TRASTUZUMAB DERUXTECAN for Advanced hormone receptor-positive, HER2-low/ultralow breast cancer

Inclusion criteria

• {"criterion_text":"- Patients must be capable to understand the purpose of the Study and have signed written informed consent form (ICF) prior to beginning specific protocol procedures."}
• {"criterion_text":"- Patients must have endocrine resistance criteria: disease progression during adjuvant ET or within the first year of completing adjuvant ET; or endocrine sensitivity criteria: de novo metastatic disease or disease progression ≥ 12 months after completing adjuvant ET with at least one of the following requirements: 1. Estrogen receptor ≤ 50% positive stained cells; 2. and/or high histological grade or Ki67 > 50% on primary tumor; 3. and/or liver metastases; 4. and/or known non-luminal subtype as per local PAM50 analysis."}
• {"criterion_text":"- No prior treatment with any systemic therapy for advanced disease. Patients treated with a CDK4/6i in the adjuvant setting with a TFI ≥ 12 months following CDK4/6i treatment completion are eligible."}
• {"criterion_text":"- Patients have adequate bone marrow, liver, and renal function: • Hematological (without platelet, red blood cell transfusion, and/or granulocyte colony-stimulating factor support within 14 days before first Study treatment dose): White blood cell (WBC) count > 3.0 x 109/L, absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelet count ≥ 100.0 x 109/L, and hemoglobin ≥ 9.0 g/dL (≥ 5.6mmol/L). • Hepatic: Serum albumin ≥ 2.5 g/dL; total bilirubin ≤ 1.5 times upper limit of normal (x ULN) (≤ 3 x ULN in patients with liver metastases or know history of Gilbert’s disease); alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5 x ULN in patients with liver/or bone metastases); aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 3 x ULN (≤ 5 x ULN in patients with liver metastases). • Renal: Creatinine clearance ≥ 30 mL/min as determined by Cockcroft Gault (using actual body weight). • Coagulation: International normalized ratio or prothrombin time and either partial thromboplastin or activated partial thromboplastin time ≤ 1.5 × ULN."}
• {"criterion_text":"- Resolution of all acute toxic effects of prior anti-cancer therapy to Grade ≤ 1 as determined by the US National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (v.5.0) (except for alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion)."}
• {"criterion_text":"- Women of childbearing potential who are sexually active with a non-sterilized male partner must have a negative serum pregnancy test within 14 days before Study treatment initiation. In addition, they must agree to use one highly effective method of birth control from the time of screening until 7 months after the last dose of T-DXd, or within the time period specified per local prescribing guidelines after the final dose of physician’s choice of CDK4/6i plus ET. Female patients must refrain from egg cell donation and breastfeeding during this same period."}
• {"criterion_text":"- Male participants who are sexually active with a female partner of childbearing potential must be surgically sterile or using an acceptable method of contraception from the time of screening until 4 months after the last dose of T-DXd, or within the time period specified per local prescribing guidelines after the final dose of physician’s choice of CDK4/6i plus ET. Male participants must not donate or bank sperm during this same period."}
• {"criterion_text":"- Patients must be accessible for treatment and follow-up."}
• {"criterion_text":"- Female or male patients ≥ 18 years of age at the time of signing ICF."}
• {"criterion_text":"- ECOG performance status of 0-1."}
• {"criterion_text":"- Minimum life expectancy of ≥ 12 weeks at screening."}
• {"criterion_text":"- Evidence of HER2-low expression (1+ by immunohistochemistry or 2+ and negative by an in situ hybridization [ISH] test) or HER2-ultralow (IHC 0 with faint membrane staining and in ≤ 10% of tumor cells) breast cancer according to the most recent American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines determined by a MEDSIR’s designated central laboratory, using Ventana 4B5 antibody. This assessment has to be done on the most recently available (archived or newly collected) formalin-fixed, paraffin-embedded (FFPE) tumor tissue blocks (obtained after last prior systemic therapy) from core or excisional biopsy from a locally recurrent (breast or locoregional lymph nodes) or metastatic tumor lesion, excluding bone metastases."}
• {"criterion_text":"- Non-luminal breast cancer subtype as per central PAM50 analysis determined in the most recently available (archived or newly collected) FFPE tumor tissue blocks (obtained after last prior systemic therapy) from core or excisional biopsy from a locally recurrent (breast or locoregional lymph nodes) or metastatic tumor lesion with the exception of bone metastases."}
• {"criterion_text":"- Patients must have HR-positive (estrogen receptor [ER] and/or progesterone receptor [PgR]-positive defined as ≥ 1% positive stained cells) status according to the most recent ASCO/CAP guidelines locally determined prior to Study entry."}
• {"criterion_text":"- Unresectable locally recurrent or metastatic breast cancer documented by computerized tomography (CT) scan or magnetic resonance imaging (MRI) that is not amenable to resection with curative intent."}
• {"criterion_text":"- Evaluable disease according to RECIST v.1.1. Patients with bone-only disease are not allowed. Patients with bone metastases with soft tissue masses measuring > 10 mm are eligible."}

Exclusion criteria

• {"criterion_text":"- Current participation in another therapeutic clinical trial, except other translational studies."}
• {"criterion_text":"- Palliative radiotherapy with a limited field of radiation within 2 weeks or with wide field of radiation or to more than 30% of the bone marrow within 4 weeks prior to start of Study treatment."}
• {"criterion_text":"- Major surgical procedure or significant traumatic injury within 4 weeks before the first dose of Study treatment or anticipation of need for major surgery within the course of the Study treatment."}
• {"criterion_text":"- Has an active cardiac disease or a history of cardiac dysfunction or conduction abnormalities including, but not confined, to any of the following: • Participants with a medical history of myocardial infarction within 6 months before screening, symptomatic CHF (NYHA Class II to IV), unstable angina pectoris, or a recent (< 6 months) cardiovascular event including stroke. Participants with troponin levels above ULN at screening (as defined by the manufacturer), and without any myocardial related symptoms, should have a cardiologic consultation to rule out myocardial infarction. • Left ventricular ejection fraction (LVEF) < 55% as determined by multigated acquisition (MUGA) scan or echocardiogram (ECHO). • History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, or ventricular tachycardia), which is symptomatic or requires treatment (NCI-CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers will be permitted to enroll. • QT interval corrected by Fridericia’s formula (QTcF) prolongation to > 470 ms (females) or > 450 ms (males) based on average of the screening triplicate 12-lead electrocardiogram (ECG). • History of QT prolongation associated with other medications that required discontinuation of that medication, or any current concomitant medication known to prolong the QT interval and cause Torsades de Pointes. • Congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives."}
• {"criterion_text":"- Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (e.g., pulmonary emboli within 3 months of the Study enrolment, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, pleural effusion, post COVID-19 pulmonary fibrosis, etc.), and any autoimmune, connective tissue, or inflammatory disorders with pulmonary involvement (e.g., rheumatoid arthritis, Sjogren's syndrome, sarcoidosis, etc.), or prior pneumonectomy (complete)."}
• {"criterion_text":"- Has a history of non-infectious interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening."}
• {"criterion_text":"- Pregnant or lactating women or patients not willing to apply highly effective contraception as defined in the protocol."}
• {"criterion_text":"- Current known infection with hepatitis B virus (HBV), or hepatitis C virus (HCV). Patients with past HBV infection or resolved HBV infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive hepatitis B core antibody [HBcAb] test, accompanied by a negative HBV DNA test), and > 6 months off anti-viral treatment are eligible. Those participants should be closely monitored for HBV reactivation and have access to a local hepatitis B expert during and after the Study. Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. Patients with HCV co-infection or history of HCV co-infection are excluded."}
• {"criterion_text":"- Patients with cirrhosis or fibrosis on prior imaging or biopsy."}
• {"criterion_text":"- Has an active primary immunodeficiency or known human immunodeficiency virus (HIV) infection."}
• {"criterion_text":"- Other active uncontrolled infection at the time of enrollment."}
• {"criterion_text":"- Treatment with approved or investigational cancer therapy within 3 weeks prior to initiation of Study drug."}
• {"criterion_text":"- Receipt of live or attenuated vaccine within 30 days prior to the first dose of Study treatment."}
• {"criterion_text":"- A history of uncontrolled seizures, CNS disorders, or serious and/or unstable pre-existing psychiatric disability judged by the investigator to be clinically significant and adversely affecting compliance to Study drugs or interfering with subject safety."}
• {"criterion_text":"- Current use of food or drugs known to be potent CYP3A4 inhibitors, drugs known to be potent CYP3A4 inducers (for examples, see the Prohibited Medications Section)."}
• {"criterion_text":"- Known substance abuse or any other concurrent severe and/or uncontrolled medical condition that would, in the investigator’s judgment, contraindicate patient participation."}
• {"criterion_text":"- Inability or unwillingness to comply with the requirements of the protocol in the opinion of the investigator."}
• {"criterion_text":"- Treatment with chloroquine/hydroxychloroquine within 14 days prior to initiation of Study drug."}
• {"criterion_text":"- Have previously been treated with T-DXd and/or fulvestrant. Note I: patients who experienced relapse after more than 1 year from completion of fulvestrant are eligible. Note II: previous treatment with anti-HER2 therapies in (neo-) adjuvant setting will be allowed for participants who showed conversion from HER2-positive expression in primary breast tumor sample to HER2-low or HER2-ultralow expression (HER2 loss) in relapsed tumor sample."}
• {"criterion_text":"- Patients with advanced, symptomatic, visceral spread, that are at risk of life-threatening complications in the short term (including patients with massive uncontrolled effusions [pleural, pericardial, and/or peritoneal] and pulmonary lymphangitis)."}
• {"criterion_text":"- Impairment of gastro-intestinal (GI) function or GI disease that may significantly alter the absorption of CDK4/6i, such as history of GI surgery which may result in intestinal blind loops and patients with clinically significant gastroparesis, short bowel syndrome, unresolved nausea, vomiting, active inflammatory bowel disease, or diarrhea of CTCAE Grade > 1."}
• {"criterion_text":"- Known central nervous system (CNS) involvement (brain metastases and/or leptomeningeal carcinomatosis). Subjects with clinically inactive brain metastases may be included in the Study. Subjects with treated brain metastases that are no longer symptomatic and who do not require treatment with corticosteroids or anticonvulsants may be included in the Study if they have recovered from the acute toxic effect of radiotherapy."}
• {"criterion_text":"- Have a concurrent malignancy or malignancy within 5 years of Study enrollment with the exception of carcinoma in situ of the cervix and basal cell carcinoma or squamous cell carcinoma of the skin that has been previously treated with curative intent. For other cancers considered to have a low risk of recurrence, discussion with the Sponsor’s Medical Monitor is required."}
• {"criterion_text":"- Known allergy or hypersensitivity reaction to any of the investigational medicinal products (IMPs) or their inactive ingredients."}

Primary endpoints

• {"endpoint_text":"- PFS, defined as the period from randomization date to the first occurrence of documented radiographic disease progression or death from any cause, whichever occurs first, as determined locally by the investigator using RECIST v.1.1. in HER2-low patients.","definition_or_measurement_approach":"Progression-free survival (PFS) measured from randomization to first documented radiographic progression or death, locally assessed by investigator using RECIST v1.1 in HER2-low population."}
• {"endpoint_text":"- PFS, defined as the period from randomization date to the first occurrence of documented radiographic disease progression or death from any cause, whichever occurs first, as determined locally by the investigator using RECIST v.1.1 in all patients.","definition_or_measurement_approach":"Progression-free survival (PFS) measured from randomization to first documented radiographic progression or death, locally assessed by investigator using RECIST v1.1 in all patients."}

Secondary endpoints

• {"endpoint_text":"- OS, defined as the period from randomization date to death from any cause, as determined locally by the investigator (in all patients and HER2-low population).","definition_or_measurement_approach":"Overall survival (OS) measured from randomization to death from any cause; locally determined by investigator."}
• {"endpoint_text":"- ORR, defined as the rate of patients with complete response (CR) or partial response (PR), as determined locally by the investigator using RECIST v.1.1 (in all patients and HER2-low population).","definition_or_measurement_approach":"Objective response rate (ORR) = proportion with CR or PR per RECIST v1.1 assessed locally."}
• {"endpoint_text":"- CBR, defined as the rate of patients with objective response (CR or PR), or stable disease for at least 24 weeks, as determined locally by the investigator using RECIST v.1.1 (in all patients and HER2-low population).","definition_or_measurement_approach":"Clinical benefit rate (CBR) = CR or PR or SD ≥ 24 weeks per RECIST v1.1 assessed locally."}
• {"endpoint_text":"- DoR, defined as the period from the first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first, as determined locally by the investigator using RECIST v.1.1 (in all patients and HER2-low population).","definition_or_measurement_approach":"Duration of response (DoR) measured from first documented objective response to progression or death per RECIST v1.1 assessed locally."}
• {"endpoint_text":"- TTR, defined as the period from randomization date to the first objective tumor response (tumor shrinkage of ≥ 30%) observed for patients who achieved a CR or PR, as determined locally by the investigator using RECIST v.1.1 (in all patients and HER2-low population).","definition_or_measurement_approach":"Time to response (TTR) measured from randomization to first objective tumor response (≥30% tumor shrinkage) per RECIST v1.1 assessed locally."}
• {"endpoint_text":"- TTF, defined as the time from randomization date to discontinuation of treatment for any reason, including progressive disease, treatment toxicity, patient choice, and death.","definition_or_measurement_approach":"Time to treatment failure (TTF) measured from randomization to treatment discontinuation for any reason."}
• {"endpoint_text":"- TFSC: time to first subsequent chemotherapy, defined as the time from randomization date to the beginning of the first subsequent chemotherapy after discontinuation of the trial regimen","definition_or_measurement_approach":"Time to first subsequent chemotherapy measured from randomization to initiation of next-line chemotherapy after stopping trial regimen."}
• {"endpoint_text":"- Best percentage of change from baseline in the size of target tumor lesions, defined as the biggest decrease, or smallest increase if no decrease will be observed, as determined locally by the investigator using RECIST v.1.1.","definition_or_measurement_approach":"Best percent change from baseline in target lesion size per RECIST v1.1 assessed locally (greatest decrease or smallest increase)."}
• {"endpoint_text":"- PFS2 is defined as the time from randomization date to the earliest progression event after that used for the primary variable PFS, or date of death as determined locally by the investigator using RECIST v.1.1.","definition_or_measurement_approach":"Second progression-free survival (PFS2) measured from randomization to earliest progression event after that used for primary PFS or death, per RECIST v1.1."}
• {"endpoint_text":"- TFST, defined as the time from randomization to the earliest date of anti-cancer therapy start date following Study treatment discontinuation, or death.","definition_or_measurement_approach":"Time to first subsequent therapy or death (TFST) measured from randomization to start of first subsequent anti-cancer therapy after discontinuation or to death."}
• {"endpoint_text":"- Changes from baseline in the EORTC QLQ-C30, EORTC QLQ-BR42 scales and the EQ-5D-5L index.","definition_or_measurement_approach":"Patient-reported outcomes: changes from baseline on EORTC QLQ-C30, QLQ-BR42 and EQ-5D-5L instruments."}
• {"endpoint_text":"- Time to deteriorate in the EORTC QLQ-C30 and QLQ-BR42 subscales.","definition_or_measurement_approach":"Time to deterioration on EORTC QLQ-C30 and QLQ-BR42 subscales as defined in protocol."}
• {"endpoint_text":"- Safety endpoints: Safety and tolerability as per NCI-CTCAE v.5.0.","definition_or_measurement_approach":"Safety and tolerability assessed using NCI-CTCAE v5.0 descriptive statistics and reporting."}
• {"endpoint_text":"- Exploratory endpoints can include (but are not limited to): Association of clinical outcomes, safety and/or tolerability profile with mutation profiling, copy number variability, gene expression, multiplex assays, proteomic analyses, digital pathology, immunohistochemistry, taxonomic or functional analyses performed on tissue and/or liquid biopsy samples.","definition_or_measurement_approach":"Exploratory translational biomarker analyses linking molecular data (mutation profiling, copy number, gene expression, proteomics, digital pathology, IHC, liquid biopsy) with clinical outcomes."}
• {"endpoint_text":"- Exploratory endpoints can include (but are not limited to): Efficacy endpoints for all patients according to different clinicopathological characteristics and prior treatment for early breast cancer.","definition_or_measurement_approach":"Subgroup efficacy analyses by clinicopathological characteristics and prior early breast cancer treatments."}
• {"endpoint_text":"- Exploratory endpoints can include (but are not limited to): Association of treatment efficacy and/or safety outcomes in all patients with radiological imaging biomarkers.","definition_or_measurement_approach":"Correlation analyses between imaging biomarkers and treatment efficacy/safety outcomes."}

Other endpoints

• {"endpoint_text":"- Exploratory endpoints can include (but are not limited to): Association of clinical outcomes, safety and/or tolerability profile with mutation profiling, copy number variability, gene expression, multiplex assays, proteomic analyses, digital pathology, immunohistochemistry, taxonomic or functional analyses performed on tissue and/or liquid biopsy samples.","definition_or_measurement_approach":"See above: molecular and translational biomarker analyses on tissue and liquid biopsies correlated with outcomes."}
• {"endpoint_text":"- Exploratory endpoints can include (but are not limited to): Efficacy endpoints for all patients according to different clinicopathological characteristics and prior treatment for early breast cancer.","definition_or_measurement_approach":"Subgroup efficacy analyses by clinicopathological characteristics and prior treatments."}
• {"endpoint_text":"- Exploratory endpoints can include (but are not limited to): Association of treatment efficacy and/or safety outcomes in all patients with radiological imaging biomarkers.","definition_or_measurement_approach":"Association analyses of imaging biomarkers with efficacy/safety outcomes."}

Methods

• K2 recruitment material: social networks, digital campaigns, website (document titled 'K2_Recruitment material social networks digital compaigns website' associated with Spain).

Belgium

Earliest CTIS Part Ii Submission Date

30-05-2025

Latest Decision Or Authorization Date

11-06-2025

Processing Time Days

12

Number Of Sites

4

Number Of Participants

4

Netherlands

Earliest CTIS Part Ii Submission Date

26-05-2025

Latest Decision Or Authorization Date

11-06-2025

Processing Time Days

16

Number Of Sites

1

Number Of Participants

4

Poland

Earliest CTIS Part Ii Submission Date

23-05-2025

Latest Decision Or Authorization Date

10-06-2025

Processing Time Days

18

Number Of Sites

3

Number Of Participants

8

Spain

Earliest CTIS Part Ii Submission Date

08-05-2025

Latest Decision Or Authorization Date

11-11-2025

Processing Time Days

187

Number Of Sites

29

Number Of Participants

66

France

Earliest CTIS Part Ii Submission Date

05-05-2025

Latest Decision Or Authorization Date

09-10-2025

Processing Time Days

157

Number Of Sites

8

Number Of Participants

28

Germany

Earliest CTIS Part Ii Submission Date

15-05-2025

Latest Decision Or Authorization Date

16-01-2026

Processing Time Days

246

Number Of Sites

6

Number Of Participants

12

Austria

Earliest CTIS Part Ii Submission Date

30-05-2025

Latest Decision Or Authorization Date

16-02-2026

Processing Time Days

262

Number Of Sites

3

Number Of Participants

10

Portugal

Earliest CTIS Part Ii Submission Date

14-04-2025

Latest Decision Or Authorization Date

02-03-2026

Processing Time Days

322

Number Of Sites

11

Number Of Participants

16

Italy

Earliest CTIS Part Ii Submission Date

14-03-2025

Latest Decision Or Authorization Date

21-04-2026

Processing Time Days

403

Number Of Sites

16

Number Of Participants

46

Primary sponsor

Full Name

Medica Scientia Innovation Research S.L.

Organisation Type

Pharmaceutical company

Country Of Registered Address

Spain