Safety and Efficacy of T-DXd vs. CDK4/6i-based ET as First-line Therapy of HR-positive and HER2-low/Ultralow Advanced Breast Cancer Patients Classified as Non-luminal Subtype

NCT06486883 | Recruiting Phase 2 DMC

• 1 other identifier: MEDOPP556
• Study Type: interventional
• Target: 200
• Locations: 7 countries
• Sites: 56

Brief Summary

This trial studies a type of advanced breast cancer defined as hormone receptor HR-positive/HER2-negative and classified as non-luminal by gene expression profiling (PAM50). Patients will be treated with trastuzumab deruxtecan (T-DXd) or with physician's choice of CDK4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET). The main purpose of the study is to analyze the efficacy of T-DXd in patients who have HR-positive and HER2-low/ultralow advanced breast cancer classified as non-luminal subtype.

Conditions

Advanced Breast Cancer; Advanced Breast Carcinoma; Hormone Receptor Positive Breast Carcinoma

Outcome Measures

Primary Outcomes (2)

• Progression-free survival (PFS)

  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.

  Up to 25 months

• Progression-free survival (PFS)

  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.

  Up to 25 months

Secondary Outcomes (14)

• Overall survival (OS)

  Up to 25 months

• Objective response rate (ORR)

  Up to 25 months

• Clinical benefit rate (CBR)

  Up to 25 months

• Duration of response (DoR)

  Up to 25 months

• Time to response (TTR)

  Up to 25 months

Study Arms (2)

Arm A

EXPERIMENTAL

Drug: Trastuzumab deruxtecan (T-DXd, DS-8201a)

Arm B

ACTIVE COMPARATOR

Drug: CDK4/6i plus ET

Interventions

CDK4/6i plus ET DRUG

Patients will receive physician's choice of CDK4/6 inhibitor (CDK4/6i) including palbociclib, ribociclib, and abemaciclib; physician's choice of endocrine therapy (ET) including fulvestrant, letrozole, anastrozole, and exemestane.

Arm B

Trastuzumab deruxtecan (T-DXd, DS-8201a) DRUG

Patients will receive T-DXd 5.4 mg/kg body weight administered as an intravenous (IV) infusion on Day 1 (D1) of each 21-day cycle. The initial dose will be administered as a 90-minute IV infusion.

Arm A

Eligibility Criteria

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

You may qualify if:

• 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.
• Female or male patients ≥ 18 years of age at the time of signing ICF.
• ECOG performance status of 0-1.
• Minimum life expectancy of ≥ 12 weeks at screening.
• Evidence of HER2-low expression (1+ by immunohistochemistry (IHC) 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 (≤ 6 weeks or FFPE of a tumor sample 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.
• Non-luminal breast cancer subtype as per central PAM50 analysis determined in the most recently available (archived or newly collected) FFPE tumor tissue blocks (≤ 6 weeks or FFPE of a tumor sample 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.
• 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.
• 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.
• 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.
• 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:
• Estrogen receptor ≤ 50% positive stained cells;
• and/or high histological grade or Ki67 \> 50% on primary tumor;

You may not qualify if:

• Current participation in another therapeutic clinical trial, except other translational studies.
• Treatment with approved or investigational cancer therapy within 3 weeks prior to initiation of study drug.
• Treatment with chloroquine/hydroxychloroquine within 14 days prior to initiation of study drug.
• Have previously been treated with T-DXd and/or fulvestrant. Note: patients who experienced relapse after more than 1 year from completion of fulvestrant are eligible.
• Note I: 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.
• 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).
• 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.
• 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 require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy.
• 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.
• Known allergy or hypersensitivity reaction to any of the investigational medicinal products (IMPs) or their inactive ingredients.
• 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.
• 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.
• 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 congestive heart failure (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).

Sponsors & Collaborators

• MedSIR: lead

Study Sites (56)

Algemeen Ziekenhuis Klina

Brasschaat, Belgium

RECRUITING

CHU Helora - Hopital de Mons

Mons, Belgium

RECRUITING

Cliniques universitaires Saint-Luc

Woluwe-Saint-Lambert, Belgium

RECRUITING

CHU Lyon Sud

Lyon, France

RECRUITING

Institut Curie

Paris, France

RECRUITING

CHU Saint Etienne

Saint-Priest-en-Jarez, 42055, France

RECRUITING

Klinikum Worms - Frauenklinik

Worms, 67550, Germany

RECRUITING

A.O.U. Ospedali Riuniti di Ancona

Ancona, 60126, Italy

RECRUITING

Centro di Riferimento Oncologico di Aviano

Aviano, 33081, Italy

RECRUITING

AOU Careggi

Florence, 50134, Italy

RECRUITING

Ospedale Policlinico San Martino

Genova, 16132, Italy

RECRUITING

Ospedale di Macerata

Macerata, 62100, Italy

RECRUITING

Instituto Europeo di Oncologia

Milan, 20141, Italy

RECRUITING

Ospedale San Gerardo

Monza, 20900, Italy

RECRUITING

Federico II Napoli

Naples, 80131, Italy

RECRUITING

Istituto Nazionale Tumori Irccs "Fondazione G Pascale"

Naples, 80131, Italy

RECRUITING

Azienda Ospedaliero- Universitaria Maggiore Della Carita

Novara, 28100, Italy

RECRUITING

Oncologia medica AUSL Piacenza

Piacenza, 29100, Italy

RECRUITING

Fondazione Policlinico Universitario Agostino Gemelli

Roma, 00168, Italy

RECRUITING

Medtrials Sp. z o.o.

Krakow, Poland

RECRUITING

Unidade Local de Saúde de Trás-os-Montes e Alto Douro

Lordelo, Vila Real District, 5000-508, Portugal

RECRUITING

Hospital de Cascais

Alcabideche, 2755-009, Portugal

RECRUITING

Unidade Local de Saúde Amadora/Sintra - Hospital Fernando da Fonseca

Amadora, 2720-276, Portugal

RECRUITING

Unidade Local de Saúde do Alto Ave

Braga, Portugal

RECRUITING

Unidade Local de Saúde de Santa Maria

Lisbon, 1649-035, Portugal

RECRUITING

Instituto Portugues Oncologia de Porto (IPO)

Porto, Portugal

RECRUITING

Hospital Quirónsalud Sagrado Corazón

Barcelona, Barcelona, 41013, Spain

RECRUITING

Hospital San Pedro de Alcántara

Cáceres, Cáceres, 1003, Spain

RECRUITING

Institut Català d' Oncologia Girona (ICO)

Girona, Girona, 17007, Spain

RECRUITING

Hospital Universitario Clínico San Cecilio

Granada, Granada, 18007, Spain

RECRUITING

Complejo Hospitalario de Jaén

Jaén, Jaén, 23007, Spain

RECRUITING

Hospital Universitario Ramón y Cajal

Madrid, Madrid, 28034, Spain

RECRUITING

Hospital Universitario Puerta de Hierro Majadahonda

Majadahonda, Madrid, 28222, Spain

RECRUITING

Hospital Clínico Universitario Virgen de la Arrixaca

Murcia, Murcia, 30120, Spain

RECRUITING

Hospital Universitari Sant Joan de Reus

Reus, Tarragona, 43204, Spain

RECRUITING

Hospital Clínico Universitario de Valencia

Valencia, Valencia, 46010, Spain

RECRUITING

Complejo Hospitalario Universitario A Coruña (CHUAC)

A Coruña, 15006, Spain

RECRUITING

Centro Oncológico de Galicia

A Coruña, 15009, Spain

RECRUITING

Hospital Universitario San Juan de Alicante

Alicante, 03550, Spain

RECRUITING

Institut Català d' Oncologia Badalona (ICO)

Badalona, 08916, Spain

RECRUITING

UOMI Cancer Center

Barcelona, 08017, Spain

RECRUITING

Hospital Universitari Dexeus

Barcelona, 08028, Spain

RECRUITING

Hospital Clínic i Provincial de Barcelona

Barcelona, 08036, Spain

RECRUITING

Hospital Universitario de Basurto

Bilbao, 48013, Spain

RECRUITING

Hospital Universitario Arnau de Vilanova de Lleida

Lleida, 25198, Spain

RECRUITING

Hospital Beata María Ana

Madrid, 28007, Spain

RECRUITING

Hospital Clínico San Carlos

Madrid, 28040, Spain

RECRUITING

Hospital Universitario Doce de Octubre

Madrid, 28041, Spain

RECRUITING

Hospital Universitario Virgen de la Victoria

Málaga, 29010, Spain

RECRUITING

Complejo Hospitalario Universitario de Santiago (CHUS)

Santiago de Compostela, 15706, Spain

RECRUITING

Hospital Universitario Virgen Macarena

Seville, 41009, Spain

RECRUITING

Instituto Valenciano de Oncología (IVO)

Valencia, 46009, Spain

RECRUITING

Hospital Universitari i Politècnic La Fe

Valencia, 46026, Spain

RECRUITING

Hospital Arnau de Vilanova de Valencia

Valencia, Spain

RECRUITING

Hospital Clínico Universitario Lozano Blesa

Zaragoza, 50009, Spain

RECRUITING

Hospital QuirónSalud Zaragoza

Zaragoza, 50012, Spain

RECRUITING

MeSH Terms

Interventions

trastuzumab deruxtecan

Central Study Contacts

MEDSIR

CONTACT

+ 34 932 214 135; contact.trials@medsir.org

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Arm A: T-DXd; Arm B CDK4/6i plus endocrine therapy (ET). The physician's choice of CDK4/6i plus ET will be limited to one CDK4/6i plus fulvestrant or an aromatase inhibitor (AI). The options for CDK4/6i are palbociclib, ribociclib, and abemaciclib, the options for ET are fulvestrant, letrozole, anastrozole, and exemestane.

Study Record Dates

• First Submitted: June 17, 2024
• First Posted: July 5, 2024
• Study Start: June 30, 2025
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2028
• Last Updated: April 2, 2026

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

BE (3); PL (1); ES (30); IT (12); PT (6); FR (3); DE (1)