Clinical trial NCT05900206: Trastuzumab Deruxtecan Versus Standard Neoadjuvant Treatment for HER2-positive Breast Cancer
Official title: A Randomized Trial of Trastuzumab Deruxtecan and Biology-Driven Selection of Neoadjuvant Treatment for HER2-positive Breast Cancer: ARIADNE
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Breast Cancer
Keywords: HER2-positive
neoadjuvant treatment
trastuzumab deruxtecan
T-DXd
PAM50
molecular subtype
ribociclib
HER2-enriched
breast cancer
Lead sponsor: Karolinska University Hospital
Sponsor class: OTHER
First posted: 2023-06-12
Enrollment: 370
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Parallel, two arms for cycles 1-3. Further treatment (cycles 4-6) decided by molecular intrinsic subtype.
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: To be eligible for the study, patients must fulfil all inclusion criteria:

1. Women or men 18 years or older
2. Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations
3. 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).
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 at the time of randomization (see Appendix B).
5. 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.
6. 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.
7. Left Ventricular Ejection Fraction (LVEF) ≥ 50%
8. Adequate bone-marrow, hepatic and renal function defined as laboratory tests within 7 days prior to enrolment:

   i. Hematology:
   1. Absolute granulocytes \> 1.5 x 109/L
   2. Platelets \> 100 x 109/L
   3. Hb \> 90 gr/L ii. Biochemistry

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   1. Bilirubin ≤ upper limit of normal (ULN)
   2. Serum creatinine ≤ 1.5 x ULN
   3. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 1.5 x ULN
   4. Albumin ≥ 30 gr/L iii. Coagulation:

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   1. INR/PT ≤ 1.5 x ULN, unless the subject is receiving anticoagulant therapy and INR/PT is within intended therapeutic range
   2. aPTT ≤ 1.5 x ULN, unless the subject is receiving anticoagulant therapy and aPTT is within intended therapeutic range
9. Availability of tumor and blood samples as described in the protocol
10. Negative serum pregnancy test for women of childbearing potential or for patients who have experienced menopause onset \<12 months prior to randomization.
11. 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.
12. 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:

1. Participation in other interventional trials
2. Presence of distant metastases, including node metastases in the contralateral thoracic region or in the mediastinum
3. 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.
4. History of invasive breast cancer
5. History of DCIS, except for patients treated exclusively with mastectomy \>5 years prior to diagnosis of current breast cancer
6. Active cardiac disease or a history of cardiac dysfunction including any of the following:

   1. History of unstable angina pectoris, myocardial infarction or recent (\<6 months) cardiovascular event including stroke and pericarditis
   2. History of documented congestive heart failure (New York Heart Association functional classification II-IV)
   3. Documented cardiomyopathy
   4. 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.
   5. Uncontrolled hypertension
   6. Symptomatic or uncontrolled arrhythmia, including atrial fibrillation.
7. 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.
8. 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
9. Pregnant or breastfeeding female patients, or patients who are planning to become pregnant
10. 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.
11. 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.)
12. 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.
13. Prior pneumonectomy
14. History of positive testing for HIV or known AIDS
15. Acute or chronic infection with hepatitis B or C virus
16. 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).
17. 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.
18. 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.
19. Allergic reactions or hypersensitivity to the study drugs or other monoclonal antibodies
20. Administration of other experimental drugs, either concomitantly or during the past 30 days before treatment initiation.
21. Pre-treatment axillary surgery
22. Recent major surgery (within 4 weeks from start of study treatment) or anticipated need for major surgery during the study.
23. A pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy (CART).

Primary outcomes:
measure: Pathologic complete response (pCR) of HER2-enriched patients
timeFrame: Binary outcome which will be assessed at the time of surgery after six cycles of treatment (each cycle is 21 days)
Secondary outcomes:
measure: Pathologic complete response (pCR) of the initially randomized patients
timeFrame: Binary outcome which will be assessed at the time of surgery after six cycles of treatment (each cycle is 21 days)
measure: Event-free survival
timeFrame: From randomization to event, up to five years
measure: Biomarkers
timeFrame: From randomization to event, up to five years
measure: Pathologic complete response (pCR) of ER-positive and luminal patients
timeFrame: Binary outcome which will be assessed at the time of surgery after six cycles of treatment (each cycle is 21 days)
measure: Pathologic complete response (pCR) of ER-negative and luminal, basal-like and normal-like patients
timeFrame: Binary outcome which will be assessed at the time of surgery after six cycles of treatment (each cycle is 21 days)
measure: Objective response rate at three cycles
timeFrame: After the completion of three treatment cycles (each cycle is 21 days)
measure: Overall survival
timeFrame: From randomization to event, up to five years
measure: Distant relapse-free survival
timeFrame: From randomization to event, up to five years
measure: Objective response rate at six cycles
timeFrame: After the completion of six treatment cycles (each cycle is 21 days)
measure: Residual Cancer Burden
timeFrame: Categorical outcome which will be assessed at the time of surgery after six cycles of treatment (each cycle is 21 days)
measure: Breast conserving surgery
timeFrame: Binary outcome which will be assessed at the time of surgery after six cycles of treatment (each cycle is 21 days)
measure: De-escalation of breast surgery
timeFrame: Binary outcome which will be assessed at the time of surgery after six cycles of treatment (each cycle is 21 days)
measure: Sentinel Lymph Node Dissection
timeFrame: Binary outcome which will be assessed at the time of surgery after six cycles of treatment (each cycle is 21 days)
measure: De-escalation of axillary surgery
timeFrame: Binary outcome which will be assessed at the time of surgery after six cycles of treatment (each cycle is 21 days)
measure: Rates of adverse events
timeFrame: During neoadjuvant treatment at the end of each treatment cycle (cycle length 21 days)
measure: 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
timeFrame: 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
measure: 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
timeFrame: 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
measure: 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
timeFrame: 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
measure: Axillary surgery
timeFrame: Binary outcome which will be assessed at the time of surgery after six cycles of treatment (each cycle is 21 days)
Other outcomes:
measure: Exploratory biomarkers
timeFrame: Binary outcome which will be assessed at the time of surgery after six cycles of treatment (each cycle is 21 days)
Locations:
city: Malmö
country: Sweden
facility: Skåne University Hospital
city: Stockholm
country: Sweden
facility: Sankt Gorans Hospital
city: Stockholm
country: Sweden
facility: Stockholm Southern Hospital
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
city: Umeå
country: Sweden
facility: Norrlands University Hospital
city: Uppsala
country: Sweden
facility: Uppsala University Hospital
city: Örebro
country: Sweden
facility: Örebro University Hospital
Study officials:
affiliation: Karolinska University Hospital
name: Theodoros Foukakis, MD/PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Karolinska University Hospital
name: Alexios Matikas, MD/PhD
role: PRINCIPAL_INVESTIGATOR
References: