Phase I/II Study of Intrathecal/Ommaya T-DXd in HER2-Expressing Breast Cancer With Leptomeningeal/Brain Metastases

Inclusion Criteria:

• Age ≥18 years, regardless of gender.

• HER2-expressing advanced or metastatic breast cancer

• Leptomeningeal metastasis

• Subjects with active brain metastases only must have at least one intracraniallymeasurable lesion (RANO-BM criteria).

• Adequate organ and bone marrow function

• No radiotherapy, chemotherapy, targeted therapy, immunotherapy, endocrine therapy,or surgery within 2 weeks prior to enrollment (or within 5 half-lives of priortherapy, whichever is shorter).

• All prior treatment-related toxicities must have resolved to ≤Grade 1

Exclusion Criteria:

• Diagnosis of other malignancies within the past 5 years, except for cured carcinomain situ of the cervix, basal cell carcinoma or squamous cell carcinoma of the skin,other in situ carcinomas, or papillary thyroid carcinoma.

• Uncontrolled concurrent illnesses including, but not limited to: persistent oractive infections, uncontrolled or clinically significant cardiovascular diseases,severe chronic gastrointestinal disorders with diarrhea, or psychiatric/socialconditions that may compromise compliance with study requirements, significantlyincrease AE risks, or impair the subject's ability to provide written informedconsent.

• History of (non-infectious) ILD/non-infectious pneumonitis requiring steroidtherapy, current ILD/non-infectious pneumonitis, or suspected ILD/non-infectiouspneumonitis that cannot be ruled out by imaging during screening.

• Clinically significant pulmonary comorbidities

• Use of immunosuppressants or systemic corticosteroids (>10 mg/day prednisoneequivalent) for immunosuppression within 2 weeks prior to first dose (excludingintranasal/inhaled corticosteroids).

• Any active autoimmune disease or history of autoimmune disease with potentialrecurrence.

• Uncontrolled infections requiring IV antibiotics, antivirals, or antifungals.

• Active primary immunodeficiency, known HIV infection, active HBV (HBsAg+ with HBVDNA ≥500 IU/mL) or HCV infection. HCV antibody-positive subjects are eligible onlyif PCR confirms HCV RNA negativity.

• Radiographic evidence of tumor encasement/invasion of major blood vessels, orinvestigator-determined high risk of fatal hemorrhage due to probable vascularinvasion during treatment.

• Pregnant/lactating women, or subjects of reproductive potential unwilling/unable touse effective contraception.

• Any other condition deemed by investigators to potentially affect trial conduct oroutcome interpretation.