Detection of tumour DNA in the blood of patients receiving standard therapy for hormone receptor-positive (HR+) HER2 low expression (HER2 low or HER2 ultra low) metastatic breast cancer as a tool to select those who may benefit from treatment with the antibody–drug conjugate trastuzumab-deruxtecan, and determine its efficacy.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Unicancer

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

29 Jul 2025 → ongoing

Decision date (initial)

2025-05-13

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Astra Zeneca

External identifiers

EU CT number

2024-515349-41-00

ClinicalTrials.gov

NCT06680596

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To assess whether early switch of standard treatment (at 8 weeks), from an endocrine therapy (AI or fulvestrant) plus CDK4/6 inh to trastuzumab deruxtecan (T-DXd) for a population expected to develop resistance to SOC treatment according to the Molecular Response is associated with an improved progression-free survival (PFS).

Secondary objectives 7

1. To evaluate the Overall Survival (OS)
2. To evaluate the objective response rates (ORR)
3. To evaluate the duration of response (DoR)
4. To evaluate the clinical benefit rate (CBR)
5. To evaluate time to response (TTR)
6. To evaluate the safety of T-DXd
7. To compare the PFS and OS of early switch of treatment (at 8 weeks) from an endocrine therapy (AI or fulvestrant) plus CDK4/6 inh to T-DXd versus pursuing endocrine therapy plus CDK4/6 inh. with historical trial data (PADA-1 and Destiny Breast-06).

Conditions and MedDRA coding

Metastatic Breast Cancer HR+, HER2-

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 21

1. Screening Phase_1. Patient must have signed the written informed consent for screening phase prior to any trial specific procedures
2. Screening Phase_10. Patient has a measurable or an evaluable disease according to RECIST v1.1.
3. Screening Phase_11. Availability of an archived metastatic tumour sample (FFPE) for exploratory research. Bone metastasis are accepted if tissue is representative of tumour tissue (at least 10% tumour cellularity).
4. Screening Phase_12. Patient must be willing and able to comply with the protocol for the duration of the study including scheduled visits, treatment plan, laboratory tests and other study procedures.
5. Screening Phase_13. Registration in a National Health Care System (or equivalent).
6. Treatment Phase_1. Patient must have signed the written informed consent for the treatment phase prior to any trial specific procedures.
7. Treatment Phase_2. Patient must have discontinued CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) at least 7 days before enrolment, but no longer than 14 days
8. Treatment Phase_3. Patients must present a no drop of ctDNA determined by a ctDNA assay after 4 weeks of standard of care treatment with a CDK4/6 inhibitor. A no-drop is defined by a Molecular Response (MR) ≥0.5 according to by MR calculation [Zhang 2020].
9. Treatment Phase_4. Patient has an Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1.
10. Treatment Phase_5. Left ventricular ejection fraction (LVEF) ≥ 50% within 28 days prior to enrolment.
11. Treatment Phase_6. Participant has adequate bone marrow and organ function within 14 days before enrolment, defined as the following laboratory values: • Absolute neutrophil count (ANC) ≥ 1500/mm3, • platelet count ≥ 100,000/mm3, • haemoglobin ≥ 9.0 g/dl, • Serum creatinine ≤1.5 × upper limit of normal (ULN) or creatinine clearance ≥ 30 mL/min, • Serum albumin ≥ 2.5 g/dL, • Total bilirubin ≤1.5 × ULN (<3 ULN if Gilbert’s disease), • In absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3 × ULN. If the participant has liver metastases, ALT and AST < 5 × ULN, he/she will be eligible for the study, • Adequate blood clotting function: defined as an international normalized ratio/prothrombin time ≤ 1.5 × ULN and either partial thromboplastin time or activated partial thromboplastin time within normal limits. Note: Transfusion (red blood cell or platelet) or G-CSF administration is not allowed within 14 days prior to the day on which bone marrow function is assessed, or at any time after this day and prior to C1D1.
12. Screening Phase_2. Patient is ≥18 years of age.
13. Treatment Phase_7. Women of childbearing potential must have a negative serum pregnancy test (with a sensitivity of at least 25 mIU/mL) result within 3 days of enrolment.
14. Treatment Phase_8. Men or women of childbearing potential must agree to the use of effective contraceptive for the study duration and for at least 7 months after the last dose of study treatment for women, and at least 4 months for men.
15. Treatment Phase_9. Patient must be willing and able to comply with the protocol for the duration of the study including scheduled visits, treatment plan, laboratory tests and other study procedures.
16. Screening Phase_3. Documented breast cancer that: • Is metastatic and eligible to biopsy for subsequent histological or cytological confirmation • Is HER2 low (HER2 1+, or 2+ and ISH negative) or HER2 ultra low (IHC 0 with incomplete and faint membrane staining in >0 and ≤ 10% of tumour cells) on the most recent tumour material available, as defined by the local pathologist under ASCO/CAP guidelines. • Is HR-positive (positive for estrogen receptor or progesterone receptor ≥ 10% of tumour cell nuclei are immunoreactive) in the metastatic setting.
17. Screening Phase_4. Patient has either: • a metastatic relapse during or within 1 year after termination of the adjuvant endocrine therapy (AI resistant), or • a metastatic relapse located on either lung and/or liver, and/or other visceral location, occurring more than one year of completing adjuvant AI or a de-novo MBC (AI sensitive/naive).
18. Screening Phase_6. Patient did not receive any therapy in the metastatic setting.
19. Screening Phase_7. Patient is eligible for a first-line treatment with a marketed CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) in combination with either AI or fulvestrant, according to its marketing authorisation
20. Screening Phase_8. Patient has an Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1.
21. Screening Phase_9. Patient has an adequate bone marrow and organ function.

Exclusion criteria 30

1. Screening Phase_1. Patient is eligible to chemotherapy because of visceral crisis (severe organ dysfunction, as assessed by signs and symptoms, laboratory studies and rapid progression of disease). Note : Visceral crisis is not the mere presence of visceral metastases but implies important organ compromise leading to a clinical indication for the most rapidly efficacious therapy.
2. Treatment Phase_8. Uncontrolled or significant cardiovascular disease, including any of the following: • History of myocardial infarction within 6 months before enrolment, • History of symptomatic congestive heart failure (New York Heart Association Class II to IV), • Patient with a corrected QT interval (QTc) prolongation to >470 ms (females) or >450 ms (males) based on average of the screening triplicate12-lead ECG. • Patients with known troponin levels above ULN at screening (as defined by the manufacturer), and without any myocardial related symptoms, should have a cardiologic consultation before enrolment to rule out MI
3. Treatment Phase_9. Clinically severe pulmonary compromise resulting from current pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (i.e., pulmonary emboli within three months of the study enrolment, severe asthma, severe chronic obstructive pulmonary disease [COPD], restrictive lung disease, pleural effusion, etc.), and any autoimmune, connective tissue, or inflammatory disorders with pulmonary involvement (i.e., rheumatoid arthritis, Sjögren’s, sarcoidosis, etc.), or prior pneumonectomy.
4. Screening Phase_2. Patient has a breast cancer amenable for resection or radiation therapy with curative intent.
5. Treatment Phase_10. Patient has spinal cord compression or clinically active central nervous system metastases, defined as untreated or symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms.
6. Treatment Phase_11. Major surgery within 4 weeks before study enrolment.
7. Treatment Phase_12. Patient who has received radiotherapy ≤4 weeks or limited field radiation for palliation ≤2 weeks prior to enrolment, or who has not recovered to grade 1 or better from related side effects of such therapy (exceptions include alopecia) and/or in whom ≥ 25% of the bone marrow was irradiated
8. Treatment Phase_14. Patient receiving drug that may cause QTc prolongations or cardiac arrhythmia. Pimozide (Orap®) and cisapride (Prepulsid®) are strictly contraindicated: they are associated with a major risk of ventricular rhythm disorder.
9. Treatment Phase_15. Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) 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 IMP.
10. Treatment Phase_16. Participation in a therapeutic clinical study within 4 weeks before enrolment.
11. Screening Phase_10. Social, familial, or geographic factors that would interfere with study participation or follow-up.
12. Treatment Phase_17. Patient is currently pregnant, breastfeeding, or planning to become pregnant
13. Treatment Phase_18. Patient has substance abuse history or any other medical conditions such as clinically significant cardiac or psychological conditions, that may, in the opinion of the investigator, interfere with the patient’s participation in the clinical study or evaluation of the clinical study results.
14. Treatment Phase_19. Person deprived of their liberty or under protective custody or guardianship.
15. Screening Phase_3. Prior exposure to ADC or CDK4/6 inhibitors (in metastatic setting). CDK4/6 inhibitors given in adjuvant setting must be stopped for at least 12 months prior screening
16. Treatment Phase_20. Social, familial, or geographic factors that would interfere with study participation or follow-up.
17. Screening Phase_4. Patient who has initiated the CDK4/6 inhibitor treatment.
18. Screening Phase_5. Patient is unable to swallow tablets.
19. Screening Phase_6. Patient has a history of (non-infectious) ILD/pneumonitis requiring steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at baseline
20. Screening Phase_7. Patient has a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the drug product.
21. Screening Phase_8. Patient has a history of severe hypersensitivity reactions to other monoclonal antibodies.
22. Treatment Phase_1. AI resistant patients who are eligible to SAFIR 03 - ARRIBA trial (i.e. PIK3CA mutated patients), until SAFIR 03 - ARRIBA study closure or study steering committee’s decision.
23. Screening Phase_9. Person deprived of their liberty or under protective custody or guardianship.
24. Treatment Phase_21.Patient is eligible to chemotherapy because of visceral crisis (severe organ dysfunction, as assessed by signs and symptoms, laboratory studies and rapid progression of disease). Note : Visceral crisis is not the mere presence of visceral metastases but implies important organ compromise leading to a clinical indication for the most rapidly efficacious therapy
25. Treatment Phase_2. Patient has received more than 2 cycles of the ongoing CDK4/6 inhibitor treatment combined with either AI or fulvestrant.
26. Treatment Phase_3. Patient has interrupted the ongoing CDK4/6 inhibitor treatment for more than 14 days.
27. Treatment Phase_4. Patient has evidence of clinical or radiological disease progression.
28. Treatment Phase_5. Patient has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤ 1 or baseline.
29. Treatment Phase_6. Patient has malignancies within 3 years, other than that under study, with the exception of: adequately resected non-melanoma skin cancer, curatively treated in-situ disease, other solid tumours curatively treated, or contralateral breast cancer.
30. Treatment Phase_7. Patient is at high medical risk because of severe or uncontrolled systemic disease, such as uncontrolled diabetes mellitus, clinically significant pulmonary disease, clinically significant neurological disorder, chronic pancreatitis, chronic active infection with hepatitis B virus, hepatitis C virus, or HIV, active untreated or uncontrolled fungal, bacterial or viral infections, active primary immunodeficiency etc.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Primary endpoint: Progression-free survival is defined as the time from the first T-DXd administration to the first documented disease progression or death from any cause, whichever occurs first. The tumour assessments are conducted by investigators according to RECIST 1.1 every 6 weeks during the first 12 months of treatment phase, and every 9 weeks thereafter.

Secondary endpoints 6

1. Overall survival (OS): defined as the time from the first T-DXd administration to death due to any cause. Patients still alive at the cut-off time (including lost to follow-up) will be censored at the last known alive date.
2. Objective response Rate (ORR): ORR will be assessed by the investigators using RECIST v1.1 and is defined as the proportion of patients who achieved a confirmed complete response (CR) or partial response (PR) up to 6 months after the first administration of treatment.
3. Duration of response (DoR) is defined as the time interval from the date of first documentation of confirmed CR or PR to the date of first documented disease progression or death, from any cause whichever occurs first. Patients without progression at the cut-off date will be censored at the last assessment date
4. Clinical Benefit Rate (CBR): CBR will be assessed by the investigators using RECIST v1.1 and is defined as the proportion of patients with at least a confirmed complete response (CR) or partial response (PR) up to 6 months after the first administration of treatment or a stable disease for 6 months or more after the first administration of treatment.
5. Time to Response (TTR): TTR is defined, for patients with an objective response according to RECIST v1.1, as the time from the first T-DXd administration to the first documentation of objective response which is subsequently confirmed.
6. The assessment of the incidences of adverse events, graded by NCI CTC-AE v5.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Unicancer

Sponsor organisation

Unicancer

Address

101 Rue De Tolbiac

City

Paris

Postcode

75013

Country

France

Scientific contact point

Organisation

Unicancer

Contact name

Nourredine AIT RAHMOUNE

Public contact point

Organisation

Unicancer

Contact name

Nourredine AIT RAHMOUNE

Locations

1 EU/EEA country · 38 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Corrective measures 1 · Art. 77 CTR

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 6 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications