Phase II Study of T-DX in HER2-positive Breast Cancer Brain Metastases (TUXEDO-1)

• ClinicalTrials.gov Identifier: NCT04752059
• Recruitment Status: Completed
• First Posted: February 12, 2021
• Last Update Posted: May 12, 2023
• Sponsor: Medical University of Vienna
• Collaborator: Daiichi Sankyo, Inc.
• Information provided by (Responsible Party): Rupert Bartsch, Medical University of Vienna

Study Description

Brief Summary:

Trastuzumab-Deruxtecan (T-DXd; DS-8201a) in HER2-positive Breast Cancer Patients with newly diagnosed or progressing Brain Metastases

Condition or disease	Intervention/treatment	Phase
Breast Cancer Stage IV	Drug: Trastuzumab deruxtecan	Phase 2

Detailed Description:

T-DXd will be administered at a dose of 5.4 mg/kg body weight once every three weeks in patients with newly diagnosed or progressive HER2 positive breast cancer brain metastases. Response rate by RANO-BM is defined the primary study endpoint.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Trastuzumab-Deruxtecan (T-DX; DS-8201a) in HER2-positive Breast Cancer Patients With Newly Diagnosed or Progressing Brain Metastases
• Actual Study Start Date: July 28, 2020
• Actual Primary Completion Date: May 1, 2023
• Actual Study Completion Date: May 1, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: T-DXd 5.4 mg; Single arm phase II trial	Drug: Trastuzumab deruxtecan; Trastuzumab-deruxtecan 5.4 mg/kg body weight i.v. on day 1 once every three weeks until progression or death; Other Names: Ds8201a; Enhertu

Outcome Measures

Primary Outcome Measures :

1. Reponse rate of brain metastases to trastuzumab-deruxtecan [ Time Frame: From date of randomization until the date of first documented progression or date of death from any cause or treatment discontinuation from any other reason, whichever came first, assessed up to 36 months ]
   measured according to RANO-BM criteria

Secondary Outcome Measures :

1. Progression-free survival [ Time Frame: From date of randomization until the date of first documented progression or date of death from any cause or treatment discontinuation from any other reason, whichever came first, assessed up to 36 months ]
   Time from inclusion until progression
2. Overall Survival [ Time Frame: From date of randomization until the date of first documented progression or date of death from any cause or treatment discontinuation from any other reason, whichever came first, assessed up to 36 months ]
   Time from inclusion until death of any cause
3. Safety of trastuzumab deruxtecan in patients with active brain metastases [ Time Frame: From date of randomization until the date of first documented progression or date of death from any cause or treatment discontinuation from any other reason, whichever came first, assessed up to 36 months ]
   Assessment of treatment-emerging adverse events

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 100 Years (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

Histologically confirmed breast cancer

• Radiologically documented metastatic disease
• HER2-positive as defined by IHC 3+ and/or HER2/neu gene amplification
• Newly diagnosed brain metastases or brain metastases progressing after prior local therapy
• Measurable disease (RANO-BM criteria)
• No indication for immediate local treatment
• No indication of leptomeningeal disease
• KPS >70%, ECOG <2
• Indication for systemic anti-HER2 treatment
• Prior exposure to trastuzumab and pertuzumab
• Prior exposure to T-DM1 allowed
• Life expectancy of at least 3 months
• Age ≥18 years
• Patient must be able to tolerate therapy, and have adequate cardiac function (defined by baseline left ventricular ejection fraction ≥50%) Adequate bone-marrow, liver and kidney function
• Adequate treatment washout period before enrolment, defined as:
• Major Surgery: ≥4 weeks
• Radiation therapy: ≥4 weeks
• Chemotherapy, small-molecule targeted agents, anticancer hormonal therapy: ≥3 weeks
• Antibody-based treatment: ≥4 weeks
• Patient must be capable of understanding the purpose of the study and have given written informed consent

Exclusion Criteria:

Metastatic breast cancer other than HER2-positve disease

• Use of any investigational agent within 28 days prior to initiation of treatment
• History of malignancy other than squamous cell carcinoma, basal cell carcinoma of the skin or carcinoma in situ of the cervix within the last 3 years including contralateral breast cancer
• Major surgery, other than diagnostic surgery, within the last 4 weeks
• Indication for immediate local therapy as defined by local standard
• Leptomeningeal involvement
• Other anticancer therapy, including cytotoxic, targeted agents, immunotherapy, antibody, retinoid, or anti-cancer hormonal treatment
• Concomitant radiotherapy
• Prior radiotherapy to the thorax other than breast irradiation or irradiation of bone metastases
• A history of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant and adversely affecting compliance to study drugs Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to randomization, congestive heart failure (NYHA III-IV), left ventricular ejection fraction <50%, arrhythmia unless controlled by therapy, with the exception of extra systoles or minor conduction abnormalities, and long QT syndrome (QTc interval >450 ms)
• Subjects who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment) including acute and chronic infections with hepatitis B and C
• Inadequate haematological status at baseline prior to study entry: Dependency on red blood cell and/or platelet transfusions, ANC (absolute neutrophil count (segmented + bands) <1.0 x 109/L; platelets <100 x 109/L
• Inadequate kidney function: serum-creatinine >1.5 times upper normal Limit Hepatic dysfunction: total bilirubin >1.5 times upper normal limit (>3 in patients with liver metastases or known history of Gilbert's disease); ALT, AST >3 times TUXEDO-1_Version 2.0 05.05.2020 Page 8 of 73 upper normal limit (>5 in patients with liver metastases); serum albumin <2.5 g/dL; INR ≥1.5
• Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (i.e. pulmonary emboli within three months of the study enrolment, severe asthma, severe COPD, restrictive lung disease, pleural effusion etc.), and any autoimmune, connective tissue or inflammatory disorders with pulmonary involvement (i.e. rheumatoid arthritis, Sjogren's syndrome, sarcoidosis etc.), or prior pneumonectomy.

Subjects with bronchopulmonary disorders who require intermittent use of bronchodilators (such as albuterol) will not be excluded from this study

• Patients with active opportunistic infections
• Known HIV infection
• Concomitant treatment with chloroquine or hydroxychloroquine
• Pregnant or lactating women. Women with childbearing potential must have a negative pregnancy test at screening
• Women with childbearing potential, including women whose last menstrual period was less than one year prior to screening, unable or unwilling to use adequate contraception from study start to one year after the last dose of protocol therapy. Acceptable contraception methods included the application of an intrauterine device, barrier method or total abstinence
• Patients with known hypersensitivity to trastuzumab
• Patients not able to provide written informed consent 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
• Patients requiring concomitant use of chronic systemic (IV or oral) corticosteroids at doses higher than 4 mg dexamethasone per day or other immunosuppressive medications except for managing adverse events (inhaled steroids or intra articular steroid injections are permitted in this study)

Contacts and Locations

Locations

Austria

AKH Universitaetsklinikum Vienna, Department f. Internal medicine I, oncology

Vienna, Austria, 1090

Sponsors and Collaborators

Medical University of Vienna

Daiichi Sankyo, Inc.

Investigators

• Principal Investigator: Rupert Bartsch, MD; Medical University of Vienna

  Study Documents (Full-Text)

Documents provided by Rupert Bartsch, Medical University of Vienna:

Study Protocol and Statistical Analysis Plan  [PDF] May 5, 2020

More Information

Publications of Results:

Bartsch R, Berghoff AS, Furtner J, Marhold M, Bergen ES, Roider-Schur S, Starzer AM, Forstner H, Rottenmanner B, Dieckmann K, Bago-Horvath Z, Haslacher H, Widhalm G, Ilhan-Mutlu A, Minichsdorfer C, Fuereder T, Szekeres T, Oehler L, Gruenberger B, Singer CF, Weltermann A, Puhr R, Preusser M. Trastuzumab deruxtecan in HER2-positive breast cancer with brain metastases: a single-arm, phase 2 trial. Nat Med. 2022 Sep;28(9):1840-1847. doi: 10.1038/s41591-022-01935-8. Epub 2022 Aug 8.

• Responsible Party: Rupert Bartsch, Consultant Medical Oncology, Medical University of Vienna
• ClinicalTrials.gov Identifier: NCT04752059
• Other Study ID Numbers: TUXEDO-1
• First Posted: February 12, 2021
• Last Update Posted: May 12, 2023
• Last Verified: May 2023

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Breast Neoplasms; Brain Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Trastuzumab; Trastuzumab deruxtecan; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunoconjugates; Immunologic Factors; Physiological Effects of Drugs