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

Overview

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.

Interventions

• Drug Trastuzumab deruxtecan
  Experimental drug. Provided in 100mg vials. IV infusion.
• Drug Docetaxel
  Active comparator. IV infusion.
• Drug Paclitaxel
  Active comparator. IV infusion.
• Drug Carboplatin
  Active comparator. IV infusion.
• Drug Trastuzumab
  Active comparator. IV infusion.
• Drug Pertuzumab
  Active comparator. IV infusion.
• Drug Ribociclib
  Experimental drug. Tablets.
• Drug Letrozole
  Experimental drug. Tablets.
• Drug Epirubicin
  Active comparator. IV infusion.
• Drug Cyclophosphamide
  Active comparator. IV infusion.

Primary outcome measures

• Pathologic complete response (pCR) of HER2-enriched patients [Time frame: Binary outcome which will be assessed at the time of surgery after six cycles of treatment (each cycle is 21 days)]

Secondary outcome measures (12)

• Pathologic complete response (pCR) of the initially randomized patients [Time frame: Binary outcome which will be assessed at the time of surgery after six cycles of treatment (each cycle is 21 days)]
• Event-free survival [Time frame: From randomization to event, up to five years]
• Biomarkers [Time frame: From randomization to event, up to five years]
• Pathologic complete response (pCR) of ER-positive and luminal patients [Time frame: 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 [Time frame: 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 [Time frame: After the completion of three treatment cycles (each cycle is 21 days)]
• Overall survival [Time frame: From randomization to event, up to five years]
• Distant relapse-free survival [Time frame: From randomization to event, up to five years]
• Objective response rate at six cycles [Time frame: After the completion of six treatment cycles (each cycle is 21 days)]
• Residual Cancer Burden [Time frame: Categorical outcome which will be assessed at the time of surgery after six cycles of treatment (each cycle is 21 days)]
• Breast conserving surgery [Time frame: 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 [Time frame: Binary outcome which will be assessed at the time of surgery after six cycles of treatment (each cycle is 21 days)]

Eligibility criteria

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

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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

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).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Sweden · 7 centers

• Skåne University Hospital — Malmö
• Örebro University Hospital — Örebro
• Sankt Gorans Hospital — Stockholm
• Stockholm Southern Hospital — Stockholm
• Karolinska University Hospital — Stockholm
• Norrlands University Hospital — Umeå
• Uppsala University Hospital — Uppsala

Publications

• Matikas A, Naume B, Wildiers H, Sonke G, Dieci MV, Karakatsanis A, Andersson A, Barnekow E, Kessler LE, Einbeigi Z, Killander F, Linderholm B, Schiza A, Valachis A, Nearchou A, Engebraaten O, Porojnicu A, Soland MH, Mannsaker B, Raj SX, Blix ES, Nordstrand CS, Lambertini M, Vernieri C, Punie K, Sotiriou C, Bergh J, Villacampa G, Zouzos A, Hellstrom M, Hartman J, Foukakis T. Randomised trial of tra PMID 40866060

Identifiers

NCT: NCT05900206 · ARIADNE

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗