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

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

Detailed Description
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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.

Official Title
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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)

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Trastuzumab Deruxtecan


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trastuzumab Deruxtecan<br>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<br>* Participants will receive T-DXd administered using an IV bag containing 5% (w/v) dextrose injection infusion solution.<br>* Other names: fam-trastuzumab deruxtecan-nxki;|

What is the study measuring?
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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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Trastuzumab deruxtecan, Human epidermal growth factor receptor 2 Positive Breast Cancer, Brain Metastasis