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

NCT05900206 | Recruiting Phase 2

• 1 other identifier: ARIADNE
• Study Type: interventional
• Target: 370
• Locations: 1 country
• Sites: 7

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.

Conditions

Breast Cancer

Keywords

HER2-positive; neoadjuvant treatment; trastuzumab deruxtecan; T-DXd; PAM50; molecular subtype; ribociclib; HER2-enriched; breast cancer

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (19)

• Pathologic complete response (pCR) of the initially randomized patients

  Binary outcome which will be assessed at the time of surgery after six cycles of treatment (each cycle is 21 days)

• Event-free survival

  From randomization to event, up to five years

• Biomarkers

  From randomization to event, up to five years

• Pathologic complete response (pCR) of ER-positive and luminal patients

  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

  Binary outcome which will be assessed at the time of surgery after six cycles of treatment (each cycle is 21 days)

Other Outcomes (1)

• Exploratory biomarkers

  Binary outcome which will be assessed at the time of surgery after six cycles of treatment (each cycle is 21 days)

Study Arms (5)

T-DXd (cycles 1-3)

EXPERIMENTAL

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

Standard treatment (TCHP or PCHP; cycles 1-3)

ACTIVE COMPARATOR

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; Drug: Paclitaxel; Drug: Carboplatin; Drug: Trastuzumab; Drug: Pertuzumab

ER-positive and Luminal (cycles 4-6)

OTHER

Ribociclib, letrozole, trastuzumab, pertuzumab

Drug: Ribociclib; Drug: Letrozole

ER-negative and Luminal, or Basal-like, or Normal-like (cycles 4-6)

OTHER

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; Drug: Cyclophosphamide

HER2-enriched (cycles 4-6)

OTHER

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; Drug: Docetaxel; Drug: Paclitaxel; Drug: Carboplatin; Drug: Trastuzumab; Drug: Pertuzumab

Interventions

Trastuzumab deruxtecan DRUG

Experimental drug. Provided in 100mg vials. IV infusion.

Also known as: T-DXd, Enhertu

HER2-enriched (cycles 4-6); T-DXd (cycles 1-3)

Docetaxel DRUG

Active comparator. IV infusion.

HER2-enriched (cycles 4-6); Standard treatment (TCHP or PCHP; cycles 1-3)

Paclitaxel DRUG

Active comparator. IV infusion.

HER2-enriched (cycles 4-6); Standard treatment (TCHP or PCHP; cycles 1-3)

Carboplatin DRUG

Active comparator. IV infusion.

HER2-enriched (cycles 4-6); Standard treatment (TCHP or PCHP; cycles 1-3)

Trastuzumab DRUG

Active comparator. IV infusion.

Also known as: Herceptin

HER2-enriched (cycles 4-6); Standard treatment (TCHP or PCHP; cycles 1-3)

Pertuzumab DRUG

Active comparator. IV infusion.

Also known as: PErjeta

HER2-enriched (cycles 4-6); Standard treatment (TCHP or PCHP; cycles 1-3)

Ribociclib DRUG

Experimental drug. Tablets.

Also known as: Kisqali

ER-positive and Luminal (cycles 4-6)

Letrozole DRUG

Experimental drug. Tablets.

ER-positive and Luminal (cycles 4-6)

Epirubicin DRUG

Active comparator. IV infusion.

ER-negative and Luminal, or Basal-like, or Normal-like (cycles 4-6)

Cyclophosphamide DRUG

Active comparator. IV infusion.

ER-negative and Luminal, or Basal-like, or Normal-like (cycles 4-6)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Karolinska University Hospital: lead

Study Sites (7)

Skåne University Hospital

Malmo, 21428, Sweden

NOT YET RECRUITING

Örebro University Hospital

Örebro, 70185, Sweden

NOT YET RECRUITING

Sankt Gorans Hospital

Stockholm, 11219, Sweden

NOT YET RECRUITING

Stockholm Southern Hospital

Stockholm, 11861, Sweden

NOT YET RECRUITING

Karolinska University Hospital

Stockholm, 17164, Sweden

RECRUITING

Norrlands University Hospital

Umeå, 90185, Sweden

NOT YET RECRUITING

Uppsala University Hospital

Uppsala, 75185, Sweden

NOT YET RECRUITING

Related Publications (1)

• 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 trastuzumab deruxtecan and biology-driven selection of neoadjuvant treatment for HER2-positive breast cancer: a study protocol of ARIADNE. BMJ Open. 2025 Aug 27;15(8):e102626. doi: 10.1136/bmjopen-2025-102626.

  PMID: 40866060 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

trastuzumab deruxtecan; Docetaxel; Paclitaxel; Carboplatin; Trastuzumab; pertuzumab; ribociclib; Letrozole; Epirubicin; Cyclophosphamide

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Coordination Complexes; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Nitriles; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Doxorubicin; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds

Study Officials

• Theodoros Foukakis, MD/PhD

  Karolinska University Hospital

  PRINCIPAL INVESTIGATOR

• Alexios Matikas, MD/PhD

  Karolinska University Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Mats Hellström, BSc

CONTACT

(0046)0812370000; mats.hellstrom@regionstockholm.se

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Model Details: Parallel, two arms for cycles 1-3. Further treatment (cycles 4-6) decided by molecular intrinsic subtype.

Study Record Dates

• First Submitted: May 21, 2023
• First Posted: June 12, 2023
• Study Start: October 26, 2023
• Primary Completion (Estimated): April 30, 2027
• Study Completion (Estimated): April 30, 2032
• Last Updated: September 2, 2025

Record last verified: 2025-08

Data Sharing

• IPD Sharing: Will not share

Locations

SE (7)