Overview

This study is a prospective, open-label, randomized, multicenter, two-cohort phase II clinical trial. Starting from December 1, 2024, it plans to enroll 120 patients with advanced first-line HR-positive, HER2-negative breast cancer. A centralized randomization system (IWRS) will be used for randomization, and stratification will be performed based on the following factors during randomization: 1) Visceral metastasis (yes vs no); 2) Disease-free interval (previously untreated vs 12 \< DFI ≤ 24 vs DFI \> 24).

Cohort A: Dalpiciclib 125mg + Letrozole 2.5mg Cohort B: Dalpiciclib 150mg + Letrozole 2.5mg Imaging assessment will be conducted in accordance with the RECIST 1.1 criteria, and tumor imaging evaluation will be performed by investigators from the participating centers.

Patients receiving dalpiciclib will undergo a safety visit 28 days after the last dose, followed by survival follow-up until the patient's death or trial termination (whichever comes first).

Pharmacokinetic assessment: Blood samples will be collected once before dosing on Cycle 1 Day 15 (C1D15), 4 hours after dosing on C1D15, before dosing on Cycle 2 Day 1 (C2D1), and before dosing on Cycle 4 Day 1 (C4D1) to explore the population pharmacokinetic characteristics of dalpiciclib and the factors affecting its pharmacokinetics. The first dosing time of the subjects, each blood collection time, the dalpiciclib dosing time within three days before blood collection, and the dalpiciclib dosing time on the day of C1D15 blood collection must be accurately recorded. If dalpiciclib is not administered within 14 days before the planned PK blood collection, no PK blood collection will be performed on the day of that visit. If possible, PK samples should be collected simultaneously with samples for other laboratory tests.

Eligibility

Inclusion Criteria:

• Female patients aged ≥18 years and ≤75 years, who are postmenopausal or premenopausal/perimenopausal, and meet one of the following conditions:
  1. Have undergone bilateral oophorectomy in the past, or be aged ≥60 years; or
  2. Aged \<60 years, in a natural postmenopausal state (defined as spontaneous cessation of regular menstruation for at least 12 consecutive months without other pathological or physiological causes), with E2 and FSH at postmenopausal levels; or
  3. Premenopausal or perimenopausal female patients can also be enrolled, but must be willing to receive LHRH agonist treatment during the study period
• Patients with breast cancer confirmed by pathological examination to be HR-positive and HER2-negative, with evidence of focal recurrence or metastasis, not suitable for surgical resection or radiotherapy with the goal of cure, and without clinical indications for chemotherapy.
  1. ER-positive and/or PR-positive is defined as: the proportion of tumor cells with positive staining among all tumor cells is ≥1% (reviewed and confirmed by the investigator at the participating trial center);
  2. HER2-negative is defined as: standard immunohistochemistry (IHC) test result is 0/1+; ISH test shows that the HER2/CEP17 ratio is less than 2.0 or the HER2 gene copy number is less than 4 (reviewed and confirmed by the investigator at the participating trial center)
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1
• Have not previously received any systemic antineoplastic treatment for focal recurrent or metastatic disease
• Have measurable lesions in line with RECIST 1.1 criteria or only bone metastatic lesions (including osteolytic lesions or mixed osteolytic/osteoblastic lesions)
• Have sufficient organ and bone marrow function
• Women of childbearing potential must be willing to use a medically approved highly effective contraceptive method during the study period and within 3 months after the last administration of the study drug
• All acute toxic effects of previous antineoplastic treatment have resolved to grade 0-1 (according to NCI-CTCAE Version 5.0) or to the level specified in the inclusion/exclusion criteria. Except for other toxicities such as alopecia that the investigator deems to pose no safety risk to the patient
• Have given informed consent and signed the informed consent form, and be willing and able to comply with the planned visits, study treatment plan, laboratory tests and other trial procedures

Exclusion Criteria:

• Previously diagnosed with HER2-positive breast cancer by pathological examination
• Inflammatory breast cancer
• Disease progression or recurrence at 12 months or within 12 months after completion of previous neoadjuvant or adjuvant endocrine drug treatment
• Patients judged by the investigator to be unsuitable for endocrine treatment. Including advanced patients with symptoms, disseminated to internal organs, and at risk of life-threatening complications in the short term (including those with uncontrollable large effusions \[pleural, pericardial, peritoneal\], lymphangitis of the lung, and patients with more than 50% liver involvement) Confirmed to have brain metastatic lesions by cranial CT or MRI examination
• Have previously received any CDK4/6 inhibitor drug treatment
• Underwent major surgery, chemotherapy, radiotherapy, any investigational drug or other anticancer treatment within 2 weeks before entering the study Diagnosed with any other malignant tumor within 3 years before entering the study, except for non-melanoma skin cancer, basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix that have undergone radical treatment Human Immunodeficiency Virus (HIV) infection or known to have Acquired Immunodeficiency Syndrome (AIDS), active hepatitis B (HBV DNA ≥1000 IU/ml), hepatitis C (positive hepatitis C antibody and HCV-RNA higher than the lower limit of detection of the analytical method), or co-infection with hepatitis B and hepatitis C
• Within 6 months before entering the study, the following occurred: myocardial infarction, severe/unstable angina pectoris, NYHA class 2 or higher cardiac insufficiency, persistent arrhythmia of grade ≥2 (according to NCI-CTCAE Version 5.0), atrial fibrillation of any grade, coronary/peripheral artery bypass surgery, symptomatic congestive heart failure, cerebrovascular accident (including transient ischemic attack or symptomatic pulmonary embolism)
• Complicated with severe infection within 4 weeks before the first administration (e.g., requiring intravenous infusion of antibiotics, antifungal or antiviral drugs according to clinical diagnosis and treatment norms), or unexplained fever \>38.5℃ during the screening period/before the first administration
• Inability to swallow, intestinal obstruction, or other factors that affect drug administration and absorption
• Known allergy to the study drug or any excipients
• Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation
• Known history of psychiatric drug abuse or drug addiction
• Patients currently participating in other studies
• Have other serious physical or mental diseases or laboratory test abnormalities that may increase the risk of participating in the study, interfere with the study results, and are deemed unsuitable for participating in this study by the investigator