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
Enrollment
82
Locations
1
Arm
30.9
Anticipated Duration (Months)
6.1
Patients Per Site
0.2
Patients Per Site Per Month

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 DiseaseIntervention/TreatmentPhase
  • 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:
N/A
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

ArmIntervention/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

    SiteCityStateCountryPostal Code
    1Research SiteBostonMassachusettsUnited States02215
    2Research SiteDurhamNorth CarolinaUnited States27710
    3Research SiteNorfolkVirginiaUnited States23502
    4Research SiteAuchenflowerAustralia4066
    5Research SiteClaytonAustralia3168
    6Research SiteHeidelbergAustralia3084
    7Research SiteSt LeonardsAustralia2065
    8Research SiteSubiacoAustralia6008
    9Research SiteBruxellesBelgium1000
    10Research SiteLeuvenBelgium3000
    11Research SiteLuikBelgium4000
    12Research SiteCopenhagenDenmark2100
    13Research SiteOdense CDenmark5000
    14Research SiteHelsinkiFinland29
    15Research SiteTampereFinlandFI-33521
    16Research SiteTurkuFinland20520
    17Research SiteAachenGermany52074
    18Research SiteBerlinGermany13125
    19Research SiteDresdenGermany1307
    20Research SiteErlangenGermany91054
    21Research SiteEssenGermany45136
    22Research SiteFrankfurtGermany60389
    23Research SiteHalle (Saale)Germany06120
    24Research SiteHamburgGermany20246
    25Research SiteHannoverGermany30625
    26Research SiteKielGermany24105
    27Research SiteMannheimGermany68167
    28Research SiteMünchenGermany80337
    29Research SiteMünchenGermany80637
    30Research SiteMünsterGermany48149
    31Research SiteTübingenGermany72076
    32Research SiteCorkIrelandT12 DV56
    33Research SiteDublinIreland7
    34Research SiteDublinIrelandD04 Y8V0
    35Research SiteAnconaItaly60122
    36Research SiteBergamoItaly24127
    37Research SiteCataniaItaly95126
    38Research SiteMilanoItaly20132
    39Research SiteNapoliItaly80131
    40Research SitePadovaItaly35128
    41Research SitePratoItaly59100
    42Research SiteIseharaJapan259-1193
    43Research SiteKawasaki-shiJapan216-8511
    44Research SiteSapporo-shiJapan003-0804
    45Research SiteShinagawa-kuJapan142-8666
    46Research SiteYokohama-shiJapan241-8515
    47Research SiteDen HaagNetherlands2545 AA
    48Research SiteMaastrichtNetherlands6229 HX
    49Research SiteRotterdamNetherlands3015 GD
    50Research SiteBergenNorway5053
    51Research SiteOsloNorway424
    52Research SiteOsloNorway450
    53Research SiteGdańskPoland80-214
    54Research SiteKrakówPoland30-688
    55Research SiteOpolePoland45-060
    56Research SiteWarszawaPoland02-781
    57Research SiteWarszawaPoland04-141
    58Research SiteLisboaPortugal1400-048
    59Research SiteLisboaPortugal1649-035
    60Research SitePortoPortugal4099-001
    61Research SiteMoscowRussian Federation105229
    62Research SiteMoscowRussian Federation111123
    63Research SiteMoscowRussian Federation115478
    64Research SiteMoscowRussian Federation143423
    65Research SiteRostov-on-DonRussian Federation344037
    66Research SiteBarcelonaSpain08036
    67Research SiteBarcelonaSpain8035
    68Research SiteMadridSpain28005
    69Research SiteMadridSpain28034
    70Research SiteMadridSpain28041
    71Research SiteSantiago De Compostela-CoruñaSpain15706
    72Research SiteSevillaSpain41013
    73Research SiteValenciaSpain46009
    74Research SiteGöteborgSweden413 45
    75Research SiteLundSweden221 85
    76Research SiteUppsalaSweden75185
    77Research SiteBaselSwitzerland4031
    78Research SiteBellinzonaSwitzerlandCH-6500
    79Research SiteLausanneSwitzerland1011
    80Research SiteLuzernSwitzerland6000
    81Research SiteEdinburghUnited KingdomEH4 2XR
    82Research SiteGlasgowUnited KingdomG12 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:
    Oct 8, 2021
    Last Verified:
    Oct 1, 2021
    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 Oct 8, 2021