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
Location: See all (2) locations...
Intervention Type: Drug
Study Type: Interventional
Study Phase: Phase 1/Phase 2
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.
Eligibility
Participation Requirements
Sex: All
Minimum Age: 18
Healthy Volunteers: f
View:
• 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
Population : T-DXd-naïve subjects with leptomeningeal metastases (LM), with or without concurrent brain metastases (BM).~Cycle 1 : Intrathecal (IT) T-DXd monotherapy to assess cerebrospinal fluid (CSF) and systemic pharmacokinetics (PK).~Cycles 2+ : IT T-DXd combined with intravenous (IV) T-DXd in a dose-escalation design to determine the maximum tolerated dose (MTD) .~DLT Evaluation : The first two cycles serve as the dose-limiting toxicity (DLT) observation window .~Endpoint : The recommended Phase 2 dose (RP2D) will be determined by investigator assessment
Population : T-DXd-naïve subjects with LM ± BM. Cycle 1 : IV T-DXd monotherapy to characterize CSF and systemic PK profiles. Cycles 2+ : IT administration of the RP2D of T-DXd combined with IV therapy
Experimental: Phase II/Arm A
HER2-positive advanced breast cancer with progressive leptomeningeal and/or brain metastases after prior T-DXd therapy
Experimental: Phase II/Arm B
HER2-low (IHC 1+ or 2+/ISH-) advanced breast cancer with progressive leptomeningeal and/or brain metastases after prior T-DXd therapy
Experimental: Phase II/Arm C
HER2-positive advanced breast cancer with progressive brain metastases (without leptomeningeal involvement) after prior T-DXd therapy
Experimental: Phase II/Arm D
HER2-low advanced breast cancer with progressive brain metastases (without leptomeningeal involvement) after prior T-DXd therapy
Experimental: Phase II/Arm E
T-DXd-naïve HER2-positive advanced breast cancer with progressive leptomeningeal and/or brain metastases
Experimental: Phase II/Arm F
T-DXd-naïve HER2-low advanced breast cancer with progressive leptomeningeal and/or brain metastases
Experimental: Phase II/Arm G
T-DXd-naïve HER2-positive advanced breast cancer with progressive brain metastases (without leptomeningeal involvement)
Experimental: Phase II/Arm H
T-DXd-naïve HER2-low advanced breast cancer with progressive brain metastases (without leptomeningeal involvement)