Intrathecal/Ommaya T-DXd for HER2‑expressing breast cancer with leptomeningeal or brain metastases

Evaluating Safety and Efficacy of INtrathecal or Ommaya ReserVoir Administration of T-DXd in Patients With HER2-Expressing Breast Cancer With Active Leptomeningeal and/or Brain Metastases Based on Systemic Therapy: Phase I/II Study

This trial will try intrathecal (Ommaya) T-DXd plus systemic therapy to see if it is safe and better controls leptomeningeal and brain metastases in people with HER2‑expressing breast cancer.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 139 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Fudan University (Academic / other)
• Drugs / interventions: chemotherapy, immunotherapy, prednisone, trastuzumab, pertuzumab
• Locations: 2 sites (Shanghai, Shanghai Municipality and 1 other locations)
• Trial ID: NCT07134153 on ClinicalTrials.gov

What this trial studies

This phase I/II open-label trial delivers T-DXd directly into the cerebrospinal fluid via intrathecal injection or an Ommaya reservoir alongside systemic therapy to measure safety and intracranial activity in patients with HER2‑expressing breast cancer and leptomeningeal or active brain metastases. Key endpoints include adverse events, intracranial response (using RANO-BM for measurable lesions), and pharmacokinetics of T-DXd and free DXd in CSF and blood. Eligible participants are adults with HER2‑expressing advanced or metastatic breast cancer who meet organ function and treatment-washout requirements. The trial aims to determine whether local intrathecal delivery can overcome blood–brain barrier limitations and inform development of targeted intracranial treatments.

Who should consider this trial

Good fit: Ideal candidates are adults with HER2‑expressing advanced or metastatic breast cancer who have leptomeningeal metastasis or active brain metastases (with at least one intracranial measurable lesion if brain-only) and who meet organ function and treatment washout requirements.

Not a fit: Patients unlikely to benefit include those without HER2 expression, those with uncontrolled medical conditions, those who have not met the protocol-specified washout from recent therapies, or those with other recent malignancies excluded by the protocol.

Why it matters

Potential benefit: If successful, this approach could improve intracranial disease control and potentially extend survival and quality of life for patients with HER2‑expressing breast cancer who have leptomeningeal or brain metastases.

How similar studies have performed: Systemic T-DXd has shown efficacy against HER2‑positive intracranial disease, but intrathecal delivery of T-DXd is largely untested in humans although intrathecal trastuzumab has shown preliminary safety and efficacy.

Eligibility criteria

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 intracranially measurable 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 prior therapy, 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 carcinoma in 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 or active infections, uncontrolled or clinically significant cardiovascular diseases, severe chronic gastrointestinal disorders with diarrhea, or psychiatric/social conditions that may compromise compliance with study requirements, significantly increase AE risks, or impair the subject's ability to provide written informed consent.
* History of (non-infectious) ILD/non-infectious pneumonitis requiring steroid therapy, current ILD/non-infectious pneumonitis, or suspected ILD/non-infectious pneumonitis that cannot be ruled out by imaging during screening.
* Clinically significant pulmonary comorbidities
* Use of immunosuppressants or systemic corticosteroids (\>10 mg/day prednisone equivalent) for immunosuppression within 2 weeks prior to first dose (excluding intranasal/inhaled corticosteroids).
* Any active autoimmune disease or history of autoimmune disease with potential recurrence.
* Uncontrolled infections requiring IV antibiotics, antivirals, or antifungals.
* Active primary immunodeficiency, known HIV infection, active HBV (HBsAg+ with HBV DNA ≥500 IU/mL) or HCV infection. HCV antibody-positive subjects are eligible only if PCR confirms HCV RNA negativity.
* Radiographic evidence of tumor encasement/invasion of major blood vessels, or investigator-determined high risk of fatal hemorrhage due to probable vascular invasion during treatment.
* Pregnant/lactating women, or subjects of reproductive potential unwilling/unable to use effective contraception.
* Any other condition deemed by investigators to potentially affect trial conduct or outcome interpretation.

Where this trial is running

Shanghai, Shanghai Municipality and 1 other locations

• Fudan University Shanghai Cancer Center — Shanghai, Shanghai Municipality, China (Recruiting)
• Fudan University Shanghai Cancer Cancer — Shanghai, Shanghai Municipality, China (Recruiting)

Study contacts

• Study coordinator: Jian Zhang, MD, PhD

Conditions Breast Cancer