Brain Radiotherapy Combined With Dalpiciclib and Endocrine Therapy in HR-Positive/HER2-Negative Advanced Breast Cancer With Brain Metastases

A Single-Arm, Phase II Study of Brain Radiotherapy Combined With Dalpiciclib and Endocrine Therapy in HR-Positive/HER2-Negative Advanced Breast Cancer Patients With Brain Metastases

This is a prospective, open-label, exploratory clinical trial designed to evaluate the efficacy and safety of brain radiotherapy combined with dalpiciclib and endocrine therapy in HR-positive/HER2-negative advanced breast cancer patients with brain metastases. A total of 46 patients are planned to be enrolled.

Participants will receive dalpiciclib plus endocrine therapy and brain radiotherapy, including fractionated stereotactic radiotherapy (FSRT) or whole-brain radiotherapy (WBRT), according to the clinical characteristics of brain metastatic lesions. Radiotherapy may start within 30 days before or after initiation of drug treatment. Dalpiciclib and endocrine therapy may be given concurrently during radiotherapy and will be continued after radiotherapy until disease progression, intolerable toxicity, withdrawal of informed consent, or investigator decision. Participants will visit the clinic once every 3 months for checkups and tests. Tumor response will be assessed according to RECIST version 1.1, and safety will be evaluated throughout the study.

Inclusion Criteria:

• 1.Female patients aged 18 to 75 years, who are postmenopausal or premenopausal/perimenopausal, and meet at least one of the following conditions:

  1. prior bilateral oophorectomy; or age ≥60 years; or
  2. age <60 years and postmenopausal status defined as at least 12 consecutive months of spontaneous amenorrhea without other pathological or physiological causes, with estradiol (E2) and follicle-stimulating hormone (FSH) levels within the postmenopausal range; or
  3. premenopausal or perimenopausal women are also eligible if they are willing to receive treatment with an LHRH agonist during the study.

• 2.Histologically or cytologically confirmed HR-positive, HER2-negative breast cancer in female patients, with evidence of locally recurrent or metastatic disease that is not amenable to curative surgery or radiotherapy, and with no clinical indication for chemotherapy.

• HR-positive is defined as ER-positive and/or PR-positive, with ≥1% of tumor cells showing positive staining, as confirmed by the investigator at the study site.

• HER2-negative is defined as IHC 0 or 1+, or ISH-negative, defined as a HER2/CEP17 ratio <2.0 or an average HER2 copy number <4.0, as confirmed by the investigator at the study site.

• 3.Presence of brain metastases confirmed by MRI, with at least one measurable intracranial lesion ≥1 cm according to RECIST version 1.1. Measurable extracranial disease is not required.

• 4.ECOG performance status 0-2, and an estimated life expectancy of at least 12 weeks at the time of enrollment.

• 5.If the patient is receiving corticosteroids, the corticosteroid dose must be stable or decreasing for at least 5 days before the brain gadolinium-enhanced MRI (Gd-MRI). This MRI must be performed within 28 days before enrollment. Patients who require an increased steroid dose before treatment, or who are receiving an unstable steroid dose, are not eligible.

• 6.Screening laboratory values must meet the following criteria( and should be obtained within 14 days prior to registration)::

  1. absolute neutrophil count (ANC) ≥ 1,500/mm³ (1.5 × 10^9/L), without growth factor support within 14 days;
  2. platelet count (PLT) ≥ 100,000/mm³ (100 × 10^9/L), without corrective treatment within 7 days;
  3. hemoglobin (Hb) ≥ 9 g/dL (90 g/L), without corrective treatment within 7 days;
  4. serum creatinine (Scr) ≤ 1.5 × upper limit of normal (ULN), or creatinine clearance ≥ 60 mL/min;
  5. total bilirubin ≤ 1.5 × ULN;
  6. aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 2.5 × ULN, or ≤ 5 × ULN for patients with liver metastases.

• 7.Prior stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT) is permitted, provided that the currently active measurable disease has not been previously treated with radiotherapy.

• 8.Women of childbearing potential must have a negative serum pregnancy test within 7 days before enrollment and must agree to use a medically acceptable highly effective method of contraception during the study and for 1 year after the last dose of study treatment.

• 9.Ability and willingness to signed the informed consent form prior to patient entry.

Exclusion Criteria:

• 1.Prior pathological diagnosis of HER2-positive breast cancer.

• 2.Prior disease progression on dalpiciclib in the metastatic setting.

• 3.Primary endocrine resistance, defined as either:

  1. disease recurrence or progression within 2 years of starting adjuvant endocrine therapy; or
  2. disease progression within 6 months of first-line endocrine therapy for advanced or metastatic disease.

• 4.Patients considered not suitable for endocrine therapy in the judgment of the investigator, including patients with symptomatic visceral disease, disseminated visceral involvement, or a risk of life-threatening complications in the short term, such as uncontrolled massive effusions (pleural, pericardial, or peritoneal), lymphangitic carcinomatosis of the lung, or >50% liver involvement.

• 5.Presence of leptomeningeal metastases.

• 6.Prior whole-brain radiotherapy (WBRT) .

• 7.Any severe neurologic symptoms caused by central nervous system metastases.

• 8.Pregnant or breastfeeding women.

• 9.Any serious uncontrolled clinical disease or infection that, in the investigator's judgment, cannot be adequately controlled with appropriate treatment or may impair the patient's ability to tolerate study treatment, including but not limited to:

  1. serious cardiovascular events such as syncope of cardiovascular origin, pathologic ventricular arrhythmias (including but not limited to ventricular tachycardia or ventricular fibrillation), or cardiac arrest;
  2. end-stage renal disease;
  3. severe liver disease;
  4. active systemic bacterial infection.

• 10.History of immunodeficiency, including HIV infection, active hepatitis B virus (HBV) infection, active hepatitis C virus (HCV) infection, other acquired or congenital immunodeficiency disorders, or prior organ transplantation.

• 11.History of malignancy other than breast cancer.

• 12.Inability to swallow oral medication, or presence of chronic diarrhea, intestinal obstruction, or other conditions that may interfere with the administration or absorption of study drugs.

• 13.History of allergy or hypersensitivity to any study drug or any of its components.