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

Sponsor
AstraZeneca (Industry)
Overall Status
Recruiting
CT.gov ID
NCT04739761
Collaborator
Daiichi Sankyo, Inc. (Industry)
500
91
1
30.9
5.5
0.2

Study Details

Study Description

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).

Condition or Disease Intervention/Treatment Phase
  • Drug: Trastuzumab Deruxtecan
Phase 3

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 Design

Study Type:
Interventional
Anticipated Enrollment :
500 participants
Allocation:
Non-Randomized
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
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).
Actual Study Start Date :
Jun 22, 2021
Anticipated Primary Completion Date :
Jan 19, 2024
Anticipated Study Completion Date :
Jan 19, 2024

Arms and Interventions

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
  • Outcome Measures

    Primary Outcome Measures

    1. Objective Response Rate (ORR) in Participants without BM at Baseline (Cohort 1) [From screening until progression of disease [PD] (Up to 2.5 Years)]

      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.

    2. Progression-free Survival (PFS) in Participants with BM at Baseline (Cohort 2) [From screening until PD (Up to 2.5 Years)]

      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.

    Secondary Outcome Measures

    1. Overall Survival (OS) in Months [At safety F/U (40+7 days after last dose) visit, thereafter survival F/U q3months ± 14 days (Approximately 2.5 Years)]

      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.

    2. Duration of Response (DoR) [Screening Day (-28 days) until end-of-treatment (EOT) (Approximately 2.5 Years)]

      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.

    3. Time to Progression [Screening Day (-28 days) until PD (Approximately 2.5 Years)]

      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.

    4. Duration of Treatment on Subsequent Lines of Therapy [At safety follow-up (40+7 days after last dose) then survival F/U q3months ± 14 days (Approximately 2.5 Years)]

      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.

    5. Time to Second Progression or Death (PFS2) [At safety F/U (40+7 days after last dose) visit, thereafter survival F/U q3months ± 14 days (Approximately 2.5 Years)]

      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.

    6. Incidence of new Symptomatic Central Nervous System (CNS) Metastasis During Treatment in Participants without BM at Baseline (Cohort 1) [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)]

      To describe the treatment effect on the development and progression of BM in participants without baseline BM using additional efficacy measurements.

    7. Time to Next Progression (CNS or extracranial) or Death [Screening Day (-28 days) until next PD (Approximately 2.5 Years)]

      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.

    8. Site (CNS vs extracranial vs both) of Next Progression [Screening Day (-28 days) until next PD (Approximately 2.5 Years)]

      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.

    9. Objective Response Rate in Participants with BM at Baseline (Cohort 2) [From screening until PD (Up to 2.5 Years)]

      To describe efficacy in participants with stable or untreated BM. An ORR will be evaluated by RECIST 1.1 per ICR.

    10. Central Nervous System Progression-free Survival in Participants with BM at Baseline (Cohort 2) [At safety follow-up (40+7 days after last dose) then survival F/U q3months ± 14 days (Approximately 2.5 Years)]

      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.

    11. Time to new CNS Lesions in Participants with BM at Baseline (Cohort 2) [Screening Day (-28 days) until EOT (Approximately 2.5 Years)]

      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.

    12. Central Nervous System Objective Response Rate in Participants with BM at Baseline by ICR (Cohort 2) [Screening Day (-28 days) until EOT (Approximately 2.5 Years)]

      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.

    13. Central Nervous System Duration of Response in Participants with BM at Baseline (Cohort 2) [Screening Day (-28 days) until EOT (Approximately 2.5 Years)]

      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.

    14. European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) [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)]

      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.

    15. Neurologic Assessment in Neuro-Oncology Scale [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)]

      To describe the effect of T-DXd on symptoms, functioning, and HRQoL in HER2+ MBC participants with or without baseline BM.

    16. Cognitive Functions Tests [Cycle 1 (15 days ± 2 days) Day 1, thereafter q12w and at EOT visit (Approximately 2.5 Years)]

      To describe the effect of T-DXd on symptoms, functioning, and HRQoL in HER2+ MBC participants with or without baseline BM.

    17. MD Anderson Symptom Inventory Brain Tumor-specific Items [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)]

      To describe the effect of T-DXd on symptoms, functioning, and HRQoL in HER2+ MBC participants with or without baseline BM.

    18. St. George's Respiratory Questionnaire - idiopathic pulmonary fibrosis version in Participants with Interstitial Lung Disease (ILD)/Pneumonitis [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)]

      To describe the effect of T-DXd on symptoms, functioning, and HRQoL in HER2+ MBC participants with or without baseline BM.

    19. Number of Participants with Adverse Events [Cycle 1 (15 days ± 2 days) Day 1 until safety F/U (40+7 days after last dose) (Approximately 2.5 Years)]

      To describe the safety profile of T-DXd.

    20. Number of Participants with Investigator-assessed ILD/Pneumonitis or Rate of Investigator-assessed ILD/Pneumonitis [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)]

      To describe the safety profile of T-DXd.

    21. Number of Participants with Adverse Events with BM at Baseline [Cycle 1 (15 days ± 2 days) Day 1 until safety F/U (40+7 days after last dose) (Approximately 2.5 Years)]

      To describe the safety profile of T-DXd.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 130 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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 trastuzumab, pertuzumab, or trastuzumab emtansine 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

    • Persistent toxicities (Common Terminology Criteria for Adverse Events Grade >1) caused by previous anticancer therapy, excluding alopecia

    • 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

    • < 1 week for tyrosine kinase inhibitor (TKIs) approved for the treatment of non-small cell lung cancer - baseline CT scan must be completed after discontinuation of TKI

    • Antibody-based anticancer therapy: < 4 weeks

    • Any concurrent anticancer treatment. Concurrent use of hormonal therapy for noncancer- related conditions is allowed

    • 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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Research Site San Diego California United States 92123
    2 Research Site Boston Massachusetts United States 02215
    3 Research Site Detroit Michigan United States 48202
    4 Research Site Durham North Carolina United States 27710
    5 Research Site Norfolk Virginia United States 23502
    6 Research Site Auchenflower Australia 4066
    7 Research Site Clayton Australia 3168
    8 Research Site Heidelberg Australia 3084
    9 Research Site St Leonards Australia 2065
    10 Research Site Subiaco Australia 6008
    11 Research Site Anderlecht Belgium 1070
    12 Research Site Bruges Belgium 8000
    13 Research Site Leuven Belgium 3000
    14 Research Site Liège Belgium 4000
    15 Research Site Vancouver British Columbia Canada V5Z 4E6
    16 Research Site Toronto Ontario Canada M4N 3M5
    17 Research Site Copenhagen Denmark 2100
    18 Research Site Herlev Denmark 2730
    19 Research Site Odense C Denmark 5000
    20 Research Site Helsinki Finland 00290
    21 Research Site Tampere Finland FI-33521
    22 Research Site Turku Finland 20520
    23 Research Site Aachen Germany 52074
    24 Research Site Berlin Germany 13125
    25 Research Site Dresden Germany 1307
    26 Research Site Erlangen Germany 91054
    27 Research Site Essen Germany 45136
    28 Research Site Frankfurt Germany 60389
    29 Research Site Halle (Saale) Germany 06120
    30 Research Site Hamburg Germany 20246
    31 Research Site Hannover Germany 30625
    32 Research Site Kiel Germany 24105
    33 Research Site Mannheim Germany 68167
    34 Research Site München Germany 80337
    35 Research Site München Germany 80637
    36 Research Site Münster Germany 48149
    37 Research Site Tübingen Germany 72076
    38 Research Site Cork Ireland T12 DV56
    39 Research Site Dublin Ireland 7
    40 Research Site Dublin Ireland D04 Y8V0
    41 Research Site Ancona Italy 60122
    42 Research Site Bergamo Italy 24127
    43 Research Site Catania Italy 95126
    44 Research Site Milano Italy 20132
    45 Research Site Napoli Italy 80131
    46 Research Site Padova Italy 35128
    47 Research Site Prato Italy 59100
    48 Research Site Isehara Japan 259-1193
    49 Research Site Kawasaki-shi Japan 216-8511
    50 Research Site Sapporo-shi Japan 003-0804
    51 Research Site Shinagawa-ku Japan 142-8666
    52 Research Site Yokohama-shi Japan 241-8515
    53 Research Site Den Haag Netherlands 2545 AA
    54 Research Site Maastricht Netherlands 6229 HX
    55 Research Site Rotterdam Netherlands 3015 GD
    56 Research Site Bergen Norway 5021
    57 Research Site Oslo Norway 450
    58 Research Site Oslo Norway N-0379
    59 Research Site Gdańsk Poland 80-214
    60 Research Site Kraków Poland 30-688
    61 Research Site Opole Poland 45-060
    62 Research Site Warszawa Poland 02-781
    63 Research Site Warszawa Poland 04-141
    64 Research Site Lisboa Portugal 1400-048
    65 Research Site Lisboa Portugal 1649-035
    66 Research Site Porto Portugal 4099-001
    67 Research Site Moscow Russian Federation 105229
    68 Research Site Moscow Russian Federation 111123
    69 Research Site Moscow Russian Federation 115478
    70 Research Site Moscow Russian Federation 143423
    71 Research Site Rostov-on-Don Russian Federation 344037
    72 Research Site Barcelona Spain 08036
    73 Research Site Barcelona Spain 8035
    74 Research Site Granada Spain 18014
    75 Research Site Madrid Spain 28005
    76 Research Site Madrid Spain 28034
    77 Research Site Madrid Spain 28041
    78 Research Site Salamanca Spain 37007
    79 Research Site Santander Spain 39008
    80 Research Site Santiago De Compostela-Coruña Spain 15706
    81 Research Site Sevilla Spain 41013
    82 Research Site Valencia Spain 46009
    83 Research Site Göteborg Sweden 413 45
    84 Research Site Lund Sweden 221 85
    85 Research Site Uppsala Sweden 751 85
    86 Research Site Basel Switzerland 4031
    87 Research Site Bellinzona Switzerland CH-6500
    88 Research Site Lausanne Switzerland 1011
    89 Research Site Luzern Switzerland 6000
    90 Research Site Edinburgh United Kingdom EH4 2XR
    91 Research Site Glasgow United Kingdom G12 OYN

    Sponsors and Collaborators

    • AstraZeneca
    • Daiichi Sankyo, Inc.

    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 Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    AstraZeneca
    ClinicalTrials.gov Identifier:
    NCT04739761
    Other Study ID Numbers:
    • D9673C00007
    First Posted:
    Feb 5, 2021
    Last Update Posted:
    Jul 20, 2022
    Last Verified:
    Jul 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    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
    Keywords provided by AstraZeneca
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Jul 20, 2022