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

Not Applicable

Recruiting

• Conditions: Breast Cancer
• Interventions: Drug: T-DXd

• Registration Number: NCT07134153
• Lead Sponsor: Fudan University

Brief 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.

Study Timeline

• Study Start: 2025-04-18
• Study First Submitted: 2025-05-11
• Status Verified: 2025-08
• Study First Submitted QC: 2025-08-20
• Last Update Submitted: 2025-08-20
• Study First Posted: 2025-08-21
• Last Update Posted: 2025-08-21
• Primary Completion: 2026-08-30
• Study Completion: 2027-02-28

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 139

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Phase I/Arm A(Intrathecal Dose-Escalation Phase)	T-DXd	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
Phase I/Arm B(Systemic-to-Intrathecal Transition Phase)	T-DXd	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
Phase II/Arm A	T-DXd	HER2-positive advanced breast cancer with progressive leptomeningeal and/or brain metastases after prior T-DXd therapy
Phase II/Arm B	T-DXd	HER2-low (IHC 1+ or 2+/ISH-) advanced breast cancer with progressive leptomeningeal and/or brain metastases after prior T-DXd therapy
Phase II/Arm C	T-DXd	HER2-positive advanced breast cancer with progressive brain metastases (without leptomeningeal involvement) after prior T-DXd therapy
Phase II/Arm D	T-DXd	HER2-low advanced breast cancer with progressive brain metastases (without leptomeningeal involvement) after prior T-DXd therapy
Phase II/Arm E	T-DXd	T-DXd-naïve HER2-positive advanced breast cancer with progressive leptomeningeal and/or brain metastases
Phase II/Arm F	T-DXd	T-DXd-naïve HER2-low advanced breast cancer with progressive leptomeningeal and/or brain metastases
Phase II/Arm G	T-DXd	T-DXd-naïve HER2-positive advanced breast cancer with progressive brain metastases (without leptomeningeal involvement)
Phase II/Arm H	T-DXd	T-DXd-naïve HER2-low advanced breast cancer with progressive brain metastases (without leptomeningeal involvement)

Primary Outcome Measures

Name	Time	Method
Phase II Stage Cohorts B: LM-OS	18 months	Cohorts B: leptomeningeal metastasis-overall survival（LM-OS）
Phase I Stage Cohort A: Maximum Tolerated Dose (MTD)	Up to 21 days after the first dose	Cohort A: Maximum Tolerated Dose (MTD) of intracapsular administration，In the dose increment stage, the highest dose whose estimated DLT rate is closest to the target DLT rate but does not exceed the upper bound of the equivalent interval of DLT rate is selected as MTD.
Phase I Stage Cohort B: Maximum serum concentration (Cmax)	Up to 21 days after the first dose	Cohort B: Maximum serum concentration (Cmax) of T-DXd in cerebrospinal fluid and blood will be investigated.
Phase I Stage Cohort B:Time to maximum serum concentration (Tmax)	Up to 21 days after the first dose	Cohort B: Time to maximum serum concentration (Tmax) of T-DXd in cerebrospinal fluid and blood will be investigated.
Phase I Stage Cohort B:Half-life (T1/2)	Up to 21 days after the first dose	Cohort B: Half-life (T1/2) of T-DXd in cerebrospinal fluid and blood will be investigated.
Phase II Stage Cohorts A: LM-OS	18 months	Cohorts A: leptomeningeal metastasis-overall survival（LM-OS）
Phase II Stage Cohorts C: LM-ORR	18 months	Cohorts C: leptomeningeal metastasis-Objective Response Rate（LM-ORR）
Phase II Stage Cohorts D: LM-ORR	18 months	Cohorts D: leptomeningeal metastasis-Objective Response Rate（LM-ORR）
Phase II Stage Cohorts E: LM-OS	18 months	Cohorts E: leptomeningeal metastasis-overall survival（LM-OS）
Phase II Stage Cohorts F: LM-OS	18 months	Cohorts F: leptomeningeal metastasis-overall survival（LM-OS）
Phase II Stage Cohorts G: LM-ORR	18 months	Cohorts G: leptomeningeal metastasis-Objective Response Rate（LM-ORR）
Phase II Stage Cohorts H: LM-ORR	18 months	Cohorts H: leptomeningeal metastasis-Objective Response Rate（LM-ORR）

Trial Locations

Locations (2)

Fudan University Shanghai Cancer Center; 🇨🇳 Shanghai, Shanghai, China

Fudan University Shanghai Cancer Cancer; 🇨🇳 Shanghai, Shanghai, China