Trastuzumab Deruxtecan (T-DXd) Alone or in Sequence With THP, Versus Standard Treatment (ddAC-THP), in HER2-positive Early Breast Cancer

Study Overview
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Brief Summary
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This study will look at the efficacy and safety of trastuzumab deruxtecan (T-DXd) in a neoadjuvant setting, in high-risk, HER2-positive early non-metastatic breast cancer.

Detailed Description
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The target population of interest in this study is participants with high-risk HER2-positive early-stage breast cancer. The purpose of this study is to determine the efficacy and safety of T-DXd neoadjuvant therapy. Participants will be randomised to one of 3 arms: T-DXd monotherapy (Arm A), T-DXd followed by THP (Arm B), or ddAC-THP (Arm C).

Official Title
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A Phase 3 Open-label Trial of Neoadjuvant Trastuzumab Deruxtecan (T-DXd) Monotherapy or T-DXd Followed by THP Compared to ddAC-THP in Participants With High-risk HER2-positive Early-stage Breast Cancer (DESTINY-Breast11)

Conditions
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Breast Neoplasms, Breast Cancer, HER2-positive Early Breast Cancer

Intervention / Treatment
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* Drug: Trastuzumab Deruxtecan
* Drug: Paclitaxel
* Drug: Trastuzumab
* Drug: Pertuzumab
* Drug: Doxorubicin
* Drug: cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Patients must be at least 18 years of age. Histologically documented HER2-positive early breast cancer (EBC) participants, including clinical stage at presentation (based on mammogram or breast MRI assessment): T0-4 (inclusive of inflammatory breast cancer), N1-3, M0 or ≥ T3, N0, M0 as determined by the AJCC staging system, 8th edition ECOG performance status of 0 or 1 at randomization Adequate organ and bone marrow function LVEF ≥ 50% within 28 days before randomization FFPE tissue block (2 cores) or 20 freshly-cut, serial tumor slides for HER2 assessment by central lab. If blocks are incomplete or fewer than 20 slides are available, participants may be eligible following discussion with the AstraZeneca Study Physician Exclusion Criteria: prior history of invasive breast cancer stage IV breast cancer (determined by AJCC staging system) any primary malignancy within 3 years (except resected non-melanoma skin cancer, curatively treated in situ disease) Note: This includes a second current breast primary malignancy (ie, bilateral breast cancer) history of DCIS (except those treated with mastectomy >5 years prior to current diagnosis) History of, or current, ILD/pneumonitis Prior systemic therapy for the treatment of breast cancer Previous treatment with anthracyclines, cyclophosphamide or taxanes for any malignancy

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: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants are assigned to one of three arms in parallel for the duration of the study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Trastuzumab deruxtecan | Drug: Trastuzumab Deruxtecan<br>* administered by intravenous infusion<br>* Other names: Enhertu;|
| Experimental: Arm B<br>T-DXd, followed by THP | Drug: Trastuzumab Deruxtecan<br>* administered by intravenous infusion<br>* Other names: Enhertu;Drug: Paclitaxel<br>* administered by intravenous infusion<br>* Other names: Onxol;Drug: Trastuzumab<br>* administered by intravenous infusion<br>* Other names: Herzuma;Drug: Pertuzumab<br>* administered by intravenous infusion<br>* Other names: Perjeta;|
| Active Comparator: Arm C<br>doxorubicin and cyclophosphamide, followed by THP | Drug: Paclitaxel<br>* administered by intravenous infusion<br>* Other names: Onxol;Drug: Trastuzumab<br>* administered by intravenous infusion<br>* Other names: Herzuma;Drug: Pertuzumab<br>* administered by intravenous infusion<br>* Other names: Perjeta;Drug: Doxorubicin<br>* administered by intravenous infusion<br>* Other names: Rubex;Drug: cyclophosphamide<br>* administered by intravenous infusion<br>* Other names: Cytoxan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| rate of pathologic complete response (pCR) | Proportion of participants who have no evidence by H&E staining of residual invasive disease | Up to 39 months after study start | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-Free Survival |  | Up to 72 months after study start | 
| Invasive Disease-Free Survival (IDFS) |  | Up to 72 months after study start | 
| Overall Survival |  | Up to 72 months after study start | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Trastuzumab Trastuzumab Deruxtecan (T-DXd; DS-8201a), DESTINY-BREAST11, Receptor, ErbB-2, breast neoplasms, Antineoplastic Agents, Phytogenic, Antineoplastic Agents;Molecular Mechanisms of Pharmacological Action, DB11, Enhertu, HER2 (human epidermal growth factor receptor 2), breast cancer