Elacestrant + Everolimus in Patients ER+/HER2-, ESR1mut, Advanced Breast Cancer Progressing to ET and CDK4/6i. (ADELA)

A Randomized Phase 3, Double-Blind, Placebo-Controlled Study of Elacestrant Plus Everolimus Versus Elacestrant in Patients With ER+/HER2-, ESR1mut Advanced Breast Cancer Progressing to Endocrine Therapy and CDK4/6 Inhibitors

This trial will study a type of advanced breast cancer (ABC) defined as endocrine receptor (ER)-positive/human epidermal growth factor receptor 2(HER2)-negative and estrogen receptor 1 (ESR1)-mutated. Patients will be treated with elacestrant, a compound that acts as a selective estrogen receptor degrader, and everolimus (or placebo), a kinase inhibitor indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer.

The main purpose of the study is to analyze the efficacy (to find out how effective a treatment is) of elacestrant plus everolimus therapy in patients who have ER-positive/HER2-negative, ESR1-mutated, ABC progressing to endocrine therapy and cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. The efficacy of elacestrant plus everolimus combination will be determined by assessing the period from elacestrant plus everolimus (or placebo) treatment initiation until to the first occurrence of disease progression, unacceptable toxicity, death, or discontinuation from the study treatment for any other reason, whichever occurs first, defined as progression free survival.

Rigorous eligibility criteria based on specific co-morbidities and clinicopathologic features of their disease have been designed to minimize the risk of patients participating in this study. The anticipated favorable clinical benefits of elacestrant combined with everolimus are projected to outweigh the risks of this treatment. This study will be performed in full compliance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and all applicable local Good Clinical Practice (GCP) and regulations.

Study Overview

• Status: Recruiting
• Conditions: Advanced Breast Cancer; ER-positive Breast Cancer; HER2-negative Breast Cancer; ESR1 Gene Mutation
• Intervention / Treatment: Drug: Auxiliary Medicinal Product - Dexamethasone; Drug: Auxiliary Medicinal Product - Luteinizing hormone-releasing hormone (LHRH) analogues; Drug: Placebo; Drug: Everolimus; Drug: Elacestrant

Detailed Description

Upon meeting all selection criteria, a total of 240 patients will be enrolled.

After signing the Informed Consent Form (ICF), patients will be randomized (ratio 1:1) as follows:

• Interventional Arm (Arm A) (N=120): Patients will receive 345 mg of elacestrant and 7.5 mg of everolimus orally once daily.
• Control Arm (Arm B) (N=120): Patients will receive elacestrant at 345 mg orally once daily plus everolimus placebo.

Patients will be stratified by presence of visceral metastases (yes versus no) and duration of prior CDK4/6 inhibitor-based therapy (≥ 12 months versus < 12 months). Patients progressing to CDK4/6 inhibitor-based therapy in the adjuvant setting will be stratified as patients with a duration of prior CDK4/6 inhibitor-based therapy < 12 months.

Patients will receive study treatment in 28-day cycles until documented disease progression, death, unacceptable toxicity, or discontinuation from the study treatment for any other reason, whichever occurs first.

Patients discontinuing the study treatment period will enter a post-treatment follow-up period during which survival and new anti-cancer therapy information will be collected every 3 months (± 14 days) from the last dose of IMPs until the End of Study (EoS) defined as 12 months after last patient is randomized unless premature termination of the trial. For patients who discontinue the study treatment for reasons other than disease progression, tumor assessments will be conducted following the frequency of the study until the start of a new anti-cancer treatment, death, or disease progression.

• Study Type: Interventional
• Enrollment (Estimated): 240
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Medsir; Phone Number: +34932214135; Email: contact.trials@medsir.org

Study Locations

• Austria
  • Innsbruck, Austria
    • Recruiting
    • Medizinische Universität Innsbruck
    • Contact: Daniel Egle, MD
  • Linz, Austria
    • Recruiting
    • Ordensklinikum Linz Barmherzige Schwestern
    • Contact: Clemens Dormann, MD
  • Schwaz, Austria
    • Recruiting
    • Ordination Priv.-Doz. Dr. Michael Hubalek
    • Contact: Michael Hubalek, MD
  • Vienna, Austria
    • Not yet recruiting
    • Medical University of Vienna
    • Contact: Rupert Bartsch, MD
• Brazil
  • Bento Gonçalves, Brazil
    • Not yet recruiting
    • Tacchini Instituto de Pesquisa
    • Contact: Andrea Borba, MD
  • Cachoeiro de Itapemirim, Brazil
    • Not yet recruiting
    • Hospital Cachoeiro de Itapemirim
    • Contact: Sabina Aleixo, MD
  • Itajaí, Brazil
    • Not yet recruiting
    • Catarina Pesquisa Clínica - Neoplasias Litoral
    • Contact: Giuliano Borges, MD
  • Porto Alegre, Brazil
    • Not yet recruiting
    • UPCO - Hospital de Clinicas de Porto Alegre
    • Contact: Carlos Barrios, MD
  • Salvador, Brazil
    • Not yet recruiting
    • NOB Ondina
    • Contact: Lucia Landero, MD
• Czechia
  • Brno, Czechia
    • Recruiting
    • Masaryk Memorial Cancer Institute
    • Contact: Milos Holanek, MD
  • Hořovice, Czechia
    • Recruiting
    • Multiscan Nemocnice Horovice
    • Contact: Martin Smakal, MD
  • Olomouc, Czechia
    • Not yet recruiting
    • University Hospital Olomouc
    • Contact: Bohuslav Melichar, MD
  • Prague, Czechia
    • Recruiting
    • General University Hospital Prague
    • Contact: Martina Zimovjanova, MD
  • Zlín, Czechia
    • Recruiting
    • Tomas Bata Regional Hospital in Zlin
    • Contact: Michaela Zábojníková, MD
• France
  • Bordeau, France
    • Recruiting
    • Polyclinique Bordeaux Nord Aquitaine
    • Contact: Nadine Dohollou, MD
  • Bordeaux, France
    • Not yet recruiting
    • Institut Bergonié Bordeaux
    • Contact: Monica Arnedos, MD
  • Dijon, France
    • Recruiting
    • Centre Georges Francois Leclerc
    • Contact: Sylvain Ladoire, MD
  • Limoges, France
    • Recruiting
    • Centre Hospitalier de Limoges
    • Contact: Monica Arnedos, MD
  • Lyon, France
    • Recruiting
    • CHU Lyon Sud
    • Contact: Gilles Freyer, MD
  • Marseille, France
    • Not yet recruiting
    • Institut Paoli Calmettes
    • Contact: Alexandre Tassin de Nonneville, MD
  • Paris, France
    • Not yet recruiting
    • APHP Tenon
    • Contact: Joseph Gligorov, MD
  • Plérin, France
    • Recruiting
    • Hospital prive des Cotes d'Amor
    • Contact: Anne Claire Hardy-Bessard
  • Saint-Priest-en-Jarez, France
    • Recruiting
    • CHU Saint Etienne
    • Contact: Esma Bougherira, MD
  • Toulouse, France
    • Recruiting
    • Iuct Oncopole
    • Contact: Florence Dalenc, MD
  • Vandœuvre-lès-Nancy, France
    • Recruiting
    • Institute de Cancerologie de Lorraine - Nancy
    • Contact: Vincent Massard, MD
• Germany
  • Aschaffenburg, Germany
    • Not yet recruiting
    • MVZ Klinikum Aschaffenburg
    • Contact: Manfred Welslau, MD
  • Augsburg, Germany
    • Not yet recruiting
    • Hämatologie-Onkologie im Zentrum MVZ GmbH
    • Contact: Bernhard Heinrich, MD
  • Dessau, Germany
    • Not yet recruiting
    • Städtisches Klinikum Dessau
    • Contact: Herrmann Voß, MD
  • Düsseldorf, Germany
    • Not yet recruiting
    • Universitatsklinikum Dusseldorf
    • Contact: Eugen Ruckhäberle, MD
  • Essen, Germany
    • Not yet recruiting
    • Universitätsklinikum Essen
    • Contact: Anja Welt, MD
  • Georgsmarienhütte, Germany
    • Recruiting
    • MVZ Ⅱ der Niels Stensen Kliniken
    • Contact: Kerstin Luedtke-Heckenkamp, MD
  • Worms, Germany
    • Recruiting
    • Klinikum Worms - Frauenklinik
    • Contact: Sebastian Züfle, MD
• Greece
  • Alexandroupoli, Greece
    • Recruiting
    • University General Hospital Alexandroupoli
    • Contact: Dimitros Matthaios, MD
  • Athens, Greece
    • Recruiting
    • Attikon University Hospital
    • Contact: Amanda Psyrri, MD
  • Athens, Greece
    • Recruiting
    • Aretaeio Hospital
    • Contact: FLORA ZAGOURI, MD
  • Athens, Greece
    • Recruiting
    • 251 Air Force General Hospital
    • Contact: Vasileios Ramfidis, MD
  • Athens, Greece
    • Recruiting
    • Metropolitan General Hospital 4th department
    • Contact: Helena Linardou, MD
  • Heraklion, Greece
    • Recruiting
    • University General Hospital of Heraklion
    • Contact: Dimitrios Mavroudis, MD
  • Larissa, Greece
    • Recruiting
    • University General Hospital of Larissa
    • Contact: Athanasios Kotsakis, MD
  • Piraeus, Greece
    • Recruiting
    • Metropolitan Hospital Greece 1st department
    • Contact: Dimitrios Bafaloukos, MD
  • Pátrai, Greece
    • Recruiting
    • General University Hospital of Patras
    • Contact: Athina Christopoulou, MD
  • Thessaloniki, Greece
    • Recruiting
    • EU Interbalkan Medical Center
    • Contact: Konstantinos Papazisis, MD
• Italy
  • Bergamo, Italy
    • Not yet recruiting
    • Cliniche Gavazzeni
    • Contact: Fabio Conforti, MD
  • Cagliari, Italy
    • Not yet recruiting
    • Azienda Ospedaliero-Universitaria (AOU) di Cagliari
    • Contact: Mario Scartozzi, MD
  • Florence, Italy
    • Recruiting
    • AOU Careggi
    • Contact: Icro Meattini, MD
  • Genova, Italy
    • Not yet recruiting
    • IRCCS Ospedale Policlinico San Martino
    • Contact: Lucia del Mestro, MD
  • Livorno, Italy
    • Recruiting
    • Ospedali Riuniti Livorno
    • Contact: Giacomo Allegrini, MD
  • Milan, Italy
    • Recruiting
    • Instituto Europeo di Oncologia
    • Contact: Carmen Criscitiello, MD
  • Modena, Italy
    • Recruiting
    • AOU Policilinico Modena
    • Contact: Federico Piacentini, MD
  • Monza, Italy
    • Not yet recruiting
    • IRCCS San Gerardo
    • Contact: Marina Cazzaniga, MD
  • Naples, Italy
    • Not yet recruiting
    • Fondazione Pascale
    • Contact: Michelino di Laurentis, MD
  • Novara, Italy
    • Recruiting
    • Azienda Ospedaliero- Universitaria Maggiore Della Carita
    • Contact: Alessandra Gennari, MD
  • Piacenza, Italy
    • Recruiting
    • Oncologia Medica AUSL Piacenza
    • Contact: Serena Madaro, MD
  • Roma, Italy
    • Not yet recruiting
    • Policlinico A. Gemelli IRCCS
    • Contact: Ida Paris, MD
• Spain
  • A Coruña, Spain
    • Recruiting
    • Centro Oncologico de Galicia
    • Contact: Pablo Alvarez, MD
  • A Coruña, Spain
    • Recruiting
    • Complejo Hospitalario Universitario de Santiago (CHUS)
    • Contact: Juan Cueva, MD
  • Alicante, Spain
    • Recruiting
    • Hospital Universitario San Juan de Alicante
    • Contact: Nieves Diaz, MD
  • Alicante, Spain
    • Recruiting
    • Hospital General Universitario Dr. Balmis (Alicante)
    • Contact: Jose Ponce Lorenzo, MD
  • Badalona, Spain
    • Recruiting
    • Institut Català d' Oncologia Badalona (ICO)
    • Contact: Laia Boronat, MD
  • Barcelona, Spain
    • Recruiting
    • Hospital Universitari Vall d'Hebron
    • Contact: Esther Zamora, MD
  • Barcelona, Spain
    • Recruiting
    • Hospital del Mar
    • Contact: Sonia Servitja, MD
  • Barcelona, Spain
    • Recruiting
    • Hospital Clínic I Provincial de Barcelona
    • Contact: Isabel García, MD
  • Bilbao, Spain
    • Recruiting
    • Hospital Universitario de Basurto
    • Contact: Elena Galve, MD
  • Burgos, Spain
    • Recruiting
    • Hospital Universitario de Burgos
    • Contact: Blanca Hernando, MD
  • Castellon, Spain
    • Recruiting
    • Hospital Provincial de Castellon
    • Contact: Eduardo Martínez, MD
  • Cáceres, Spain
    • Recruiting
    • Hospital San Pedro de Alcantara
    • Contact: Santiago González, MD
  • Granada, Spain
    • Recruiting
    • Hospital Universitario Clínico San Cecilio de Granada
    • Contact: Isabel Blancas, MD
  • Jaén, Spain
    • Recruiting
    • Complejo Hospitalario de Jaén
    • Contact: Rocio Urbano, MD
  • Las Palmas de Gran Canaria, Spain
    • Recruiting
    • Hospital Universitario Insular de Gran Canaria
    • Contact: Elisenda Llabres, MD
  • León, Spain
    • Recruiting
    • Hospital Universitario de Leon
    • Contact: Mariana López, MD
  • Lleida, Spain
    • Recruiting
    • Hospital Universitario Arnau de Vilanova de Lleida
    • Contact: Serafin Morales, MD
  • Madrid, Spain
    • Recruiting
    • Hospital Universitario La Paz
    • Contact: Virginia Martinez, MD
  • Madrid, Spain
    • Recruiting
    • Hospital Universitario Ramon y Cajal
    • Contact: Alfonso Cortes, MD
  • Madrid, Spain
    • Recruiting
    • Hospital Universitario Doce de Octubre
    • Contact: Pablo Tolosa, MD
  • Madrid, Spain
    • Recruiting
    • Hospital Universitario Puerta de Hierro Majadahonda
    • Contact: Blanca Cantos, MD
  • Madrid, Spain
    • Recruiting
    • MD Anderson Cancer Center Madrid
    • Contact: Laura Garcia, MD
  • Madrid, Spain
    • Recruiting
    • Hospital Beata María Ana
    • Contact: Cristina Saavedra, MD
  • Madrid, Spain
    • Recruiting
    • Hospital Universitario Sanchinarro-START-CIOCC
    • Contact: Raquel Bratos, MD
  • Murcia, Spain
    • Recruiting
    • Hospital Clinico Universitario Virgen de La Arrixaca
    • Contact: Jose Luis Alonso, MD
  • Palma de Mallorca, Spain
    • Recruiting
    • Hospital Universitari Son Espases
    • Contact: Antonia Perelló, MD
  • Pamplona, Spain
    • Recruiting
    • Hospitalario Universitario de Navarra
    • Contact: Susana Cruz, MD
  • Santa Cruz de Tenerife, Spain
    • Recruiting
    • Hospital Universitario de Canarias
    • Contact: Josefina Cruz, MD
  • Seville, Spain
    • Recruiting
    • Hospital Universitario Virgen Macarena
    • Contact: Luis Cruz, MD
  • Seville, Spain
    • Recruiting
    • Hospital Universitario Virgen del Rocio
    • Contact: Manuel Ruiz, MD
  • Seville, Spain
    • Recruiting
    • Hospital Quirónsalud Sagrado Corazón
    • Contact: María Valero, MD
  • Tarragona, Spain
    • Recruiting
    • Hospital Universitari Sant Joan de Reus
    • Contact: Alba Cochs, MD
  • Valdecilla, Spain
    • Recruiting
    • Hospital Universitario Marqués de Valdecilla
    • Contact: Carmen Hinojo, MD
  • Valencia, Spain
    • Recruiting
    • Consorci Hospital General Universitari de València
    • Contact: Vega Iranzo, MD
  • Valencia, Spain
    • Recruiting
    • Hospital Clinico Universitario de Valencia
    • Contact: Begoña Bermejo, MD
  • Valencia, Spain
    • Recruiting
    • Hospital Arnau de Vilanova de Valencia
    • Contact: Vicente Carañana, MD
  • Valencia, Spain
    • Recruiting
    • Hospital Universitario La Ribera - Alzira
    • Contact: Athanasios Pouptsis, MD
  • Zaragoza, Spain
    • Recruiting
    • Hospital Clinico Universitario Lozano Blesa
    • Contact: Raquel Andres, MD
  • Barcelona
    • Barcelona, Barcelona, Spain
      • Recruiting
      • Hospital Universitari Dexeus
      • Contact: Laia Garrigós, MD
• United Kingdom
  • Edinburgh, United Kingdom
    • Not yet recruiting
    • Western General Hospital
    • Contact: Olga Oikonomidou, MD
  • London, United Kingdom
    • Recruiting
    • Barts Health NHS Trust
    • Contact: Peter Schmid, MD
  • Oxford, United Kingdom
    • Recruiting
    • Genesis Care Oxford
    • Contact: Mark Tthill, MD
  • Surrey Quays, United Kingdom
    • Recruiting
    • Royal Surrey County Hospital
    • Contact: Felicity Paterson, MD
  • Truro, United Kingdom
    • Recruiting
    • Royal Cornwall Hospital NHS Trust
    • Contact: Alastair Thomson, MD
  • Waterlooville, United Kingdom
    • Recruiting
    • Genesis Cancer Care UK
    • Contact: Mark Tuthill, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Patients will be included in the study only if they meet ALL of the following criteria:

1. Patient must be capable to understand the purpose of the study and have signed written informed consent form (ICF) prior to beginning specific protocol procedures.
2. Female or male patients ≥ 18 years of age at the time of signing ICF.

3. Pre- or perimenopausal women, who do not meet the criteria for post-menopausal status (defined in continuation) and men must be concurrently receiving a LHRH analogue for at least 28 days (if shorter, post-menopausal levels of serum estradiol/follicle-stimulating hormone [FSH] must be confirmed analytically) prior to study randomization and are planning to continue LHRH agonist treatment during the study.

   Post-menopausal women as defined by any of the following criteria:

   1. Age ≥ 60 years;
   2. Age < 60 years and cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and serum estradiol and/or FSH levels within the laboratory's reference range for post-menopausal females;
   3. Documented bilateral surgical oophorectomy.
4. Histologically- or cytologically proven diagnosis of adenocarcinoma of the breast with evidence of either unresectable locally recurrent or metastatic disease confirmed by computerized tomography (CT) scan or magnetic resonance imaging (MRI) that is not amenable to resection with curative intent.
5. Documentation of ER[+] (≥10% positive stained cells) and HER2[-] (0-1+ by immunohistochemistry [IHC] or 2+ and negative by in situ hybridization [ISH] test) tumor according to the most recent American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines as per local assessment. ER[+]/HER2[-] status should be confirmed in metastatic setting, with exception of patients with bone and lung only disease.

6. Patients with ESR1 mutational status will be determined before patient randomization using Guardant360 CDx (Guardant Health) test.

   Note: Patients with previously determined ESR1 mutation using appropriately validated tests (Guardant360 CDx [Guardant Health], FoundationOne CDx, FoundationOne Liquid [Foundation Medicine Inc]) will be eligible for inclusion. This local determination can be performed either in blood or tumor samples.

7. Radiological or objective evidence of disease progression on prior treatment with a CDK4/6 inhibitor in combination with endocrine therapy for advanced disease after at least 6 months of treatment. Patients receiving CDK4/6 inhibitor-based therapy in the adjuvant setting are also eligible provided that disease progression is confirmed after at least 12 months of treatment but no more than 12 months following CDK4/6 inhibitor treatment completion in this scenario.
8. Patients must have previously received at least one and no more than two lines of endocrine therapy for ABC. Progression during or within 12 months of adjuvant endocrine therapy is considered as a line of endocrine therapy for advanced disease.

9. No prior elacestrant or other investigational SERDs, proteolysis targeting chimera (PROTAC), complete estrogen receptor antagonist (CERAN), or novel SERM, and/or PI3K/AKT/mTOR inhibitors, including everolimus, for advanced disease are permitted.

   Note: Fulvestrant is permitted if treatment was completed administered at least 28 days before randomization.

10. No prior chemotherapy for advanced disease is allowed.
11. Evidence of measurable disease as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v.1.1), or non-measurable, but evaluable, disease, including bone-only disease with at least one lytic or mixed lytic-blastic bone lesion.
12. Willingness and ability to provide the most recently available formalin-fixed paraffin-embedded (FFPE) tumor tissue or block. If a newly obtained baseline biopsy of an accessible tumor lesion is not possible to be obtained prior randomization, an archival tissue sample will be accepted.
13. Fasting serum cholesterol ≤ 300 mg/dL or 7.75 mmol/L and fasting triglycerides ≤ 2.5 times the upper limit of normal (x ULN).

14. Adequate bone marrow and organ function:

    1. Hematological (without platelet, red blood cell transfusion, and/or granulocyte colony-stimulating factor support within seven days before randomization): absolute neutrophil count (ANC) ≥ 1.5 x 109/L; platelet count ≥ 100.0 x109/L; and hemoglobin ≥ 9.0 g/dL.
    2. Hepatic: Serum albumin ≥ 2.5 g/dL; total serum bilirubin < 1.5 x ULN except for patients with Gilbert's syndrome who may be included if the total serum bilirubin is ≤ 3 x ULN or direct bilirubin ≤ 1.5 x ULN; alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 3 x ULN in patients with liver and/or bone metastases); aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 1.5 x ULN (≤ 3 x ULN in patients with liver metastases).
    3. Renal: Serum creatinine ≤ 1.5 x ULN or estimated creatinine clearance ≥ 50 mL/min as calculated by Cockcroft- Gault equation.
    4. Coagulation: International normalized ratio (INR) ≤ 1.5 x ULN, unless that the patient meets the exception described in the exclusion criteria 16.

15. Resolution of all acute toxic effects of prior anti-cancer therapy to grade ≤ 1 as determined by the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) v.5.0 (except for toxicities not considered a safety risk for the patient at Investigator's discretion).

    Note: Patients with grade 2 alopecia are allowed.

16. Women of childbearing potential who are sexually active with a non-sterilized male partner must have a negative serum pregnancy test within 7 days before randomization. In addition, they agree to use one highly effective method of birth control 28 days prior to start of treatment until 120 days after the last dose of study treatments. Female patients must refrain from egg cell donation and breastfeeding during this same time period.
17. Male participants with a female partner of childbearing potential must be surgically sterile or using a highly effective method of contraception 28 days prior to treatment until 120 days after the last dose of study treatments to prevent pregnancy in a partner. Male participants must not donate or bank sperm during this same time period. Not engaging in heterosexual activity (sexual abstinence) for the duration of the study and 120 days after the last dose of study treatments is an acceptable practice if this is the preferred usual lifestyle of the participant.
18. ECOG performance status of 0-1.
19. Minimum life expectancy of ≥ 12 weeks at screening.

Exclusion Criteria:

Any patient meeting ANY of the following criteria will be excluded from the study:

1. Inability to comply with study and follow-up procedures.
2. Formal contraindication to endocrine therapy defined as visceral crisis and/or rapidly or symptomatic progressive visceral disease.
3. Current participation in another therapeutic clinical trial.
4. Treatment with approved or investigational cancer therapy within 14 days prior to randomization except for fulvestrant that must be administered completed at least 28 days before randomization.
5. Known active uncontrolled or symptomatic central nervous system (CNS) metastases and/or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth. Patients with a history of CNS metastases are eligible if they have been previously treated with local therapy, are clinically stable, and off anticonvulsants and steroids for at least 14 days before randomization.
6. Intact uterus with a history of endometrial intraepithelial neoplasia (atypical endometrial hyperplasia or higher-grade lesion).
7. Concurrent malignancy or malignancy within three years before randomization with the exception of carcinoma in situ of the cervix, non-melanoma skin carcinoma, or stage I uterine cancer. For other cancers considered to have a low risk of recurrence, discussion with the Medical Monitor is required.
8. Known allergy or hypersensitivity reaction to any investigational medicinal products (IMPs) or their incorporated substances.
9. History of malabsorption syndrome or other condition that would interfere with enteral absorption (ongoing gastrointestinal obstruction/motility disorder, malabsorption syndrome, or prior gastric bypass) or results in the inability or unwillingness to swallow pills.
10. Palliative radiotherapy with a limited field of radiation within two weeks or with wide field of radiation or to more than 30% of the bone marrow within four weeks prior to randomization.
11. Major surgical procedure or significant traumatic injury within 14 days before randomization or anticipation of need for major surgery within the course of the study treatment.

12. Clinically relevant cardiovascular/cerebrovascular disease and/or cardiac dysfunction or conduction abnormalities including, but not confined, to any of the following:

    a. Symptomatic pericarditis, unstable angina pectoris, documented myocardial infarction, coronary/peripheral artery bypass graft, symptomatic cardiac heart failure (CHF) (New York Heart Association [NYHA] Class II-IV), or cerebrovascular accident including transient ischemic attack within six months before study randomization.

13. Concurrent uncontrolled atrial fibrillation, other ongoing cardiac dysrhythmias grade ≥ 2 as determined by NCI-CTCAE v.5.0, or prolonged QT Interval Corrected by Fridericia's formula ([QTcF] > 480 msec).

14. Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited, to any of the following:

    1. Massive lung metastatic involvement (e.g., pleural effusion, lymphangitic carcinomatosis, etc.).
    2. Any underlying pulmonary disorder (e.g., severe asthma, severe chronic obstructive pulmonary disease [COPD], restrictive lung disease, post Coronavirus disease (COVID-19) pulmonary fibrosis, etc.).
    3. Any autoimmune, connective tissue, or inflammatory disorders with pulmonary involvement (e.g., rheumatoid arthritis, Sjogren's syndrome, sarcoidosis, etc.).
    4. Prior pneumonectomy.
15. 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.

16. Coagulopathy or any history of coagulopathy within six months before study enrollment, including history of deep vein thrombosis or pulmonary embolism. However, patients with the following conditions will be allowed to participate:

    1. Adequately treated catheter-related venous thrombosis occurring more than 28 days prior to randomization.
    2. Treatment with an anticoagulant (e.g., warfarin or heparin) for a thrombotic event occurring more than six months before randomization, or for an otherwise stable and allowed medical condition (e.g., well controlled atrial fibrillation), provided dose and coagulation parameters (as defined by local standard of care) are stable for at least 28 days prior to randomization.
17. Concomitant treatment with immunosuppressive agents or chronic corticosteroids use before randomization with the following exceptions: topical applications, inhaled sprays, eye drops, mouthwash, or local injections are allowed. Patients on stable low dose of corticosteroids ( ≤ 10 mg/day of prednisone or equivalent) for at least two weeks before randomization are also permitted.
18. Unable or unwilling to avoid prescription medications, over-the-counter medications, dietary/herbal supplements (e.g., St. John's wort), and/or foods (e.g., grapefruit, pomelos, star fruit, Seville oranges and their juices) that are moderate/strong inhibitors or inducers of CYP3A4 activity. Participation will be allowed if the medication, supplements, and/or foods are discontinued for at least five half-lives or 14 days (whichever is shorter) prior to randomization and for the duration of the study.
19. Pregnant or lactating women or patients not willing to apply highly effective contraception as defined in the protocol.
20. Current known infection with human immunodeficiency virus (HIV), 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 antibody [HBsAg] test and a positive hepatitis B core antibody [HBcAb] test, accompanied by a negative HBV DNA test) are eligible. Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. Any other active uncontrolled infection at the time of screening is not allowed.
21. Known substance abuse or any other concurrent severe and/or uncontrolled psychiatric or medical condition that would, in the Investigator's judgment, contraindicate patient participation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Interventional Arm 1; Patients will receive 345 mg of elacestrant and 7.5 mg of everolimus orally once daily. Patients will remain in treatment until disease progression, treatment discontinuation, the start of new anti-cancer treatment, withdrawal of consent, death, or EoS, whichever occurs first.	Drug: Auxiliary Medicinal Product - Dexamethasone; 10 mL of alcohol-free dexamethasone 0.5 mg per 5 mL mouthwashes (swish for 2 min and spit, four times daily for 8 weeks). After 8 weeks, dexamethasone mouthwash could be continued for up to eight additional weeks at the discretion of the clinician and patient. Used for prevention of treatment-induced stomatitis.; Drug: Auxiliary Medicinal Product - Luteinizing hormone-releasing hormone (LHRH) analogues; According to clinical practice (for premenopausal/perimenopausal patients and male patients in both treatment arms). Used to suppress estrogen production.; Drug: Everolimus; Patients will receive 7.5 mg of everolimus orally once daily.; Other Names: Afinitor; Certican; RAD001; Votubia; Zortress; Drug: Elacestrant; Patients will receive elacestrant 345 mg orally once daily; Other Names: RAD1901; ER-306323; Selective estrogen receptor degrader/selective estrogen receptor modulator (SERD/SERM) RAD1901
Active Comparator: Control Arm 2; Patients will receive elacestrant at (345 mg orally once daily) plus matched everolimus placebo. Patients will remain in treatment until disease progression, treatment discontinuation, the start of new anti-cancer treatment, withdrawal of consent, death, or EoS, whichever occurs first.	Drug: Auxiliary Medicinal Product - Dexamethasone; 10 mL of alcohol-free dexamethasone 0.5 mg per 5 mL mouthwashes (swish for 2 min and spit, four times daily for 8 weeks). After 8 weeks, dexamethasone mouthwash could be continued for up to eight additional weeks at the discretion of the clinician and patient. Used for prevention of treatment-induced stomatitis.; Drug: Auxiliary Medicinal Product - Luteinizing hormone-releasing hormone (LHRH) analogues; According to clinical practice (for premenopausal/perimenopausal patients and male patients in both treatment arms). Used to suppress estrogen production.; Drug: Placebo; Patients will receive placebo orally once daily; Drug: Elacestrant; Patients will receive elacestrant 345 mg orally once daily; Other Names: RAD1901; ER-306323; Selective estrogen receptor degrader/selective estrogen receptor modulator (SERD/SERM) RAD1901

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To demonstrate superiority of elacestrant+everolimus vs. elacestrant+placebo in prolonging PFS based on a BIRC in patients with ER[+]/HER2[-], ESR1-mutated, ABC that have previously received ET+CDK4/6i (all patients).	Progression Free Survival (PFS), defined as the period from randomization to the first occurrence of disease progression or death from any cause, whichever occurs first, as assessed by a Blinded Imaging Review Committee (BIRC) through the use of RECIST v.1.1.	Until disease progression, treatment discontinuation, the start of new anti-cancer treatment, withdrawal of consent, death, or EoS, whichever occurs first, assessed through study completion, an average of 12 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To compare overall survival (OS) between treatment groups, in all patients.	OS, defined as the period from randomization to death from any cause, as determined locally by the Investigator.	Until disease progression, treatment discontinuation, the start of new anti-cancer treatment, withdrawal of consent, death, or EoS, whichever occurs first, assessed through study completion, an average of 12 months.
To compare investigator-assessed PFS based on local assessment between treatment groups, in all patients.	Investigator-assessed PFS, defined as the period from randomization to the first occurrence of disease progression or death from any cause, whichever occurs first, as determined locally using RECIST v.1.1.	Until disease progression, treatment discontinuation, the start of new anti-cancer treatment, withdrawal of consent, death, or EoS, whichever occurs first, assessed through study completion, an average of 12 months.
To compare objective response rate (ORR) between treatment groups, in all patients.	ORR is defined as the rate of patients with a Best Overall Response (BOR) of complete response (CR) or partial response (PR) based on a BIRC and local Investigator assessment through the use of RECIST v.1.1.	Until disease progression, treatment discontinuation, the start of new anti-cancer treatment, withdrawal of consent, death, or EoS, whichever occurs first, assessed through study completion, an average of 12 months.
To compare clinical benefit rate (CBR) between treatment groups, in all patients.	CBR is defined as the rate of patients with an objective response (CR or PR), or stable disease for at least 24 weeks based on a BIRC and local Investigator assessment through the use of RECIST v.1.1.	Until disease progression, treatment discontinuation, the start of new anti-cancer treatment, withdrawal of consent, death, or EoS, whichever occurs first, assessed through study completion, an average of 12 months.
To compare overall time to response (TTR) between treatment groups, in all patients.	TTR is defined as the period from the randomization to time of the first objective tumor response (tumor shrinkage of ≥ 30%) observed for patients who achieved a BOR of CR or PR based on a BIRC and local Investigator assessment through the use of RECIST v.1.1.	Until disease progression, treatment discontinuation, the start of new anti-cancer treatment, withdrawal of consent, death, or EoS, whichever occurs first, assessed through study completion, an average of 12 months.
To compare duration of response (DoR) between treatment groups, in all patients.	DoR is defined as the period from the first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first, based on a BIRC and local Investigator assessment through the use of RECIST v.1.1.	Until disease progression, treatment discontinuation, the start of new anti-cancer treatment, withdrawal of consent, death, or EoS, whichever occurs first, assessed through study completion, an average of 12 months.
To compare best percentage of change in tumor burden between treatment groups, in all patients.	Best percentage of change from baseline in the size of target tumor lesions is defined as the biggest decrease, or smallest increase if no decrease will be observed, based on a BIRC and local Investigator assessment through the use of RECIST v.1.1.	Until disease progression, treatment discontinuation, the start of new anti-cancer treatment, withdrawal of consent, death, or EoS, whichever occurs first, assessed through study completion, an average of 12 months.
To describe the changes in health-related quality-of-life (HRQoL) from baseline using the EuroQoL 5 Dimension 5 Level (EQ-5D-5L) scale.	Changes from baseline in the EQ-5D-5L scale. The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels, indicating, from 1 to 5: no problems, slight problems, moderate problems, severe problems and extreme problems. The patient is asked to indicate their health state by ticking the box next to the most appropriate statement in each of the five dimensions. This decision results in a 1-digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5-digit number that describes the patient's health state.	Until disease progression, treatment discontinuation, the start of new anti-cancer treatment, withdrawal of consent, death, or EoS, whichever occurs first, assessed through study completion, an average of 12 months.
To describe the changes in HRQoL from baseline using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30).	Changes from baseline in the EORTC QLQ-C30 scale. All of the scales and single item measures range in score from 0 to 100. A high score for the functional scales and functional single items represents a high/healthy level of functioning, whereas a high score for the symptom scales and symptom item represents a high level of symptomatology or problems.	Until disease progression, treatment discontinuation, the start of new anti-cancer treatment, withdrawal of consent, death, or EoS, whichever occurs first, assessed through study completion, an average of 12 months.
To assess adverse events (AEs) between treatment groups in all patients.	Measures will include AEs and treatment-emergent AEs (TEAEs), including NCI CTCAE v5.0 severity grade and relationship to study drugs.	Until disease progression, treatment discontinuation, the start of new anti-cancer treatment, withdrawal of consent, death, or EoS, whichever occurs first, assessed through study completion, an average of 12 months.
To assess adverse events leading to study treatment withdrawal.	Measures will include deaths, serious adverse events (SAEs), and AEs leading to study treatment withdrawal.	Until disease progression, treatment discontinuation, the start of new anti-cancer treatment, withdrawal of consent, death, or EoS, whichever occurs first, assessed through study completion, an average of 12 months.
To assess adverse events leading to dose modification.	Measures will include dose interruption and reductions due to AEs.	Until disease progression, treatment discontinuation, the start of new anti-cancer treatment, withdrawal of consent, death, or EoS, whichever occurs first, assessed through study completion, an average of 12 months.
To assess the number of participants with abnormal hematology and/or chemistry values that are related to treatment.	Number of participants with treatment-related AEs as measured by laboratory parameters (hematology and chemistry) and assessed by NCI CTCAE v5.0 grade.	Until disease progression, treatment discontinuation, the start of new anti-cancer treatment, withdrawal of consent, death, or EoS, whichever occurs first, assessed through study completion, an average of 12 months.
To assess the number of participants with changes on vital signs and/or AEs that are related to treatment.	Number of participants with treatment-related changes on vital sign values as determined by respiratory rate, blood pressure (systolic and diastolic), pulse rate, and body temperature over time and assessed by NCI-CTCAE v.5.0.	Until disease progression, treatment discontinuation, the start of new anti-cancer treatment, withdrawal of consent, death, or EoS, whichever occurs first, assessed through study completion, an average of 12 months.
To assess the number of participants with changes on cardiac function measured by ECG QT Interval Corrected by Fridericia formula (QTcF) that are related to treatment effect .	Measurement of treatment-related changes in cardiac function measured by ECG QTcF over time.	Until disease progression, treatment discontinuation, the start of new anti-cancer treatment, withdrawal of consent, death, or EoS, whichever occurs first, assessed through study completion, an average of 12 months.
To assess the number of participants with changes on Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) that are related to treatment.	Measurement of treatment-related changes on patient's level of functioning in terms of their ability to care for themself, daily activity, and physical ability (walking, working, etc.), as measured with the ECOG PS scale over time.	Until disease progression, treatment discontinuation, the start of new anti-cancer treatment, withdrawal of consent, death, or EoS, whichever occurs first, assessed through study completion, an average of 12 months.
To describe the changes in HRQoL from baseline using the EORTC Quality of Life Questionnaire Breast Cancer module (EORTC QLQ-BR42).	Changes from baseline in the QLQ-BR42 scale. All of the scales and single item measures range in score from 0 to 100. A high score for the functional scales and functional single items represents a high/healthy level of functioning, whereas a high score for the symptom scales and symptom item represents a high level of symptomatology or problems.	Until disease progression, treatment discontinuation, the start of new anti-cancer treatment, withdrawal of consent, death, or EoS, whichever occurs first, assessed through study completion, an average of 12 months.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory endpoint: protein expression studies using blood samples to investigate the potential association with clinical outcomes.	Protein expression (IHC and proteomics) profiling analyses performed on blood samples to investigate the potential association with clinical outcomes.	Until disease progression, treatment discontinuation, the start of new anti-cancer treatment, withdrawal of consent, death, or EoS, whichever occurs first, assessed through study completion, an average of 12 months.
Exploratory endpoint: analysis of allele mutation frequencies in circulating tumor DNA (ctDNA) in blood samples to investigate the potential association with clinical outcomes.	Changes in biomarkers allele mutation frequencies in ctDNA in blood samples to investigate the potential association with clinical outcomes.	Until disease progression, treatment discontinuation, the start of new anti-cancer treatment, withdrawal of consent, death, or EoS, whichever occurs first, assessed through study completion, an average of 12 months.
Exploratory endpoint: Genetic studies using blood samples to investigate the potential association with clinical outcomes.	Gene expression profiling analyses performed on blood samples to investigate the potential association with clinical outcomes.	Until disease progression, treatment discontinuation, the start of new anti-cancer treatment, withdrawal of consent, death, or EoS, whichever occurs first, assessed through study completion, an average of 12 months.
Exploratory endpoint: Analysis of medical imaging (radiomics) to identify potential biomarkers associated with clinical outcomes.	Analysis of oncological biomarkers, such as growth rate of tumor derived by tumor growth rate modeling or tumor heterogeneity according to quantitative estimation performed on radiological images (radiomics) to investigate the potential association with clinical outcomes.	Until disease progression, treatment discontinuation, the start of new anti-cancer treatment, withdrawal of consent, death, or EoS, whichever occurs first, assessed through study completion, an average of 12 months.
Exploratory endpoint: Pharmacokinetic (PK) parameter of maximum (Peak) Observed Serum Concentration (Cmax).	Blood samples of 40 patients/arm will be collected for the determination of Maximum Serum Concentration (Cmax). Timeframe: samples will be collected in a subset of approximately 40 patients/arm at Cycle 1 Day 14 at pre-dose (within 1h prior to study drug administration) and between 2 and 6h post-dose. Trough concentrations (pre-dose within 1h prior to study drug administration) will be collected at Day 1 of Cycle 3 and Day 1 of the following cycles every 8 weeks (CXD1) in conjunction with tumor assessments when applicable. Additional blood samples (one timepoint) for PK analysis will be collected in case of significant AE or SAEs considered as potentially related to the study drug (the time of the last dose intake and the sampling time should be reported to allow the determination of the corresponding actual time after dose).	Until disease progression, treatment discontinuation, the start of new anti-cancer treatment, withdrawal of consent, death, or EoS, whichever occurs first, assessed through study completion, an average of 12 months.
Exploratory endpoint: Pharmacokinetic (PK) parameter of Plasma Through Concentration (Ctrough).	Blood samples of 40 patients/arm will be collected for the determination of Minimum Concentration (Plasma trough concentration [Ctrough]). Timeframe: samples will be collected in a subset of approximately 40 patients/arm at Cycle 1 Day 14 at pre-dose (within 1h prior to study drug administration) and between 2 and 6h post-dose. Trough concentrations (pre-dose within 1h prior to study drug administration) will be collected at Day 1 of Cycle 3 and Day 1 of the following cycles every 8 weeks (CXD1) in conjunction with tumor assessments when applicable. Additional blood samples (one timepoint) for PK analysis will be collected in case of significant AE or SAEs considered as potentially related to the study drug (the time of the last dose intake and the sampling time should be reported to allow the determination of the corresponding actual time after dose).	Until disease progression, treatment discontinuation, the start of new anti-cancer treatment, withdrawal of consent, death, or EoS, whichever occurs first, assessed through study completion, an average of 12 months.

Collaborators and Investigators

• Sponsor: MedSIR
• Collaborators: Stemline Therapeutics, Inc.
• Investigators: Principal Investigator: Javier Cortés, M.D., Ph.D., IOB Institute of Oncology, Quironsalud Group, Madrid & Barcelona, Spain; Principal Investigator: Antonio Llombart-Cussac, M.D., Ph.D., Arnau de Vilanova Hospital, Valencia, Spain; Principal Investigator: José Pérez-García, M.D., Ph.D., International Breast Cancer Center, Barcelona, Spain

Study record dates

Study Major Dates

• Study Start (Actual): December 5, 2024
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): April 1, 2028

Study Registration Dates

• First Submitted: April 5, 2024
• First Submitted That Met QC Criteria: April 18, 2024
• First Posted (Actual): April 24, 2024

Study Record Updates

• Last Update Posted (Actual): April 3, 2026
• Last Update Submitted That Met QC Criteria: March 30, 2026
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: ER-positive; HER22-negative; ESR1-mutation; CDK4/6-inhibitor; Selective endocrine receptor degrader (SERD)
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Estrogen Receptor Modulators; Pituitary Hormone-Releasing Hormones; Hypothalamic Hormones; Peptide Hormones; Neuropeptides; Peptides; Amino Acids, Peptides, and Proteins; Oligopeptides; Nerve Tissue Proteins; Proteins; Organic Chemicals; Pharmacologic Actions; Chemical Actions and Uses; Macrolides; Lactones; Sirolimus; Everolimus; Selective Estrogen Receptor Modulators; Gonadotropin-Releasing Hormone; elacestrant; RAD1901
• Other Study ID Numbers: MedOPP545; 2024-512926-27-00 (Ctis)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No