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

Fudan University

Status and phase: Enrolling; Phase 2; Phase 1

Conditions: Breast Cancer

Treatments: Drug: T-DXd

Study type: Interventional

Funder types: Other

Identifiers

NCT07134153

2501313-7

Details and patient eligibility

About

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.

Full 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.

Enrollment: 139 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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139 participants in 10 patient groups

Phase I/Arm A(Intrathecal Dose-Escalation Phase)

Experimental group

Description:

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

Treatment:

Drug: T-DXd

Phase I/Arm B(Systemic-to-Intrathecal Transition Phase)

Experimental group

Description:

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

Treatment:

Drug: T-DXd

Phase II/Arm A

Experimental group

Description:

HER2-positive advanced breast cancer with progressive leptomeningeal and/or brain metastases after prior T-DXd therapy

Treatment:

Drug: T-DXd

Phase II/Arm B

Experimental group

Description:

HER2-low (IHC 1+ or 2+/ISH-) advanced breast cancer with progressive leptomeningeal and/or brain metastases after prior T-DXd therapy

Treatment:

Drug: T-DXd

Phase II/Arm C

Experimental group

Description:

HER2-positive advanced breast cancer with progressive brain metastases (without leptomeningeal involvement) after prior T-DXd therapy

Treatment:

Drug: T-DXd

Phase II/Arm D

Experimental group

Description:

HER2-low advanced breast cancer with progressive brain metastases (without leptomeningeal involvement) after prior T-DXd therapy

Treatment:

Drug: T-DXd

Phase II/Arm E

Experimental group

Description:

T-DXd-naïve HER2-positive advanced breast cancer with progressive leptomeningeal and/or brain metastases

Treatment:

Drug: T-DXd

Phase II/Arm F

Experimental group

Description:

T-DXd-naïve HER2-low advanced breast cancer with progressive leptomeningeal and/or brain metastases

Treatment:

Drug: T-DXd

Phase II/Arm G

Experimental group

Description:

T-DXd-naïve HER2-positive advanced breast cancer with progressive brain metastases (without leptomeningeal involvement)

Treatment:

Drug: T-DXd

Phase II/Arm H

Experimental group

Description:

T-DXd-naïve HER2-low advanced breast cancer with progressive brain metastases (without leptomeningeal involvement)

Treatment:

Drug: T-DXd