A Phase II Observational Clinical Study on the Relationship Between Cerebrospinal Fluid Drug Concentration and Efficacy of Trastuzumab Deruxtecan in Central Nervous System Metastatic Breast Cancer

A Phase II Observational Clinical Study on the Relationship Between Cerebrospinal Fluid Drug Concentration of Trastuzumab Deruxtecan and Efficacy in Central Nervous System Metastatic Breast Cancer

Approximately 5-15% breast cancer patients develop brain metastases. Current local treatments (surgery/radiotherapy) are associated with significant complications, and systemic treatments have limited efficacy. Although new-generation ADC drugs, such as trastuzumab deruxtecan, have demonstrated breakthrough efficacy in patients with brain metastases, the mechanisms of action are not fully elucidated, moreover the current treatment regimens still have limitations for patients with HER2-low expressing, safer and more effective systemic treatment options are urgently needed to improve patient survival. BCBM-006 is an open-label, prospective, single-arm, single-center Phase II clinical study to evaluate the relationship between cerebrospinal fluid drug concentration and efficacy of trastuzumab deruxtecan in central nervous system metastatic breast cancer, and explore the incidence of leptomeningeal metastases diagnosed via lumbar puncture in patients with brain parenchymal metastases, facilitate early intervention to improve prognosis.

Inclusion Criteria:

• 1. ≥18 years（2007-06）, any gender. 2. ECOG Performance Status 0-2. 3. Evidence of local recurrence or metastatic breast cancer not amenable to curative surgery or radiotherapy, and planned for intravenous trastuzumab deruxtecan treatment.

  4. Expected survival time ≥8 weeks. 5. Provision of sufficient fresh tissue specimen or ≥10 unstained slides of tumor sample (primary and/or metastatic site) for biomarker analysis prior to treatment (intracranial metastatic lesion specimens preferred).

  6. Cohort 2 (Experimental Cohort): Presence of brain parenchymal metastases confirmed by contrast-enhanced brain MRI, with at least one measurable brain lesion not previously irradiated, evaluable per RECIST 1.1 criteria.

  7. Patients receiving mannitol, steroids, or anticonvulsant therapy prior to the first dose are eligible if the drug doses are stable for at least one week without requiring an increase, and neurological symptoms are stable for ≥1 week.

  8. Organ function levels must meet the following requirements:

  1. Hematology:

     • ANC≥1.5×109/L;
     • PLT≥75×109/L;
     • Hb≥90 g/L (allowing blood transfusion or medication to ensure hemoglobin content);

  2. Coagulation function: APTT≤1.5×ULN；PT≤1.5×ULN;

  3. Blood Chemistry:

     • TBIL≤1.5×ULN;

     • ALT and AST≤3×ULN (≤ 5.0×ULN for liver metastases);
     • Creatinine ≤1.5 × ULN or Creatinine Clearance ≥50 mL/min (Cockcroft-Gault formula);

  4. Cardiac Ultrasound: LVEF ≥50%;

  5. 12-Lead ECG: Fridericia-corrected QT interval (QTcF) <470 ms for females, <450 ms for males; 9. Voluntary participation in this study, signed informed consent, good compliance, and willingness to cooperate with follow-up.

Exclusion Criteria:

• 1. Presence of uncontrolled third-space fluid accumulation (e.g., large pleural effusion or ascites) not manageable by drainage or other methods, deemed unsuitable for enrollment by the investigator.

  2. Previous treatment with an anti-HER2 ADC drug carrying the same payload resulting in resistance. Patients who discontinued prior ADC therapy for other reasons, including but not limited to toxicity, are eligible.

  3. Adverse reactions from prior anti-tumor therapy have not recovered to ≤ Grade 1 per CTCAE v5.0 (except for ≤ Grade 2 toxicities judged by the investigator as having no safety risk, such as alopecia or long-term toxicities from radiotherapy).

  4. History of other malignancies within the past 5 years, excluding cured carcinoma in situ of the cervix, basocellular skin carcinomas, or cutaneous squamous cell carcinoma.

  5. History of severe cardiovascular or cerebrovascular diseases, including but not limited to:

  • Severe cardiac rhythm or conduction abnormalities requiring clinical intervention, such as ventricular arrhythmia, II-III degree atrioventricular block, etc.

  • Cardiac insufficiency of Class III~IV according to the New York Heart Association (NYHA) criteria.

  • Acute coronary syndrome, congestive heart failure, aortic dissection, stroke, or other Grade 3 or higher cardiovascular/cerebrovascular events within 6 months prior to the first dose.

  • Clinically uncontrolled hypertension.

  • Any factors increasing the risk of QTc prolongation or arrhythmia, such as heart failure, hypokalemia, congenital long QT syndrome, use of any concomitant medications known or suspected to prolong the QT interval; Known history of allergy to any component of the study drug.

    6. History of immunodeficiency disease, including other acquired or congenital immunodeficiency diseases, history of organ transplantation, allogeneic bone marrow transplantation, or autologous hematopoietic stem cell transplantation.

    7. HIV infection, active HBV or HCV infection. The following exceptions are allowed:

  • Patients positive for hepatitis B surface antigen (HBsAg), with or without positive hepatitis B core antibody (anti-HBc), if HBV DNA < 1000 IU/mL or below the lower limit of detection at the research center, and per investigator assessment excluding active infection based on clinical treatment and presentation.

  • Hepatitis C (HCV) antibody-positive patients who are HCV RNA-negative. 8. History of autoimmune diseases, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, Guillain-Barré syndrome, multiple sclerosis, or glomerulonephritis, except for autoimmune thyroid dysfunction treated with stable-dose hormone replacement therapy.

    9. Patients with known idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, interstitial lung disease, severe radiation pneumonitis, or evidence of active pneumonia on screening chest CT scan.

    10. Inability to cooperate with lumbar puncture. 11. Vaccination with any vaccine within 28 days prior to the first dose. 12. Pregnant or lactating female patients; female patients of childbearing potential with baseline pregnancy test positive; or patients unwilling to use effective contraception throughout the trial period.

    13. Presence of any concomitant disease, per investigator judgment, that seriously endangers the patient's safety or affects the patient's ability to complete the study (including but not limited to severe hypertension that cannot be controlled by medication, severe diabetes, active infection, thyroid disease, etc.).

    14. Any other circumstances where the researcher deems the patient unsuitable for participation in this study.