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

NCT07134153 | Recruiting Phase 1

• 1 other identifier: 2501313-7
• Study Type: interventional
• Target: 139
• Locations: 1 country
• Sites: 2

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.

Conditions

Breast Cancer

Outcome Measures

Primary Outcomes (12)

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

  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.

  Up to 21 days after the first dose

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

  Cohort B: Maximum serum concentration (Cmax) of T-DXd in cerebrospinal fluid and blood will be investigated.

  Up to 21 days after the first dose

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

  Cohort B: Time to maximum serum concentration (Tmax) of T-DXd in cerebrospinal fluid and blood will be investigated.

  Up to 21 days after the first dose

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

  Cohort B: Half-life (T1/2) of T-DXd in cerebrospinal fluid and blood will be investigated.

  Up to 21 days after the first dose

• Phase II Stage Cohorts A: LM-OS

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

  18 months

• Phase II Stage Cohorts B: LM-OS

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

  18 months

• Phase II Stage Cohorts C: LM-ORR

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

  18 months

• Phase II Stage Cohorts D: LM-ORR

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

  18 months

• Phase II Stage Cohorts E: LM-OS

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

  18 months

• Phase II Stage Cohorts F: LM-OS

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

  18 months

• Phase II Stage Cohorts G: LM-ORR

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

  18 months

• Phase II Stage Cohorts H: LM-ORR

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

  18 months

Study Arms (10)

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

EXPERIMENTAL

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

Drug: T-DXd

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

EXPERIMENTAL

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

Drug: T-DXd

Phase II/Arm A

EXPERIMENTAL

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

Drug: T-DXd

Phase II/Arm B

EXPERIMENTAL

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

Drug: T-DXd

Phase II/Arm C

EXPERIMENTAL

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

Drug: T-DXd

Phase II/Arm D

EXPERIMENTAL

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

Drug: T-DXd

Phase II/Arm E

EXPERIMENTAL

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

Drug: T-DXd

Phase II/Arm F

EXPERIMENTAL

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

Drug: T-DXd

Phase II/Arm G

EXPERIMENTAL

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

Drug: T-DXd

Phase II/Arm H

EXPERIMENTAL

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

Drug: T-DXd

Interventions

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

Also known as: DS8201a

Phase I/Arm A(Intrathecal Dose-Escalation Phase); Phase I/Arm B(Systemic-to-Intrathecal Transition Phase); Phase II/Arm A; Phase II/Arm B; Phase II/Arm C; Phase II/Arm D; Phase II/Arm E; Phase II/Arm F; Phase II/Arm G; Phase II/Arm H

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Fudan University: lead

Study Sites (2)

Fudan University Shanghai Cancer Center

Shanghai, Shanghai Municipality, 200032, China

RECRUITING

Fudan University Shanghai Cancer Cancer

Shanghai, Shanghai Municipality, 200043, China

RECRUITING

MeSH Terms

Conditions

Breast Neoplasms

Interventions

trastuzumab deruxtecan

Condition Hierarchy (Ancestors)

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

Central Study Contacts

Jian Zhang, MD, PhD

CONTACT

+8664175590; syner2000@163.com

Yanchun Meng, MD

CONTACT

+8664175590; ycmclinicaltrials@126.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of Phase I Clinical Trial Department; Professor, Chief physician of oncology department

Study Record Dates

• First Submitted: May 11, 2025
• First Posted: August 21, 2025
• Study Start: April 18, 2025
• Primary Completion (Estimated): August 30, 2026
• Study Completion (Estimated): February 28, 2027
• Last Updated: August 21, 2025

Record last verified: 2025-08

Locations

CN (2)