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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)

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ClinicalTrials.gov Identifier: NCT04739761
Recruitment Status : Recruiting
First Posted : February 5, 2021
Last Update Posted : September 13, 2021
Sponsor:
Collaborator:
Daiichi Sankyo, Inc.
Information provided by (Responsible Party):
AstraZeneca

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
Breast Cancer 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.

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Study Type : Interventional  (Clinical Trial)
Estimated 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 : June 22, 2021
Estimated Primary Completion Date : January 19, 2024
Estimated Study Completion Date : January 19, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
Drug Information available for: Trastuzumab

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 Name: fam-trastuzumab deruxtecan-nxki




Primary Outcome Measures :
  1. Objective Response Rate (ORR) in Participants without BM at Baseline (Cohort 1) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 130 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04739761


Contacts
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Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

Locations
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Sponsors and Collaborators
AstraZeneca
Daiichi Sankyo, Inc.
Investigators
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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
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT04739761    
Other Study ID Numbers: D9673C00007
First Posted: February 5, 2021    Key Record Dates
Last Update Posted: September 13, 2021
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.

Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
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.
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.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

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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:
Trastuzumab deruxtecan
Human epidermal growth factor receptor 2 Positive Breast Cancer
Brain Metastasis
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasm Metastasis
Brain Neoplasms
Neoplasms by Site
Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Central Nervous System Diseases
Breast Diseases
Skin Diseases
Neoplastic Processes
Pathologic Processes
Brain Diseases
Nervous System Diseases
Trastuzumab
Antineoplastic Agents, Immunological
Antineoplastic Agents