Trastuzumab Deruxtecan Versus Standard Neoadjuvant Treatment for HER2-positive Breast Cancer

Study Overview
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Brief Summary
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The goal of this clinical trial is to compare trastuzumab deruxtecan (T-DXd) to standard preoperative treatment in patients with non-metastatic HER2-positive breast cancer. The main questions it aims to answer are: is T-DXd more effective than standard preoperative treatment? are there markers in the tumor or blood of patients with HER2-positive breast cancer that can help us predict response to treatment? Participants will be divided into two groups, where one group will be treated with three courses of T-DXd and the other group will be treated with three courses standard of care treatment. Thereafter, further treatment will be decided by the tumor's molecular subtype.

Official Title
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A Randomized Trial of Trastuzumab Deruxtecan and Biology-Driven Selection of Neoadjuvant Treatment for HER2-positive Breast Cancer: ARIADNE

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Trastuzumab deruxtecan
* Drug: Docetaxel
* Drug: Paclitaxel
* Drug: Carboplatin
* Drug: Trastuzumab
* Drug: Pertuzumab
* Drug: Ribociclib
* Drug: Letrozole
* Drug: Epirubicin
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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To be eligible for the study, patients must fulfil all inclusion criteria: Women or men 18 years or older Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations Histologically confirmed breast cancer with an invasive component measuring ≥ 20 mm and/or with morphologically confirmed spread to regional lymph nodes (stage cT2-cT4 with any cN, or cN1-cN3 with any cT). Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 at the time of randomization (see Appendix B). Known estrogen-receptor and/or progesterone receptor status, as assessed locally by IHC. The cut-off for positivity for ER/PR for this study is at least 10% of cell nuclei staining for ER or PR, respectively. Known HER2-positive breast cancer defined as an IHC status of 3+. If IHC is 2+, a positive in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory testing. ISH positivity is defined as a ratio of ≥ 2 for the number of HER2 gene copies to the number of signals for chromosome 17 copies. Left Ventricular Ejection Fraction (LVEF) ≥ 50% Adequate bone-marrow, hepatic and renal function defined as laboratory tests within 7 days prior to enrolment: i. Hematology: Absolute granulocytes > 1.5 x 109/L Platelets > 100 x 109/L Hb > 90 gr/L ii. Biochemistry Bilirubin ≤ upper limit of normal (ULN) Serum creatinine ≤ 1.5 x ULN Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 1.5 x ULN Albumin ≥ 30 gr/L iii. Coagulation: INR/PT ≤ 1.5 x ULN, unless the subject is receiving anticoagulant therapy and INR/PT is within intended therapeutic range aPTT ≤ 1.5 x ULN, unless the subject is receiving anticoagulant therapy and aPTT is within intended therapeutic range Availability of tumor and blood samples as described in the protocol Negative serum pregnancy test for women of childbearing potential or for patients who have experienced menopause onset <12 months prior to randomization. Patients of childbearing potential must be willing to use one highly effective contraception or two effective forms of nonhormonal contraception. See also 5.6 Precautions. Participants must be able to communicate with the investigator and comply with the requirements of the study procedures To be eligible for the study, patients must not fulfil any exclusion criteria: Participation in other interventional trials Presence of distant metastases, including node metastases in the contralateral thoracic region or in the mediastinum Other malignancy diagnosed during the past five years, except adequately controlled limited basal cell carcinoma or squamous-cell carcinoma of the skin, in situ melanoma or carcinoma in situ of the cervix. History of invasive breast cancer History of DCIS, except for patients treated exclusively with mastectomy >5 years prior to diagnosis of current breast cancer Active cardiac disease or a history of cardiac dysfunction including any of the following: History of unstable angina pectoris, myocardial infarction or recent (<6 months) cardiovascular event including stroke and pericarditis History of documented congestive heart failure (New York Heart Association functional classification II-IV) Documented cardiomyopathy QTc > 450 msec as measured by Fridericia's formula, family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation or Torsade de Pointes. Uncontrolled hypertension Symptomatic or uncontrolled arrhythmia, including atrial fibrillation. Patients with ER-positive BC being treated with drugs recognized as strong inhibitors or inducers of the isoenzyme CYP3A (see table 5) which cannot be discontinued at least 7 days prior to planned treatment with ribociclib. Concomitant medication(s) with a known risk to prolong the QT interval and/or known to cause Torsades de Pointes that cannot be discontinued or replaced by safe alternative medication Pregnant or breastfeeding female patients, or patients who are planning to become pregnant 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. Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (e.g. pulmonary emboli within three months of the study enrollment, severe asthma, severe COPD, restrictive lung disease, pleural effusion etc.) Any autoimmune, connective tissue or inflammatory disorders (e.g. Rheumatoid arthritis, Sjogren's, sarcoidosis etc.) where there is documented, or a suspicion of pulmonary involvement at the time of screening. Full details of the disorder should be recorded in the eCRF for patients who are included in the study. Prior pneumonectomy History of positive testing for HIV or known AIDS Acute or chronic infection with hepatitis B or C virus Any impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., uncontrolled ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection). Receipt of live, attenuated vaccine within 30 days prior to the first dose of trastuzumab deruxtecan. Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of study drug. Any psychological, including substance abuse, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial. Allergic reactions or hypersensitivity to the study drugs or other monoclonal antibodies Administration of other experimental drugs, either concomitantly or during the past 30 days before treatment initiation. Pre-treatment axillary surgery Recent major surgery (within 4 weeks from start of study treatment) or anticipated need for major surgery during the study. A pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy (CART).

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: Parallel, two arms for cycles 1-3. Further treatment (cycles 4-6) decided by molecular intrinsic subtype.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: T-DXd (cycles 1-3)<br>Trastuzumab Deruxtecan, administered every three weeks for three courses. Further treatment is decided by the intrinsic molecular (PAM50) subtype of the tumor. | Drug: Trastuzumab deruxtecan<br>* Experimental drug. Provided in 100mg vials. IV infusion.<br>* Other names: T-DXd, Enhertu;|
| Active Comparator: Standard treatment (TCHP or PCHP; cycles 1-3)<br>TCHP (Docetaxel, Carboplatin, Trastuzumab, Pertuzumab) or PCHP (Paclitaxel, Carboplatin, Trastuzumab, Pertuzumab), administered every three weeks for three courses. Further treatment is decided by the intrinsic molecular (PAM50) subtype of the tumor. | Drug: Docetaxel<br>* Active comparator. IV infusion.<br>Drug: Paclitaxel<br>* Active comparator. IV infusion.<br>Drug: Carboplatin<br>* Active comparator. IV infusion.<br>Drug: Trastuzumab<br>* Active comparator. IV infusion.<br>* Other names: Herceptin;Drug: Pertuzumab<br>* Active comparator. IV infusion.<br>* Other names: PErjeta;|
| Other: ER-positive and Luminal (cycles 4-6)<br>Ribociclib, letrozole, trastuzumab, pertuzumab | Drug: Ribociclib<br>* Experimental drug. Tablets.<br>* Other names: Kisqali;Drug: Letrozole<br>* Experimental drug. Tablets.<br>|
| Other: ER-negative and Luminal, or Basal-like, or Normal-like (cycles 4-6)<br>Epirubicin and Cyclophosphamide in case of no complete radiologic response after the initial three courses. In case of complete radiologic response, treatment from cycles 1-3 (T-DXd or TCHP/PCHP) will continue instead for three more courses. | Drug: Epirubicin<br>* Active comparator. IV infusion.<br>Drug: Cyclophosphamide<br>* Active comparator. IV infusion.<br>|
| Other: HER2-enriched (cycles 4-6)<br>The same treatment with T-DXd or TCHP/PCHP administered every three weeks for three more courses will continue from cycles 1-3 | Drug: Trastuzumab deruxtecan<br>* Experimental drug. Provided in 100mg vials. IV infusion.<br>* Other names: T-DXd, Enhertu;Drug: Docetaxel<br>* Active comparator. IV infusion.<br>Drug: Paclitaxel<br>* Active comparator. IV infusion.<br>Drug: Carboplatin<br>* Active comparator. IV infusion.<br>Drug: Trastuzumab<br>* Active comparator. IV infusion.<br>* Other names: Herceptin;Drug: Pertuzumab<br>* Active comparator. IV infusion.<br>* Other names: PErjeta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic complete response (pCR) of HER2-enriched patients | Locally assessed rate of pCR at the molecularly HER2-enriched population, defined as ypT0/Tis, ypN0, as determined at the surgical specimen by a pathologist blinded to treatment assignment (intention-to-treat analysis) | Binary outcome which will be assessed at the time of surgery after six cycles of treatment (each cycle is 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic complete response (pCR) of the initially randomized patients | Locally assessed rate of pCR, defined as ypT0/Tis, ypN0, at the two patient groups of the initial randomization of TCHP versus T-DXd, regardless of administered therapy after cycle 3 | Binary outcome which will be assessed at the time of surgery after six cycles of treatment (each cycle is 21 days) | 
| Event-free survival | Event-free survival (EFS), defined as time from randomization to breast cancer relapse, contralateral breast cancer, other malignant neoplasms, or death by any cause, for each molecular group, including the comparison of TCHP versus T-DXd in HER2-enriched patients, and at the two patient groups of the initial randomization of TCHP versus T-DXd | From randomization to event, up to five years | 
| Biomarkers | Exploratory analysis of biomarkers of response/resistance to administered neoadjuvant therapy using genomics, transcriptomics and proteomics in both tumor tissue and blood/plasma | From randomization to event, up to five years | 
| Pathologic complete response (pCR) of ER-positive and luminal patients | Locally assessed rate of pCR at ER-positive and luminal subgroup | Binary outcome which will be assessed at the time of surgery after six cycles of treatment (each cycle is 21 days) | 
| Pathologic complete response (pCR) of ER-negative and luminal, basal-like and normal-like patients | Locally assessed rate of pCR at ER-negative and luminal subgroup, at the basal-like subgroup and the normal-like subgroup | Binary outcome which will be assessed at the time of surgery after six cycles of treatment (each cycle is 21 days) | 
| Objective response rate at three cycles | Rates of radiologic complete response after three courses of either standard therapy or T-DXd | After the completion of three treatment cycles (each cycle is 21 days) | 
| Overall survival | Overall survival (OS), defined as time from randomization to death by any cause, for each molecular group, including the comparison of TCHP versus T-DXd in HER2-enriched patients, and at the two patient groups of the initial randomization of TCHP versus T-DXd | From randomization to event, up to five years | 
| Distant relapse-free survival | Distant relapse-free survival (DRFS), defined as time from randomization to distant metastases or death by any cause, for each molecular group, including the comparison of TCHP versus T-DXd in HER2-enriched patients, and at the two patient groups of the initial randomization of TCHP versus T-DXd | From randomization to event, up to five years | 
| Objective response rate at six cycles | Rates of complete radiologic response, for each molecular group, including the comparison of TCHP versus T-DXd in HER2-enriched patients, and at the two patient groups of the initial randomization of TCHP versus T-DXd | After the completion of six treatment cycles (each cycle is 21 days) | 
| Residual Cancer Burden | Pathologic response according to Residual Cancer Burden Class for each molecular group, including the comparison of TCHP versus T-DXd in HER2-enriched patients, and at the two patient groups of the initial randomization of TCHP versus T-DXd | Categorical outcome which will be assessed at the time of surgery after six cycles of treatment (each cycle is 21 days) | 
| Breast conserving surgery | Rate of breast conserving surgery, for each molecular group, including the comparison of TCHP versus T-DXd in HER2-enriched patients, and at the two patient groups of the initial randomization of TCHP versus T-DXd | Binary outcome which will be assessed at the time of surgery after six cycles of treatment (each cycle is 21 days) | 
| De-escalation of breast surgery | Rate of de-escalation of breast surgery (conversion from mastectomy to breast conserving surgery or de-escalation of complexity from an oncoplastic breast-conserving procedure to simple wide local excisions) for each molecular group, including the comparison of TCHP versus T-DXd in HER2-enriched patients, and at the two patient groups of the initial randomization of TCHP versus T-DXd | Binary outcome which will be assessed at the time of surgery after six cycles of treatment (each cycle is 21 days) | 
| Sentinel Lymph Node Dissection | Rate of Sentinel Lymph Node Dissection (SLND), for each molecular group, including the comparison of TCHP versus T-DXd in HER2-enriched patients, and at the two patient groups of the initial randomization of TCHP versus T-DXd | Binary outcome which will be assessed at the time of surgery after six cycles of treatment (each cycle is 21 days) | 
| De-escalation of axillary surgery | Rate of de-escalation of axillary surgery (conversion from axillary lymph node dissection to either targeted axillary dissection or sentinel lymph node dissection) for each molecular group, including the comparison of TCHP versus T-DXd in HER2-enriched patients, and at the two patient groups of the initial randomization of TCHP versus T-DXd | Binary outcome which will be assessed at the time of surgery after six cycles of treatment (each cycle is 21 days) | 
| Rates of adverse events | Frequency and grade of adverse events (AE) (according to NCI CTCAE v. 5.0) and rate of discontinuation due to toxicity | During neoadjuvant treatment at the end of each treatment cycle (cycle length 21 days) | 
| Change From Baseline in Global Health Status/Quality of Life Score on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) in all participants | The EORTC QLQ-C30 is a cancer specific health-related quality-of life (QoL) questionnaire. Participant responses to the questions regarding Global Health Status (GHS; How would you rate your overall health during the past week?) and Quality of Life (QoL; How would you rate your overall quality of life during the past week?) are scored on a 7-point scale (1= Very poor to 7=Excellent). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The change from baseline in GHS (EORTC QLQ-C30 Item 29) and QoL (EORTC QLQ-C30 Item 30) combined score will be presented in all participants. A higher score indicates a better level of function. | During neoadjuvant treatment (before first treatment and after three cycles, 21-day cycles), at the end of treatment (after six 21-day cycles), one year post-surgery and five years post-surgery | 
| Change From Baseline in Physical Functioning Score on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) in all participants | The EORTC QLQ-C30 is a cancer specific health-related quality-of life (QoL) questionnaire. Participant responses to 5 questions about their physical functioning (Items 1-5) are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The change from baseline in the physical functioning score will be presented in all participants. A higher score indicates a better level of function. | During neoadjuvant treatment (before first treatment and after three cycles, 21-day cycles), at the end of treatment (after six 21-day cycles), one year post-surgery and five years post-surgery | 
| Change From Baseline in Emotional Functioning Score on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) in all participants | The EORTC QLQ-C30 is a cancer specific health-related quality-of life (QoL) questionnaire. Participant responses to 4 questions about their emotional functioning (Items 21-24) are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. The change from baseline in the emotional functioning score will be presented in all participants. A higher score indicates a better level of function. | During neoadjuvant treatment (before first treatment and after three cycles, 21-day cycles), at the end of treatment (after six 21-day cycles), one year post-surgery and five years post-surgery | 
| Axillary surgery | Rate of Sentinel Lymph Node detection, Targeted Axillary Dissection success and false-negative rates of these procedures in initially node-positive patients for each molecular group, including the comparison of TCHP versus T-DXd in HER2-enriched patients, and at the two patient groups of the initial randomization of TCHP versus T-DXd | Binary outcome which will be assessed at the time of surgery after six cycles of treatment (each cycle is 21 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HER2-positive, neoadjuvant treatment, trastuzumab deruxtecan, T-DXd, PAM50, molecular subtype, ribociclib, HER2-enriched, breast cancer