neoadjuvant treatment, as judged by the investigator.

• Prior hormone-replacement therapy that has not been discontinued for at least 2 weeks before study treatment initiation.

• Previous history of anti-tumor chemotherapy, selective estrogen-receptor modulators, or aromatase inhibitor therapy.

• Severe cardiac diseases or conditions that would preclude tolerability of study treatment, including but not limited to:

  i. Life-threatening arrhythmias or higher-grade atrioventricular block (Mobitz type II second-degree or third-degree atrioventricular block); ii. Unstable angina pectoris; iii. Clinically significant valvular heart disease; iv. Electrocardiogram evidence of transmural myocardial infarction; v. Poorly controlled hypertension.

• Major surgery unrelated to breast cancer within 4 weeks prior to enrollment, or incomplete recovery from such surgical procedures.

• Severe or uncontrolled infections that may interfere with study treatment or outcome assessment, including but not limited to active viral hepatitis, positive human immunodeficiency virus antibody, pulmonary infection.

• History of other malignancies within the past 5 years (except cured carcinoma in-situ of cervix or basal-cell carcinoma of skin).

• Underlying gastrointestinal disorders (especially chronic diarrhea or constipation), inability to swallow, intestinal obstruction, or other conditions interfering with drug intake and absorption.

• Any other condition rendering the patient unsuitable for study participation, in the investigator's opinion