A Study of T-DXd in Participants With or Without Brain Metastasis Who Have Previously Treated Advanced or Metastatic HER2 Positive Breast Cancer (DESTINY-B12)

An Open-Label, Multinational, Multicenter, Phase 3b/4 Study of Trastuzumab Deruxtecan in Patients With or Without Baseline Brain Metastasis With Previously Treated Advanced/Metastatic HER2-Positive Breast Cancer (DESTINY-Breast12)

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).

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Trastuzumab Deruxtecan

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.

• Study Type: Interventional
• Enrollment (Actual): 506
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Adelaide, Australia, 5000
    • Research Site
  • Auchenflower, Australia, 4066
    • Research Site
  • Clayton, Australia, 3168
    • Research Site
  • St Leonards, Australia, 2065
    • Research Site
  • Subiaco, Australia, 6008
    • Research Site
• Belgium
  • Anderlecht, Belgium, 1070
    • Research Site
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1H7
      • Research Site
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • Research Site
• Denmark
  • Copenhagen, Denmark, 2100
    • Research Site
  • Herlev, Denmark, 2730
    • Research Site
  • Odense C, Denmark, 5000
    • Research Site
• Finland
  • Helsinki, Finland, 00290
    • Research Site
  • Tampere, Finland, FI-33521
    • Research Site
  • Turku, Finland, 20520
    • Research Site
• Germany
  • Berlin, Germany, 13125
    • Research Site
  • Dresden, Germany, 1307
    • Research Site
  • Erlangen, Germany, 91054
    • Research Site
  • Essen, Germany, 45136
    • Research Site
  • Frankfurt, Germany, 60389
    • Research Site
  • Hamburg, Germany, 20246
    • Research Site
  • Hannover, Germany, 30625
    • Research Site
  • Kiel, Germany, 24105
    • Research Site
  • Mannheim, Germany, 68167
    • Research Site
  • München, Germany, 80336
    • Research Site
  • München, Germany, 80637
    • Research Site
  • Münster, Germany, 48149
    • Research Site
  • Tübingen, Germany, 72076
    • Research Site
• Ireland
  • Cork, Ireland, T12 DV56
    • Research Site
  • Dublin, Ireland, 7
    • Research Site
  • Dublin, Ireland, D04 Y8V0
    • Research Site
• Italy
  • Ancona, Italy, 60122
    • Research Site
  • Bergamo, Italy, 24127
    • Research Site
  • Catania, Italy, 95126
    • Research Site
  • Milano, Italy, 20132
    • Research Site
  • Napoli, Italy, 80131
    • Research Site
  • Padova, Italy, 35128
    • Research Site
  • Prato, Italy, 59100
    • Research Site
• Japan
  • Isehara, Japan, 259-1193
    • Research Site
  • Kawasaki-shi, Japan, 216-8511
    • Research Site
  • Sapporo-shi, Japan, 003-0804
    • Research Site
  • Shinagawa-ku, Japan, 142-8666
    • Research Site
  • Yokohama-shi, Japan, 241-8515
    • Research Site
• Netherlands
  • Den Haag, Netherlands, 2545 AA
    • Research Site
  • Maastricht, Netherlands, 6229 HX
    • Research Site
• Norway
  • Bergen, Norway, 5021
    • Research Site
  • Oslo, Norway, 450
    • Research Site
  • Oslo, Norway, N-0379
    • Research Site
• Poland
  • Gdańsk, Poland, 80-214
    • Research Site
  • Kraków, Poland, 31-501
    • Research Site
  • Opole, Poland, 45-060
    • Research Site
  • Warszawa, Poland, 02-781
    • Research Site
  • Warszawa, Poland, 04-141
    • Research Site
• Portugal
  • Lisboa, Portugal, 1649-035
    • Research Site
  • Lisboa, Portugal, 1400-048
    • Research Site
  • Porto, Portugal, 4099-001
    • Research Site
• Spain
  • Barcelona, Spain, 08036
    • Research Site
  • Barcelona, Spain, 8035
    • Research Site
  • Bilbao (Vizcaya), Spain, 48013
    • Research Site
  • Granada, Spain, 18014
    • Research Site
  • Madrid, Spain, 28034
    • Research Site
  • Madrid, Spain, 28041
    • Research Site
  • Madrid, Spain, 28005
    • Research Site
  • Salamanca, Spain, 37007
    • Research Site
  • Santander, Spain, 39008
    • Research Site
  • Santiago De Compostela-Coruña, Spain, 15706
    • Research Site
  • Sevilla, Spain, 41013
    • Research Site
  • Valencia, Spain, 46009
    • Research Site
• Sweden
  • Göteborg, Sweden, 413 45
    • Research Site
  • Lund, Sweden, 221 85
    • Research Site
  • Uppsala, Sweden, 751 85
    • Research Site
• Switzerland
  • Basel, Switzerland, 4031
    • Research Site
  • Bellinzona, Switzerland, CH-6500
    • Research Site
  • Lausanne, Switzerland, 1011
    • Research Site
  • Luzern, Switzerland, 6000
    • Research Site
• United Kingdom
  • Edinburgh, United Kingdom, EH4 2XR
    • Research Site
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Research Site
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 130 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion:

• 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

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: 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.	Drug: Trastuzumab Deruxtecan; Participants will receive T-DXd administered using an IV bag containing 5% (w/v) dextrose injection infusion solution.; Other Names: fam-trastuzumab deruxtecan-nxki

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR) in Participants without BM at Baseline (Cohort 1)	To describe the overall treatment effect of T- DXd in HER2-positive metastatic breast cancer (MBC) participants without baseline BM. An ORR is defined as the proportion of participants who have a confirmed complete response (CR) or confirmed partial response (PR), as determined by independent central review (ICR) per RECIST 1.1.	From screening until progression of disease [PD] (Up to 2.5 Years)
Progression-free Survival (PFS) in Participants with BM at Baseline (Cohort 2)	To describe the overall treatment effect of T- DXd in HER2-positive MBC participants with baseline BM. The PFS will be defined as the time from the date of the first dose of study intervention until the date of objective PD per RECIST 1.1 as assessed by ICR or death.	From screening until PD (Up to 2.5 Years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS) in Months	To describe the treatment effect on the development and progression of BM in participants with or without baseline BM using additional efficacy measurements. An OS is defined as the time from the date of the first dose of study intervention until death due to any cause.	At safety F/U (40+7 days after last dose) visit, thereafter survival F/U q3months ± 14 days (Approximately 2.5 Years)
Duration of Response (DoR)	To describe the treatment effect on the development and progression of BM in participants with or without baseline BM using additional efficacy measurements. The DoR will be defined as the time from the date of first documented confirmed response until date of documented progression per RECIST 1.1 as assessed by ICR or death due to any cause.	Screening Day (-28 days) until end-of-treatment (EOT) (Approximately 2.5 Years)
Time to Progression	To describe the treatment effect on the development and progression of BM in participants with or without baseline BM using additional efficacy measurements. Time to progression by RECIST 1.1 per ICR is defined as the time from the date of the first dose of study intervention to the date of documented disease progression.	Screening Day (-28 days) until PD (Approximately 2.5 Years)
Duration of Treatment on Subsequent Lines of Therapy	To describe the treatment effect on the development and progression of BM in participants with or without baseline BM using additional efficacy measurements. Duration of treatment on subsequent therapy will be defined as the time from the date of first dose of a subsequent therapy until date of the last dose of that therapy.	At safety follow-up (40+7 days after last dose) then survival F/U q3months ± 14 days (Approximately 2.5 Years)
Time to Second Progression or Death (PFS2)	To describe the treatment effect on the development and progression of BM in participants with or without baseline BM using additional efficacy measurements. The PFS2 is defined as time from the first dose of study intervention to second progression (the earliest of the progression event subsequent to first subsequent therapy) or death.	At safety F/U (40+7 days after last dose) visit, thereafter survival F/U q3months ± 14 days (Approximately 2.5 Years)
Incidence of new Symptomatic Central Nervous System (CNS) Metastasis During Treatment in Participants without BM at Baseline (Cohort 1)	To describe the treatment effect on the development and progression of BM in participants without baseline BM using additional efficacy measurements.	At Screening day (-28 days), Cycle 1 (15 days ± 2 days) Day 1 and Cycle 3 (15 days ± 2 days) Day 1 and thereafter every 3 subsequent cycles (Approximately 2.5 Years)
Time to Next Progression (CNS or extracranial) or Death	To describe the treatment effect on the development and progression (central nervous system [CNS] progression) of BM in participants without baseline BM using additional efficacy measurements. The time to next progression is defined as the time from the date of the first documented isolated CNS progression to the date of the next documented disease progression (CNS or extracranial) per RECIST 1.1 or death, and will be summarized descriptively in participants who develop isolated CNS progression, receive local therapy, and continue on protocol therapy.	Screening Day (-28 days) until next PD (Approximately 2.5 Years)
Site (CNS vs extracranial vs both) of Next Progression	To describe the treatment effect on the development and progression (CNS progression) of BM in participants without baseline BM using additional efficacy measurements. Site of next progression will be summarized descriptively in participants who develop isolated CNS progression, receive local therapy, continue on protocol therapy, and have a subsequent documented disease progression (CNS or extracranial) per RECIST 1.1.	Screening Day (-28 days) until next PD (Approximately 2.5 Years)
Objective Response Rate in Participants with BM at Baseline (Cohort 2)	To describe efficacy in participants with stable or untreated BM. An ORR will be evaluated by RECIST 1.1 per ICR.	From screening until PD (Up to 2.5 Years)
Central Nervous System Progression-free Survival in Participants with BM at Baseline (Cohort 2)	To describe efficacy in participants with stable or untreated BM. The CNS PFS is defined as time from the first dose of study intervention to CNS progression per CNS RECIST 1.1 or death resulting from any cause, whichever occurs first.	At safety follow-up (40+7 days after last dose) then survival F/U q3months ± 14 days (Approximately 2.5 Years)
Time to new CNS Lesions in Participants with BM at Baseline (Cohort 2)	To describe efficacy in participants with stable or untreated BM. The time to new CNS lesions is defined as the time from the date of the first dose of study intervention to the date of documented new CNS lesions.	Screening Day (-28 days) until EOT (Approximately 2.5 Years)
Central Nervous System Objective Response Rate in Participants with BM at Baseline by ICR (Cohort 2)	To describe efficacy in participants with stable or untreated BM. The CNS ORR is defined as the proportion of participants with measurable BM at baseline who have a confirmed CR or confirmed PR of brain lesions, as determined by ICR per CNS RECIST 1.1.	Screening Day (-28 days) until EOT (Approximately 2.5 Years)
Central Nervous System Duration of Response in Participants with BM at Baseline (Cohort 2)	To describe efficacy in participants with stable or untreated BM. The CNS DoR will be defined as the time from the date of first documented confirmed CNS response until date of documented CNS progression per CNS RECIST 1.1 as assessed by ICR or death due to any cause.	Screening Day (-28 days) until EOT (Approximately 2.5 Years)
European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)	To describe the effect of T-DXd on symptoms, functioning, and health-related quality of life (HRQoL) in HER2+ MBC participants with or without baseline BM.	Cycle 1 (15 days ± 2 days) Day 1, thereafter every 3 weeks (q3w) until 24 weeks post EOT visit and prior to second progression, and at the EOT visit (Approximately 2.5 Years)
Neurologic Assessment in Neuro-Oncology Scale	To describe the effect of T-DXd on symptoms, functioning, and HRQoL in HER2+ MBC participants with or without baseline BM.	Cycle 1 (15 days ± 2 days [Day 1]), Cycle 2 (15 days ± 2 days) Day 1, Cycle 3 (15 days ± 2 days) Day 1, Cycle 4 (15 days ± 2 days) Day 1 thereafter subsequent Cycles until PD and at EOT visit (Approximately 2.5 Years)
Cognitive Functions Tests	To describe the effect of T-DXd on symptoms, functioning, and HRQoL in HER2+ MBC participants with or without baseline BM.	Cycle 1 (15 days ± 2 days) Day 1, thereafter q12w and at EOT visit (Approximately 2.5 Years)
MD Anderson Symptom Inventory Brain Tumor-specific Items	To describe the effect of T-DXd on symptoms, functioning, and HRQoL in HER2+ MBC participants with or without baseline BM.	Cycle 1 (15 days ± 2 days) Day 1, thereafter q3w until 24 weeks post EOT visit and prior to second progression, and at the EOT visit (Approximately 2.5 Years)
St. George's Respiratory Questionnaire - idiopathic pulmonary fibrosis version in Participants with Interstitial Lung Disease (ILD)/Pneumonitis	To describe the effect of T-DXd on symptoms, functioning, and HRQoL in HER2+ MBC participants with or without baseline BM.	After diagnosis of ILD/pneumonitis and thereafter once weekly until EOT and safety F/U (40+7 days after last dose) (Approximately 2.5 Years)
Number of Participants with Adverse Events	To describe the safety profile of T-DXd.	Cycle 1 (15 days ± 2 days) Day 1 until safety F/U (40+7 days after last dose) (Approximately 2.5 Years)
Number of Participants with Investigator-assessed ILD/Pneumonitis or Rate of Investigator-assessed ILD/Pneumonitis	To describe the safety profile of T-DXd.	Cycle 1 (15 days ± 2 days) Day 1 until C4 (15 days ± 2 days) Day 1 and thereafter subsequent cycles until PD (Approximately 2.5 Years)
Number of Participants with Adverse Events with BM at Baseline	To describe the safety profile of T-DXd.	Cycle 1 (15 days ± 2 days) Day 1 until safety F/U (40+7 days after last dose) (Approximately 2.5 Years)

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Daiichi Sankyo
• Investigators: Principal Investigator: Nadia Harbeck, MD, PhD, Head, Breast Center, Ludwig-Maximilians-University of Munich Department of Obstetrics and Gynecology Marchioninistr. 15, 81377 Munich, Germany; Principal Investigator: Nancy U. Lin, MD, 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

Study record dates

Study Major Dates

• Study Start (Actual): June 22, 2021
• Primary Completion (Actual): February 8, 2024
• Study Completion (Actual): February 8, 2024

Study Registration Dates

• First Submitted: January 20, 2021
• First Submitted That Met QC Criteria: February 2, 2021
• First Posted (Actual): February 5, 2021

Study Record Updates

• Last Update Posted (Actual): February 20, 2024
• Last Update Submitted That Met QC Criteria: February 19, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Brain Metastasis; Trastuzumab deruxtecan; Human epidermal growth factor receptor 2 Positive Breast Cancer
• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Neoplastic Processes; Central Nervous System Neoplasms; Nervous System Neoplasms; Breast Neoplasms; Neoplasm Metastasis; Brain Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Immunoconjugates; Trastuzumab; Trastuzumab deruxtecan
• Other Study ID Numbers: D9673C00007; 2020-005048-46 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment:

https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please refer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes