Trastuzumab Deruxtecan (T-DXd) in Patients Who Have Hormone Receptor-negative and Hormone Receptor-positive HER2-low or HER2 IHC 0 Metastatic Breast Cancer

Study Overview
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Brief Summary
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This study will evaluate the safety and efficacy of trastuzumab deruxtecan (T-DXd) in participants with human epidermal growth factor receptor 2 (HER2)-low or HER2 immunohistochemistry (IHC) 0 (who are both hormone receptor [HR]-negative and HR-positive) unresectable and/or metastatic breast cancer.

Detailed Description
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The primary endpoint of interest in this study is time to next treatment (TTNT), a measure that will determine how long T-DXd allows patients to derive clinical benefit from the study drug.

Official Title
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A Phase 3b, Multicenter, Global, Interventional, Open-label Study of Trastuzumab Deruxtecan (T-DXd), an Anti-HER2-Antibody Drug Conjugate (ADC), in Subjects Who Have Unresectable and/or Metastatic HER2-low or HER2 Immunohistochemistry (IHC) 0 Breast Cancer (DESTINY-Breast15)

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 Criteria: Sign and date the main informed consent form Must agree to provide a newly obtained or archival baseline biopsy from primary and/or metastatic lesion. Pathologically documented Breast Cancer (BC) tumor Is unresectable and/or metastatic. Is hormone receptor-negative or hormone receptor-positive. Must include percentage of positively stained cells to characterize if hormone receptor-positive or -negative. Has confirmed HER2 IHC 1+ or IHC 2+/ISH- (HER2-low) status or HER2 IHC 0 status as determined according to ASCO CAP 2018 guidelines1 based on sample collected during Tissue Screening as described above. Was never previously HER2-positive (IHC 3+ or IHC 2+/ISH+) on prior pathology testing (per ASCO CAP guidelines). Was never previously treated with anti-HER2 therapy in the metastatic setting. Has had at least one and up to two prior lines of therapy in the metastatic setting. In participants with hormone receptor-positive HER2-low metastatic BC (Cohort 3): Has recurrent disease <2 years from the initiation of adjuvant ET OR Has disease progression on CDK4/6 inhibitor-based regimen within 12 months of completion of adjuvant therapy with a CDK4/6 inhibitor OR Has disease progression within the first 12 months of CDK4/6 in the first line metastatic setting Presence of at least one measurable lesion based on computed tomography or magnetic resonance imaging. Participants with brain metastases are allowed in the study. The brain lesion(s) should be small (<2 cm), untreated, asymptomatic, not requiring urgent medical intervention, and are asymptomatic and clinically stable. Has an Eastern Cooperative Oncology Group performance status of 0 or 1. Has a minimum life expectancy of 12 weeks at Screening. Has a left ventricular ejection fraction ≥50% within 28 days before enrollment. Has adequate organ and bone marrow function within 28 days before enrollment. Has adequate treatment washout period before enrollment. Male and female subjects of reproductive/childbearing potential must agree to use a highly effective form of contraception. Exclusion Criteria: Prior treatment with an antibody drug conjugate (ADC). Uncontrolled or significant cardiovascular disease. Has a corrected QT interval prolongation. Has a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening. Has spinal cord compression or clinically active central nervous system metastases. Has multiple primary malignancies within 3 years, except adequately resected non-melanoma skin cancer, curatively treated in situ disease, other solid tumors curatively treated, or contralateral BC. Has a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the drug product. Has a history of severe hypersensitivity reactions to other monoclonal antibodies. Has an uncontrolled infection requiring intravenous (IV) antibiotics, antivirals, or antifungals. Active primary immunodeficiency, known uncontrolled active human immunodeficiency virus (HIV) infection, or active hepatitis B or C infection. Has history of receiving a live, attenuated vaccine (messenger RNA and replication-deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first exposure to study drug. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤1 or baseline. Is pregnant or breastfeeding or planning to become pregnant. Lung-specific intercurrent clinically significant illnesses. Any autoimmune, connective tissue, or inflammatory disorders. Prior complete pneumonectomy.

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: HR-negative, HER2-low<br>Participants with HR-negative HER2-low unresectable and/or metastatic breast cancer who have received at least one and at most two prior lines of therapy in the metastatic setting will receive T-DXd. | Drug: Trastuzumab Deruxtecan<br>* Intravenous administration, 5.4 mg/kg on Day 1 of each 21-day cycle until radiographic disease progression as assessed by the investigator, unacceptable toxicity, other discontinuation criteria are met, or 2 years after first dose of study drug<br>* Other names: Enhertu®;|
| Experimental: Cohort 2: HR-negative, HER2 IHC 0<br>Participants with HR-negative HER2 IHC 0 unresectable and/or metastatic breast cancer who have received at least one and at most two prior lines of therapy in the metastatic setting will receive T-DXd. | Drug: Trastuzumab Deruxtecan<br>* Intravenous administration, 5.4 mg/kg on Day 1 of each 21-day cycle until radiographic disease progression as assessed by the investigator, unacceptable toxicity, other discontinuation criteria are met, or 2 years after first dose of study drug<br>* Other names: Enhertu®;|
| Experimental: Cohort 3: HR-positive, HER2-low<br>Participants with HR-positive HER2-low unresectable and/or metastatic breast cancer who have received at least one and at most two prior lines of therapy in the metastatic setting will receive T-DXd. Participants must also have recurrent disease <2 years from the initiation of adjuvant ET or have disease progression on CDK4/6 inhibitor-based regimen within 12 months of completion of adjuvant therapy with a CDK4/6 inhibitor or have disease progression within the first 12 months of CDK4/6 in the first line metastatic setting. | Drug: Trastuzumab Deruxtecan<br>* Intravenous administration, 5.4 mg/kg on Day 1 of each 21-day cycle until radiographic disease progression as assessed by the investigator, unacceptable toxicity, other discontinuation criteria are met, or 2 years after first dose of study drug<br>* Other names: Enhertu®;|
| Experimental: Cohort 4: HR-positive, HER2 IHC 0<br>Participants with HR-positive HER2 IHC 0 unresectable and/or metastatic breast cancer who have received at least one and at most two prior lines of therapy in the metastatic setting will receive T-DXd. | Drug: Trastuzumab Deruxtecan<br>* Intravenous administration, 5.4 mg/kg on Day 1 of each 21-day cycle until radiographic disease progression as assessed by the investigator, unacceptable toxicity, other discontinuation criteria are met, or 2 years after first dose of study drug<br>* Other names: Enhertu®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time From the Start of T-DXd to Initiation of Subsequent Anticancer Treatment (TTNT) | TTNT is defined as the time interval from the date of first dose of T-DXd to the initiation of the next anticancer treatment or death due to any cause. | Until subsequent therapy or death, assessed up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Real-World Progression Free Survival (PFS) | Real-world PFS is defined as time from date of first dose of T-DXd to time of disease progression per investigator assessment based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or death due to any cause. | Until progression or death, assessed up to 24 months | 
| Time From Start of T-DXd to Discontinuation of T-DXd or Death (TTD) | TTD is defined as the time interval from the date of first dose of T-DXd to the date of discontinuation of T-DXd or death due to any cause. | Until treatment discontinuation or death, up to 24 months | 
| Objective Response Rate (ORR) | ORR is defined as the proportion of participants with a best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR) according to the investigator and per RECIST version 1.1 criteria. | Until progression, assessed up to 24 months | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAEs are graded according to National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0. A TEAE is defined as an adverse event (AE) that occurs, having been absent before the first dose of study drug, or has worsened in severity or seriousness after initiating the study drug until 47 days after the last dose of the study drug. | Up to follow up period, up to 24 months | 
| Mean Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaires (EORTC-QLQ)-C30 Score | Change from baseline in the EORTC-QLQ-C30 scale scores range from 0-100. For functioning and global health status/ QoL scales, higher scores indicate better functioning or global health status/QoL. For symptom scales, higher scores indicate greater symptom burden. | Assessed up to 24 months | 
| Mean Change from Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaires (EORTC-QLQ)-BR45 Score | Change from baseline in the EORTC QLQ-BR45 scale scores range from 0-100. For functioning and global health status/ QoL scales, higher scores indicate better functioning or global health status/QoL. For symptom scales, higher scores indicate greater symptom burden. | Assessed up to 24 months | 
| Time to First and Definitive Deterioration in European Organization for Research and Treatment of Cancer Quality of Life Questionnaires (EORTC-QLQ) Scales | Time to first and definitive deterioration in EORTC-QLQ scales. Scale scores range from 0-100. For functioning and global health status/ QoL scales, higher scores indicate better functioning or global health status/QoL. For symptom scales, higher scores indicate greater symptom burden. | Assessed up to 24 months | 
| Mean Change from Baseline in EuroQol Questionnaire-5 Dimensions-5 Levels (EQ-5D-5L) | Change from baseline in EQ-5D-5L. The EQ-5D-5L is a health-related QoL questionnaire based on five dimensions of health: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension contains five levels: no problems, slight, moderate, severe, and extreme problems. The EQ-5D-5L results can be converted into a single utility value. Utility values range from 0 to 1, with 1 corresponding to perfect health and 0 corresponding to a health status equivalent to death. In addition, participants can provide an overall rating of their current health status using a visual analog scale ranging from 0 (worse) to 100 (better). | Assessed up to 24 months | 
| Mean Change From Baseline in EuroQol Questionnaire-5 Dimensions-5 Levels (EQ-5D-5L) Index Score | Change from baseline in EQ-5D-5L index score. The EQ-5D-5L index score ranges from less than 0 (worse) to 1 (better), with higher scores representing a better health status. | Assessed up to 24 months | 
| Mean Change From Baseline in EuroQol Questionnaire-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analog Scale (VAS) | Change from baseline in EQ-5D-5L VAS. The EQ-5D-5L VAS ranging from 0 (worse) to 100 (better) is used to assess an overall rating of participant's current health status. Higher scores indicate better clinical outcomes. | Assessed up to 24 months | 
| Time to First and Definitive Deterioration in EuroQol Questionnaire-5 Dimensions-5 Levels (EQ-5D-5L) Visual Analog Scale (VAS) | Time to first and definitive deterioration in EQ-5D-5L VAS. The EQ-5D-5L VAS ranging from 0 (worse) to 100 (better) is used to assess an overall rating of participant's current health status. Higher scores indicate better clinical outcomes. | Assessed up to 24 months | 
| Patient's Global Impression of Change (PGI-C) Response | The PGI-C is a single-item questionnaire asking for the participant's overall impression of changes in clinical condition from baseline (prior to study drug initiation), where 1 is Normal and 7 is Severely ill. Lower scores indicate better clinical outcome. | Assessed up to 24 months | 
| Patient's Global Impression of Severity (PGI-S) Response | The PGI-S is a single-item questionnaire asking for the subject's overall impression of symptoms assessed over the past week, where 1 is Normal and 4 is Severe. Lower scores indicate better clinical outcome. | Assessed up to 24 months | 
| Patient's Global Impression of Treatment Tolerability (PGI-TT) Response | The PGI-TT is a single-item questionnaire asking for the subject's overall impression of treatment tolerability over the past week, where 1 is Not at all and 5 is Very much. Higher scores indicate a worse outcome. | Assessed up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Trastuzumab Derextecan, Enhertu®, DS8201-a, Breast Cancer, Anti-HER2-Antibody Drug Conjugate