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