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Breast CancerPhase 2TUXEDO-4NCT06048718

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

A Phase 2 study testing Trastuzumab-Deruxtecan (T-DXd) in people with Breast Cancer and Metastatic Breast Cancer, run by MedSIR at 13 sites in 2 countries.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Breast Cancer, Metastatic Breast Cancer
What is being tested?
Trastuzumab-Deruxtecan (T-DXd)
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
28 participants
Where
13 sitesin 2 countries
Study dates
5 Jun 2024to Nov 2026
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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.
  • Hepatic: Serum albumin ≥ 2.5 g/dL; total bilirubin ≤ 1.5 times upper limit of normal (ULN) (≤ 3 in patients with liver metastases or known history of Gilbert's disease); alkaline phosphatase (ALP) ≤ 2.5 times ULN; aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 times ULN; international normalized ratio (INR) < 1.5. Note: ALP, ALT and AST can be ≤ 5 times ULN in patients with liver metastases.
  • Renal: serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min/1.73 m2 based on Cockcroft-Gault glomerular filtration rate estimation for patients with creatinine levels above institutional normal.
  • Resolution of all acute toxic effects of prior anti-cancer therapy to grade ≤ 1 as determined by the US National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (v.5.0). Participants with chronic Grade 2 toxicities may be eligible per the discretion of the investigator. Note: Except for alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion.
  • For women of childbearing potential: agreement to remain abstinent (must refrain from heterosexual intercourse) or use highly effective contraceptive methods, or two effective contraceptive methods, as defined in the CSP, during the treatment period and for at least 7 months after the last dose of Study treatment, whichever is longer. Women of childbearing potential must have a negative serum pregnancy test within 14 days before Study treatment initiation and must agree to refrain from donating eggs during the entire Study treatment period and for 7 months after the last administration of the Study drug.
  • Being male subjects, surgically sterile or having agreed with true abstinence (must refrain from heterosexual intercourse), or whose female partners are willing to agree with true abstinence or use barrier contraceptive measures mentioned above during the entire Study treatment period and for 4 months after the last administration of the Study drug. Males must agree to refrain from donating sperm during the entire Study treatment period and for 4 months after the last administration of the Study drug.
  • Patients must be able to tolerate therapy.
  • Patients must be accessible for treatment and follow-up.

Who cannot join

  • 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.
Show all 24Show fewer
  • 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.
  • Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the Study.
  • Current known infection with hepatitis B virus (HBV), or hepatitis C virus (HCV). Patients with past HBV infection or resolved HBV infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive hepatitis B core antibody [HBcAb] test, accompanied by a negative HBV DNA test) are eligible. Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
  • Known human immunodeficiency virus (HIV) infection that is not well controlled. All of the following criteria are required to define an HIV infection that is well controlled: undetectable viral RNA, CD4+ count ≥ 350, no history of AIDS-defining opportunistic infection within the past 12 months, and stable for at least 4 weeks on the same anti-HIV medications (meaning there are no expected further changes in that time to the number or type of antiretroviral drugs in the regimen). If an HIV infection meets the above criteria, monitoring of viral RNA load and CD4+ count is recommended.
  • History of a major surgical procedure (defined as requiring general anesthesia) or significant traumatic injury within 21 days prior to enrolment, or patients who have not recovered from the side effects of any major surgery.
  • A history of uncontrolled seizures, central nervous system (CNS) disorders or serious and/or unstable pre-existing psychiatric disability judged by the investigator to be clinically significant and adversely affecting compliance to Study drugs or interfering with subject safety.
  • Patients requiring concomitant use of chronic systemic (intravenously [IV] or oral) corticosteroids or other immunosuppressive medications except for managing adverse events (inhaled steroids or intra articular steroid injections are permitted in this Study). Corticosteroids (dexamethasone at 4 mg or equivalent doses) are allowed only for the treatment of bone metastases or perifocal brain metastases oedema and for the treatment of specific adverse drug reactions. The use of ≥ 4 weeks of stable corticosteroid therapy (4 mg/day) in patients with BM can be discussed with the Medical Monitor. Note: Hematopoietic growth factors may be used for prophylaxis or treatment based on the clinical judgment of the investigator. Concomitant use of dietary supplements, medications not prescribed by the Investigator, and alternative/complementary treatments is discouraged, but not prohibited. Prophylactic or supportive treatment of Study-drug induced adverse events will be otherwise as per investigator's discretion and institutional guidelines.
  • Patients with known substance abuse or any other medical conditions such as clinically significant cardiac or psychological conditions, that may, in the opinion of the investigator, interfere with the subject's participation in the clinical Study or evaluation of the clinical Study results.
  • Use of concurrent investigational agents, endocrine treatments, or other concomitant anti-cancer therapies.
  • Participants who are unable or unwilling to comply with the requirements of the protocol in the opinion of the investigator.

Trial locations and contacts

13 sites in 2 countries.

13 sites in 2 countries

Spain11 sites

  • Hospital Universitario San Juan de Alicante

    Alicante, Alicante, 03550

  • Hospital Universitari Dexeus

    Barcelona, Barcelona, 08028

  • Hospital Universitari Vall D'Hebron

    Barcelona, Barcelona, 08035

  • Hospital Universitario de Basurto

    Bilbao, Bilbao, 48013

  • Hospital Universitario Reina Sofía

    Córdoba, Córdoba, 14004

  • Hospital Universitario Clínico San Cecilio de Granada

    Granada, Granada, 18016

  • Hospital Beata María Ana

    Madrid, Madrid, 28007

  • Hospital Universitario Ramón y Cajal

    Madrid, Madrid, 28034

  • Hospital Universitario Virgen del Rocío

    Seville, Sevilla, 41013

  • Hospital Clínico Universitario de Valencia

    Valencia, Valencia, 46010

  • Hospital Arnau de Vilanova de Valencia

    Valencia, Valencia, 46015

Other trials in Spain

Austria2 sites

  • Salzburg Cancer research Institute-Center

    Salzburg

  • Medical University of Vienna

    Vienna, 1090

Other trials in Austria

About this study

Official title: Phase II Study of Trastuzumab-Deruxtecan (T-DXd; DS-8201a) in HER2-Low Breast Cancer Patients Presenting With Newly Diagnosed or Progressing Brain Metastases

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.

Read the detailed description

This is an international, multicentric, single arm, phase II study to evaluate the safety and efficacy of T-DXd in HER2-low breast cancer with newly diagnosed or progressing brain metastases with or without untreated type II leptomeningeal disease (LMD).

Upon meeting all selection criteria, a total of 27 patients will be enrolled as follows: 13 patients will be accrued in stage 1 to receive T-DXd and additional 14 patients will be accrued in stage 2 according to the number of responses seen in stage 1.

The main objective is to analyze the efficacy of T-DXd as determined by ORR at any timepoint as judged by best CNS response according to RANO-BM criteria.

End of study (EoS) will occur 11 months after the last patient included in the Study initiates T-DXd treatment, unless premature termination of the Study. EoS is defined as the last data point at the last participant's visit and will occur after the Study treatment termination of the last patient in the Study.

Being tested
Trastuzumab-Deruxtecan (T-DXd)
Keywords
breast cancer, HER2-low, brain metastases, T-DXd
Medical subject headings
Breast Neoplasms, Brain Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Trastuzumab-Deruxtecan (T-DXd)Drug

    Also called DS-8021a, ENHERTU

    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.

Study groups in NCT06048718
Study groupRoleWhat they receive
T-DXdExperimentalPatients 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.
Receives: Drug: Trastuzumab-Deruxtecan (T-DXd)

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

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

Secondary outcomes (13)

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

    ORR for EC and overall lesions, defined as the rate of patients with complete response (CR) or partial response (PR), determined locally by the investigator per RECIST criteria v.1.1.

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

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

    Bi-CBR defined as the sum of CR rate, PR rate and more than 24 weeks stable disease (SD) rate, and determined locally by the investigator through the use of RANO-BM criteria for intracranial (IC) lesions and RECIST v.1.1 for EC and overall lesions.

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

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

    Bi-DCR, defined as CR+PR+SD, determined locally by the investigator per RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both EC and overall lesions.

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

  4. Time to response (TTR) in all patients.

    TTR, defined as the period from the treatment initiation to time of the first objective tumor response (tumor shrinkage of ≥ 30%) observed for patients who achieved a CR or PR, as per RANO-BM for intracranial lesions and RECIST v.1.1 for extracranial and overall lesions.

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

  5. Duration of response (DoR) in all patients.

    DoR, defined as the period from the first occurrence of a documented objective response to disease progression or death from any cause, observed for patients who achieved a CR or PR, as per RANO-BM for intracranial lesions and RECIST v.1.1 for extracranial and overall lesions.

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

  6. Best percentage of change in tumor burden in all patients.

    Best percentage of change in tumor burden as per RANO-BM for intracranial lesions and RECIST v.1.1 for extracranial and overall measurable lesions.

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

  7. Progression-free survival (PFS) in all patients.

    PFS, defined as the period from treatment initiation to the first occurrence of disease progression or death from any cause, whichever occurs first. Progression will be determined locally per RANO-BM criteria for IC lesions and RECIST criteria v.1.1 for both EC and overall lesions.

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

  8. Overall survival (OS) in all patients.

    OS, defined as the period from treatment initiation to death from any cause, determined locally by the investigator.

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

  9. Incidence of Adverse Events [Safety and Tolerability]

    To evaluate incidence and severity of adverse events, with severity determined in accordance to NCI-CTCAE v.5.0

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

  10. Evaluation of the quality of life (QoL) in all patients (QLQ-c30 questionnaire).

    Assessment of QoL with the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ-c30).

    Changes from baseline is fitted to a repeated measures model including subjects as a random effect, baseline, and post-baseline evaluations. Time to Improvement and Deterioration Analysis Using a threshold value for improvement and deterioration specific to the measures of interest, time to improvement and time to deterioration could be estimated. Distributions of time-to-event variables will be estimated using the Kaplan-Meier method. Median times to event with 2-sided 95% confidence intervals will be estimated.

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

  11. Evaluation of the quality of life (QoL) in all patients (QLQ-BN20 questionnaire).

    Assessment of QoL with the brain cancer specific questionnaire (QLQ-BN20 ). Changes from baseline is fitted to a repeated measures model including subjects as a random effect, baseline, and post-baseline evaluations. Time to Improvement and Deterioration Analysis Using a threshold value for improvement and deterioration specific to the measures of interest, time to improvement and time to deterioration could be estimated. Distributions of time-to-event variables will be estimated using the Kaplan-Meier method. Median times to event with 2-sided 95% confidence intervals will be estimated.

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

  12. Evaluation of the quality of life (QoL) in all patients (QLQ-BR45 questionnaire).

    Assessment of QoL with the BC specific questionnaire (QLQ-BR45). Changes from baseline is fitted to a repeated measures model including subjects as a random effect, baseline, and post-baseline evaluations. Time to Improvement and Deterioration Analysis Using a threshold value for improvement and deterioration specific to the measures of interest, time to improvement and time to deterioration could be estimated. Distributions of time-to-event variables will be estimated using the Kaplan-Meier method. Median times to event with 2-sided 95% confidence intervals will be estimated.

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

  13. Evaluation of neurologic function in all patients.

    To evaluate the neurologic function with clinician-reported outcome Neurologic Assessment in Neuro-Oncology (NANO) scale.

    The NANO is an objective clinician-reported outcome of neurologic function that consists of 9 neurologic domains: gait, strength, ataxia (upper extremity), sensation, visual fields, facial strength, language, level of consciousness, and behavior.

    Each domain is subdivided into 3 or 4 levels of function with scores based on discrete quantifiable measures. Levels of function for each domain range from 0 to 2 or 0 to 3. A score of 0 indicates normal function, while the highest score indicates the most severe level of deficit for that domain.

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 Sep 2023
  2. Study start5 Jun 2024
  3. Primary completionNov 2026 (estimated)
  4. Study completionNov 2026 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Model description
Single-arm, two-stage optimal Simon's design, phase II clinical trial.
Masking
None (open label)
Enrolment
28 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT06048718
Sponsor's protocol ID
MEDOPP596
Other IDs
2023-506702-39-00, 2023
Acronym
TUXEDO-4
Status last verified
May 2026
First submitted
6 Sep 2023
Last updated
8 May 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • 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.

    PubMed 40018758

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Trastuzumab-Deruxtecan (T-DXd) in people with Breast Cancer and Metastatic Breast Cancer, run by MedSIR at 13 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 22 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 8 May 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 13 sites in Spain, Austria. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

ORR at any time point as judged by best central nervous system (CNS) response in all patients. (time frame: From baseline until approximately 11 months after the last patient included in the study starts treatment.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT06048718, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 May 2026.

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