T-DXd Therapy for HER2-low Breast Cancer Patients With Brain Metastases

NCT06048718 | Active Not Recruiting Phase 2 DMC

• 2 other identifiers: MEDOPP5962023-506702-39-00
• Study Type: interventional
• Target: 28
• Locations: 2 countries
• Sites: 13

Brief Summary

TUXEDO-4 is an international, multicentric, single arm, phase II study aiming to gather additional solid evidence of Trastuzumab-Deruxtecan (T-DXd) activity in patients with Human Epidermal Growth Factor Receptor 2 (HER2)-low breast cancer with active brain metastases. This study will analyze the efficacy of T-DXd as determined by overall response rate (ORR) at any timepoint as judged by best CNS response according to RANO-BM criteria.

Conditions

Breast Cancer; Metastatic Breast Cancer

Keywords

breast cancer; HER2-low; brain metastases; T-DXd

Outcome Measures

Primary Outcomes (1)

• ORR at any time point as judged by best central nervous system (CNS) response in all patients.

  To assess efficacy, defined as overall response rate (ORR) at any timepoint as judged by best CNS response according to RANO-BM criteria.

  From baseline until approximately 11 months after the last patient included in the study starts treatment.

Secondary Outcomes (13)

• ORR as judged by best response for extracranial (EC) and overall lesions in all patients.

  From baseline until approximately 11 months after the last patient included in the study starts treatment.

• Bicompartmental clinical benefit rate (Bi-CBR) in all patients.

  From baseline until approximately 11 months after the last patient included in the study starts treatment.

• Bicompartmental disease control rate (Bi-DCR) in all patients.

  From baseline until approximately 11 months after the last patient included in the study starts treatment.

• Time to response (TTR) in all patients.

  From baseline until approximately 11 months after the last patient included in the study starts treatment.

• Duration of response (DoR) in all patients.

  From baseline until approximately 11 months after the last patient included in the study starts treatment.

Study Arms (1)

T-DXd

EXPERIMENTAL

Patients will receive T-DXd at 5.4 mg/kg administered as an intravenous (IV) infusion every three-weeks (Q3W) until disease progression, unacceptable toxicity, death, or discontinuation from the study.

Drug: Trastuzumab-Deruxtecan (T-DXd)

Interventions

Trastuzumab-Deruxtecan (T-DXd) DRUG

Trastuzumab-deruxtecan is a human HER2-directed antibody-drug conjugate (ADC) composed of humanized anti-HER2 immunoglobulin G1 (IgG1) monoclonal antibody (mAb) with the same amino acid sequence as trastuzumab, covalently linked to the membrane-permeable topoisomerase I inhibitor payload, DXd, an exatecan derivative, via a stable tetrapeptide-based linker, selectively cleaved within tumor cells.

Also known as: DS-8021a, ENHERTU

T-DXd

Eligibility Criteria

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

You may qualify if:

• Patient must be capable to understand the purpose of the Study and have signed written informed consent form (ICF) prior to beginning specific protocol procedures.
• Female or male patients ≥ 18 years of age at the time of signing ICF.
• Radiologically documented metastatic breast cancer with locally documented HER2-low status according to the 2018 ASCO/CAP guidelines.
• Life expectancy ≥ 12 weeks.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2.
• Participants with contraindications to T-DXd therapy cannot be enrolled to the Study.
• Newly diagnosed or progressive BM without indication for immediate local therapy.
• Presenting with ≥1 brain lesion (≥10 mm per local radiological assessment), measurable disease by Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Note: Patients may or may not have untreated type II LMD per European Association of Neuro-Oncology (EANO)- European Society for Molecular Oncology (ESMO) criteria.
• Patients must have undergone ≥1 line of systemic treatment in the advanced setting.
• Patients have adequate treatment washout period before enrolment, defined as:
• local therapy (major surgery and radiotherapy) or antibody treatment ≥4 weeks;
• targeted agents, chemotherapy, small molecule, or anti-cancer hormonal therapy ≥3 weeks.
• Patients must have left ventricular ejection fraction (LVEF) ≥ 50% by either an echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days before enrolment.
• Patient has adequate bone marrow, liver, renal and coagulation function.
• Hematological: without platelet, red blood cell transfusion, and/or granulocyte colony-stimulating factor support within 7 days before first Study treatment dose.

You may not qualify if:

• Current participation in another therapeutic clinical trial.
• Treatment with approved or investigational cancer therapy such as antibody treatment within 4 weeks prior to initiation of Study drug; or targeted agents, chemotherapy, small molecule, or anti-cancer hormonal therapy within 3 weeks prior to initiation of Study drug.
• Patients have a concurrent malignancy or malignancy within five years of Study enrolment with the exception of carcinoma in situ of the cervix, non-melanoma skin carcinoma, stage I uterine cancer or contralateral breast cancer within the last 3 years. For other cancers considered to have a low risk of recurrence, discussion with the Medical Monitor is required.
• Prior treatment with T-DXd.
• Patients with type I LMD or previously treated type II LMD.
• Known allergy or hypersensitivity to T-DXd or any of the drug components.
• Medical history of myocardial infarction (MI) within 6 months before enrolment, symptomatic congestive heart failure (New York Heart Association Class II to IV).
• LVEF \< 50% as determined by echocardiogram (ECHO) or multi-gated acquisition (MUGA) scan within 28 days prior to treatment.
• Long corrected QTcF interval prolongation to \> 470 ms based on average of screening 12-lead electrocardiogram (ECG).
• History of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening.
• Lung criteria:
• Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (e.g., pulmonary emboli within 3 months of Study enrolment, severe asthma, severe COPD, restrictive lung disease, etc).
• Any autoimmune, connective tissue or inflammatory disorders (ie, rheumatoid arthritis, Sjogren's, sarcoidosis, etc.) where there is documented, or a suspicion of pulmonary involvement at the time of screening. Full details of the disorder should be recorded in the eCRF for participants who are included in the Study.
• Prior pneumonectomy.
• Pregnant or lactating women.

Sponsors & Collaborators

• MedSIR: lead
• Daiichi Sankyo: collaborator

Study Sites (13)

Salzburg Cancer research Institute-Center

Salzburg, Austria

Location

Medical University of Vienna

Vienna, 1090, Austria

Location

Hospital Universitario San Juan de Alicante

Alicante, Alicante, 03550, Spain

Location

Hospital Universitari Dexeus

Barcelona, Barcelona, 08028, Spain

Location

Hospital Universitari Vall D'Hebron

Barcelona, Barcelona, 08035, Spain

Location

Hospital Universitario de Basurto

Bilbao, Bilbao, 48013, Spain

Location

Hospital Universitario Reina Sofía

Córdoba, Córdoba, 14004, Spain

Location

Hospital Universitario Clínico San Cecilio de Granada

Granada, Granada, 18016, Spain

Location

Hospital Beata María Ana

Madrid, Madrid, 28007, Spain

Location

Hospital Universitario Ramón y Cajal

Madrid, Madrid, 28034, Spain

Location

Hospital Universitario Virgen del Rocío

Seville, Sevilla, 41013, Spain

Location

Hospital Clínico Universitario de Valencia

Valencia, Valencia, 46010, Spain

Location

Hospital Arnau de Vilanova de Valencia

Valencia, Valencia, 46015, Spain

Location

Related Publications (1)

• Marhold M, Vaz Batista M, Blancas I, Morales C, Saura-Manich C, Saavedra C, Ruiz-Borrego M, Cortez P, Slebe F, Campolier M, Santos JC, Guerrero-Martinez JA, Jimenez-Cortegana C, Rottenmanner B, Forstner H, Bartsch R, Preusser M. TUXEDO-4: phase II study of trastuzumab-deruxtecan in HER2-low breast cancer with new or progressing brain metastases. Future Oncol. 2025 Apr;21(9):1065-1073. doi: 10.1080/14796694.2025.2470604. Epub 2025 Feb 28.

  PMID: 40018758 DERIVED

MeSH Terms

Conditions

Breast Neoplasms; Brain Neoplasms

Interventions

trastuzumab deruxtecan

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Study Officials

• Maximilian Marhold, MD, PhD, PD

  Medical University of Vienna, Vienna General Hospital, Vienna, Austria

  PRINCIPAL INVESTIGATOR

• Matthias Preusser, MD, Prof

  Medical University of Vienna, Vienna General Hospital, Vienna, Austria

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Single-arm, two-stage optimal Simon's design, phase II clinical trial.

Study Record Dates

• First Submitted: September 6, 2023
• First Posted: September 21, 2023
• Study Start: June 5, 2024
• Primary Completion (Estimated): November 1, 2026
• Study Completion (Estimated): November 1, 2026
• Last Updated: May 8, 2026

Record last verified: 2026-05

Locations

AU (2); ES (11)