A Study of T-DXd in Participants With or Without Brain Metastasis Who Have Previously Treated Advanced or Metastatic HER2 Positive Breast Cancer

NCT ID: NCT04739761

Last Updated: 2025-09-10

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 506 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-06-22
• Study Completion Date: 2026-02-03

Brief Summary

This is open-label, multicenter, international study, assessing the efficacy and safety of Trastuzumab deruxtecan (T-DXd) in participants with or without brain metastasis (BMs), with previously-treated advanced/metastatic HER2-positive breast cancer whose disease has progressed on prior anti-HER2-based regimens and who received no more than 2 lines/regimens of therapy in the metastatic setting (excluding tucatinib).

Detailed Description

Approximately 500 eligible participants will be enrolled into 1 of 2 cohorts (250 participants in each cohort) according to the presence or absence of BMs at baseline. Cohort 1 will include participants without BM at baseline and Cohort 2 will consist of participants with BM at baseline.

After study intervention discontinuation, all participants will undergo an end-of-treatment visit (within 7 days of discontinuation) and will be followed up for safety assessments 40 (+ up to 7) days after the discontinuation of all study intervention.

All participants will be followed up for survival status and duration of treatment on subsequent therapies after intervention discontinuation every 3 months (± 14 days) from the date of the safety follow-up until death, withdrawal of consent, or the end of the study, as per defined in the protocol.

Conditions

Breast Cancer

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Trastuzumab Deruxtecan

Participants with or without BM at baseline will receive intravenous (IV) T-DXd, 5.4 mg/kg, every 3 weeks (21-day cycle) until Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) defined radiological progression outside central nervous system, unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation is met.

Group Type: EXPERIMENTAL

Trastuzumab Deruxtecan

Intervention Type: DRUG

Participants will receive T-DXd administered using an IV bag containing 5% (w/v) dextrose injection infusion solution.

Interventions

Trastuzumab Deruxtecan

Participants will receive T-DXd administered using an IV bag containing 5% (w/v) dextrose injection infusion solution.

Intervention Type: DRUG

Other Intervention Names

fam-trastuzumab deruxtecan-nxki

Eligibility Criteria

Inclusion Criteria

• Participants should have pathologically documented breast cancer that is: unresectable/advanced or metastatic; confirmed HER2-positive status expression as determined according to American Society of Clinical Oncology/College of American Pathologists guidelines
• Participant must have either: no evidence of BM, or untreated BM on screening contrast brain magnetic resonance imaging/ computed tomography (MRI/CT) scan, not needing immediate local therapy or previously-treated stable or progressing BM
• Participants with BMs must be neurologically stable
• For participants requiring radiotherapy due to BMs, there should be an adequate washout period before day of first dosing:
• ≥ 7 days since stereotactic radiosurgery or gamma knife
• ≥ 21 days since whole brain radiotherapy
• Eastern Cooperative Oncology Group performance status 0-1
• Previous breast cancer treatment: radiologic or objective evidence of disease progression on or after HER2 targeted therapies and no more than 2 lines/regimens of therapy in the metastatic setting
• Participant with the following measurable: at least 1 lesion that can be accurately measured at baseline as ≥ 10 mm in the longest diameter with CT or MRI and is suitable for accurate repeated measurements; or following Non-measurable diseases: Non-measurable, bone-only disease that can be assessed by CT or MRI or X-Ray. Lytic or mixed lytic bone lesions that can be assessed by CT or MRI or X-ray in the absence of measurable disease as defined above is acceptable; Participants with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible; and Non-measurable CNS disease (Cohort 2 only)
• Adequate organ and bone marrow function within 14 days before the day of first dosing as defined in the protocol
• Left ventricular ejection fraction ≥ 50% within 28 days before enrollment
• Negative pregnancy test (serum) for women of childbearing potential

Exclusion Criteria

• Known or suspected leptomeningeal disease
• Prior exposure to tucatinib treatment
• Refractory nausea and vomiting, chronic gastrointestinal disease, or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretion of T-DXd
• History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before the first dose of study intervention and of low potential risk for recurrence
• Based on screening contrast brain MRI/CT scan, participants must not have any of the following: any untreated brain lesions > 2.0 cm in size; ongoing use of systemic corticosteroids for control of symptoms of BMs; any brain lesion thought to require immediate local therapy; have poorly controlled (> 1/week) generalized or complex partial seizures, or manifest neurologic progression due to BMs not withstanding CNS-directed therapy
• Has spinal cord compression
• Known active hepatitis B or C infection, such as those with serologic evidence of viral infection within 28 days of Cycle 1 Day 1. Participants with past or resolved hepatitis B virus infection are eligible, if negative for hepatitis B surface antigen and positive for anti-hepatitis B core antigen
• Participants positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA
• Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
• Receipt of live, attenuated vaccine within 30 days prior to the first dose of T-DXd
• Participants with a medical history of myocardial infarction within 6 months before screening, symptomatic congestive heart failure (New York Heart Association Class II to IV)
• History of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
• Lung-specific intercurrent clinically significant illnesses and any autoimmune, connective tissue or inflammatory disorders
• Prior exposure, without adequate treatment washout period before the day of first dosing, to chloroquine/hydroxychloroquine: < 14 days
• Anticancer chemotherapy: immunotherapy (non-antibody-based therapy), retinoid therapy, hormonal therapy: < 3 weeks
• < 6 weeks for nitrosoureas or mitomycin
• Antibody-based anticancer therapy: < 4 weeks
• Any concurrent anticancer treatment. Concurrent use of hormonal therapy for noncancer- related conditions is allowed
• Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤ 1 or baseline
• Palliative radiotherapy with a limited field of radiation within 2 weeks or with wide field of radiation, radiation to the chest, or to more than 30% of the bone marrow within 4 weeks before the first dose of study intervention
• Participants with prior exposure to immunosuppressive medication within 14 days prior to first study dose
• Participants with a known hypersensitivity to study intervention or any of the excipients of the product or other monoclonal antibodies

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 130 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Daiichi Sankyo

INDUSTRY

Sponsor Role: collaborator

AstraZeneca

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Nadia Harbeck, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Head, Breast Center, Ludwig-Maximilians-University of Munich Department of Obstetrics and Gynecology Marchioninistr. 15, 81377 Munich, Germany

Nancy U. Lin, MD

Role: PRINCIPAL_INVESTIGATOR

Associate Chief, Division of Breast Oncology, Susan F. Smith Center for Women's Cancers Director, Metastatic Breast Cancer Program, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215

Locations

Research Site

Boston, Massachusetts, United States

Research Site

Durham, North Carolina, United States

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Adelaide, , Australia

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Auchenflower, , Australia

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Clayton, , Australia

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Heidelberg, , Australia

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St Leonards, , Australia

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Subiaco, , Australia

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Anderlecht, , Belgium

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Bruges, , Belgium

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Leuven, , Belgium

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Liège, , Belgium

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Vancouver, British Columbia, Canada

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Toronto, Ontario, Canada

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Copenhagen, , Denmark

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Herlev, , Denmark

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Odense C, , Denmark

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Helsinki, , Finland

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Tampere, , Finland

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Turku, , Finland

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Berlin, , Germany

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Dresden, , Germany

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Erlangen, , Germany

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Essen, , Germany

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Frankfurt, , Germany

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Hamburg, , Germany

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Hanover, , Germany

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Kiel, , Germany

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Mannheim, , Germany

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München, , Germany

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München, , Germany

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Münster, , Germany

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Tübingen, , Germany

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Cork, , Ireland

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Dublin, , Ireland

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Dublin, , Ireland

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Ancona, , Italy

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Bergamo, , Italy

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Catania, , Italy

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Milan, , Italy

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Napoli, , Italy

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Padua, , Italy

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Prato, , Italy

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Isehara, , Japan

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Kawasaki-shi, , Japan

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Sapporo, , Japan

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Shinagawa-ku, , Japan

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Yokohama, , Japan

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Maastricht, , Netherlands

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The Hague, , Netherlands

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Bergen, , Norway

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Oslo, , Norway

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Oslo, , Norway

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Gdansk, , Poland

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Krakow, , Poland

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Opole, , Poland

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Warsaw, , Poland

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Warsaw, , Poland

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Lisbon, , Portugal

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Lisbon, , Portugal

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Porto, , Portugal

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Barcelona, , Spain

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Barcelona, , Spain

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Bilbao (Vizcaya), , Spain

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Granada, , Spain

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Madrid, , Spain

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Madrid, , Spain

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Madrid, , Spain

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Salamanca, , Spain

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Santander, , Spain

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Santiago de Compostela-Coruña, , Spain

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Seville, , Spain

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Valencia, , Spain

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Gothenburg, , Sweden

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Lund, , Sweden

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Uppsala, , Sweden

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Basel, , Switzerland

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Bellinzona, , Switzerland

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Lausanne, , Switzerland

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Lucerne, , Switzerland

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Edinburgh, , United Kingdom

Countries

United States; Australia; Belgium; Canada; Denmark; Finland; Germany; Ireland; Italy; Japan; Netherlands; Norway; Poland; Portugal; Spain; Sweden; Switzerland; United Kingdom

References

Harbeck N, Ciruelos E, Jerusalem G, Muller V, Niikura N, Viale G, Bartsch R, Kurzeder C, Higgins MJ, Connolly RM, Baron-Hay S, Gion M, Guarneri V, Bianchini G, Wildiers H, Escriva-de-Romani S, Prahladan M, Bridge H, Kuptsova-Clarkson N, Scotto N, Verma S, Lin NU; DESTINY-Breast12 study group. Trastuzumab deruxtecan in HER2-positive advanced breast cancer with or without brain metastases: a phase 3b/4 trial. Nat Med. 2024 Dec;30(12):3717-3727. doi: 10.1038/s41591-024-03261-7. Epub 2024 Sep 13.

Reference Type: DERIVED

PMID: 39271844 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

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Redacted Statistical Analysis Plan

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Redacted CSP

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Redacted CSR synopsis

Other Identifiers

2024-510588-53-00

Identifier Type: REGISTRY

Identifier Source: secondary_id

2020-005048-46

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

D9673C00007

Identifier Type: -

Identifier Source: org_study_id