Skip to main content
OpenTrials
Recruiting

NCT Number: NCT07134153

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

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.

Recruiting

Interested in participating?

Request Info

Key information

Conditions

Breast Cancer Breast Diseases Breast Neoplasms Neoplasms Neoplasms by Site Skin Diseases Skin and Connective Tissue Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

Fudan University Shanghai Cancer Cancer, Shanghai, Shanghai Municipality, China

Loading trial locations.

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

T-DXd

Drug

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

Other names: DS8201a

Primary outcomes

  1. Phase I Stage Cohort A: Maximum Tolerated Dose (MTD)

    Time frame: 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.

  2. Phase I Stage Cohort B: Maximum serum concentration (Cmax)

    Time frame: 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.

  3. Phase I Stage Cohort B:Time to maximum serum concentration (Tmax)

    Time frame: 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.

  4. Phase I Stage Cohort B:Half-life (T1/2)

    Time frame: 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.

  5. Phase II Stage Cohorts A: LM-OS

    Time frame: 18 months

    Cohorts A: leptomeningeal metastasis-overall survival（LM-OS）

  6. Phase II Stage Cohorts B: LM-OS

    Time frame: 18 months

    Cohorts B: leptomeningeal metastasis-overall survival（LM-OS）

  7. Phase II Stage Cohorts C: LM-ORR

    Time frame: 18 months

    Cohorts C: leptomeningeal metastasis-Objective Response Rate（LM-ORR）

  8. Phase II Stage Cohorts D: LM-ORR

    Time frame: 18 months

    Cohorts D: leptomeningeal metastasis-Objective Response Rate（LM-ORR）

  9. Phase II Stage Cohorts E: LM-OS

    Time frame: 18 months

    Cohorts E: leptomeningeal metastasis-overall survival（LM-OS）

  10. Phase II Stage Cohorts F: LM-OS

    Time frame: 18 months

    Cohorts F: leptomeningeal metastasis-overall survival（LM-OS）

  11. Phase II Stage Cohorts G: LM-ORR

    Time frame: 18 months

    Cohorts G: leptomeningeal metastasis-Objective Response Rate（LM-ORR）

  12. Phase II Stage Cohorts H: LM-ORR

    Time frame: 18 months

    Cohorts H: leptomeningeal metastasis-Objective Response Rate（LM-ORR）

Study contacts

Contact information is provided by the study sponsor or research team.

Jian Zhang, MD, PhD

CONTACT

[email protected]

+8664175590 ext. 85000

Yanchun Meng, MD

CONTACT

[email protected]

+8664175590 ext. 63028

Sponsors and collaborators

Lead sponsor

Fudan University

Other

Registry information

Official study title

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

Acronym: INOVATE

Important dates

Study start
2025
Primary completion
2026
Study completion
2027
First posted
Aug 21, 2025
Registry last updated
Aug 21, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

Related clinical trials

Published trials that share one or more normalized conditions with this study.