NCT07134153

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

• Status: Recruiting
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 139 (estimated)
• Sponsor: Fudan University · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

Multiple trials confirm systemic T-DXd efficacy in HER2+ breast cancer with leptomeningeal/brain metastases, yet median LM survival remains 3-4 months, highlighting unmet needs. While systemic therapies improve survival, intracranial disease control remains limited due to poor BBB penetration. Preclinical data show no detectable T-DXd/DXd in CSF, though intrathecal trastuzumab demonstrates preliminary safety/efficacy in HER2+ LM. This study evaluates intrathecal/intra-Ommaya T-DXd plus systemic therapy in active HER2+ meningeal/brain metastases, assessing safety, intracranial efficacy, and CSF/peripheral blood T-DXd distribution to clarify BBB penetration potential. Findings may guide novel therapeutic strategies for this high-need population.

Detailed description

Multiple clinical trials have demonstrated the efficacy of systemic T-DXd in advanced HER2-expressing breast cancer with leptomeningeal and/or brain metastases. However, the median survival of leptomeningeal metastasis (LM) patients remains only 3-4 months, and treatment options for isolated brain metastases are limited, underscoring the need for more effective therapeutic strategies. While systemic therapies have prolonged survival in advanced breast cancer, intracranial disease management remains constrained by a lack of effective local treatments. As the use of T-DXd increases, the progression of intracranial lesions in patients who have received prior local therapy or lack indications for radiotherapy has become a critical unmet clinical challenge. Conventional understanding holds that large biologic molecules poorly penetrate the blood-brain barrier (BBB). Preclinical studies detected neither T-DXd nor free DXd (payload) in cerebrospinal fluid (CSF), and the distribution of T-DXd in human CSF remains uncharacterized. However, preliminary data suggest that intrathecal trastuzumab-alone or combined with pertuzumab-exhibits acceptable safety and efficacy in HER2-positive LM.

Conditions

• Breast Cancer

Interventions

Type	Name	Description
DRUG	T-DXd	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

Timeline

• Start date: 2025-04-18
• Primary completion: 2026-08-30
• Completion: 2027-02-28
• First posted: 2025-08-21
• Last updated: 2025-08-21

Locations

2 sites across 1 country: China