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

Phase II Study of Trastuzumab-Deruxtecan (T-DX; DS-8201a) in HER2-positive Breast Cancer Patients With Newly Diagnosed or Progressing Brain Metastases

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

Study Overview

• Status: Completed
• Conditions: Breast Cancer Stage IV
• Intervention / Treatment: Drug: Trastuzumab deruxtecan

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 Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1090
    • AKH Universitaetsklinikum Vienna, Department f. Internal medicine I, oncology

Participation Criteria

Eligibility Criteria

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

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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: Enhertu; Ds8201a

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reponse rate of brain metastases to trastuzumab-deruxtecan	measured according to RANO-BM criteria	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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival	Time from inclusion until progression	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
Overall Survival	Time from inclusion until death of any cause	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
Safety of trastuzumab deruxtecan in patients with active brain metastases	Assessment of treatment-emerging adverse events	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

Collaborators and Investigators

• Sponsor: Medical University of Vienna
• Collaborators: Daiichi Sankyo, Inc.
• Investigators: Principal Investigator: Rupert Bartsch, MD, Medical University of Vienna

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): July 28, 2020
• Primary Completion (Actual): May 1, 2023
• Study Completion (Actual): May 1, 2023

Study Registration Dates

• First Submitted: January 26, 2021
• First Submitted That Met QC Criteria: February 8, 2021
• First Posted (Actual): February 12, 2021

Study Record Updates

• Last Update Posted (Actual): May 12, 2023
• Last Update Submitted That Met QC Criteria: May 10, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Central Nervous System Neoplasms; Nervous System Neoplasms; Breast Neoplasms; Brain Neoplasms; Antineoplastic Agents; Antineoplastic Agents, Immunological; Trastuzumab
• Other Study ID Numbers: TUXEDO-1

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No