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

Plain English Summary

Elacestrant + Everolimus in Patients ER+/HER2-, ESR1mut, Advanced Breast Cancer Progressing to ET and CDK4/6i. is a Phase 3 clinical trial sponsored by MedSIR studying Advanced Breast Cancer, ER-positive Breast Cancer, HER2-negative Breast Cancer, ESR1 Gene Mutation. This trial tests if a combination of elacestrant and everolimus is more effective than elacestrant alone in treating advanced breast cancer. It is for patients with ER+/HER2- advanced breast cancer that has a specific ESR1 gene mutation and has progressed after standard endocrine therapy and CDK4/6 inhibitors. Participants will receive either elacestrant plus everolimus or elacestrant plus a placebo, assigned randomly. Alternative treatments for this type of advanced breast cancer may include other targeted therapies or chemotherapy, depending on prior treatments and disease characteristics. The trial aims to enroll 240 participants.

Official Summary

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.

Who Can Participate

Here is what you need to know about eligibility for this trial. Patients must have ER-positive, HER2-negative advanced breast cancer with an ESR1 gene mutation. The cancer must have progressed despite treatment with endocrine therapy and CDK4/6 inhibitors. Patients must be at least 18 years old and have adequate organ and bone marrow function. Individuals who have previously received certain types of targeted therapies for advanced disease, or chemotherapy for advanced disease, may not be eligible. This trial is studying Advanced Breast Cancer, ER-positive Breast Cancer, HER2-negative Breast Cancer, ESR1 Gene Mutation, so participants generally need a confirmed diagnosis. The trial is currently accepting new participants.

What They're Measuring

The primary outcome measures how long patients live without their cancer getting worse, which means it assesses how well the new combination treatment controls the disease. The specific primary outcome measures are: 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). (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.). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 3, the final and most rigorous stage before seeking FDA approval. Phase 3 trials involve 300-3,000+ patients across multiple sites and compare the new treatment directly against the current standard of care. These pivotal trials generate the evidence needed for regulatory review. About 58% of Phase 3 drugs receive FDA approval. Successful Phase 3 results typically lead to a New Drug Application submission.

Why This Trial Matters

This trial addresses a critical need for new treatments in advanced breast cancer that has become resistant to current therapies, specifically targeting a common resistance mechanism. As a Phase 3 trial, positive results could directly lead to FDA approval, making this treatment available to the broader patient population. This research targets Advanced Breast Cancer, ER-positive Breast Cancer, HER2-negative Breast Cancer, ESR1 Gene Mutation, where improved treatment options are needed.

Investor Insight

This trial targets a specific subtype of advanced breast cancer, representing a significant market opportunity for novel therapies, with a moderate probability of approval if the combination shows cle Phase 3 trials have approximately a 50-60% chance of gaining FDA approval if they reach this stage.

Is This Trial Right for Me?

Ask your doctor about the specific genetic mutations in your cancer and if this trial is a suitable option for you. Participation involves regular clinic visits for treatment, monitoring, and tests to assess your cancer's response and any side effects. You will be randomly assigned to one of two treatment groups, and neither you nor your doctor will know which treatment you are receiving until the study is over. This trial is currently recruiting participants. The trial is being conducted at 20 sites. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: DOUBLE
• Enrollment: 240 participants

Interventions

• DRUG: Everolimus — Patients will receive 7.5 mg of everolimus orally once daily.
• DRUG: Elacestrant — Patients will receive elacestrant 345 mg orally once daily
• DRUG: Placebo — Patients will receive placebo orally once daily
• 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.

Primary Outcomes

• 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). (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 Outcomes

• To compare overall survival (OS) between treatment groups, in all patients. (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. (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. (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. (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. (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.)

Full Eligibility Criteria

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

Trial Locations

• Medizinische Universität Innsbruck, Innsbruck, Austria
• Ordensklinikum Linz Barmherzige Schwestern, Linz, Austria
• Ordination Priv.-Doz. Dr. Michael Hubalek, Schwaz, Austria
• Medical University of Vienna, Vienna, Austria
• Tacchini Instituto de Pesquisa, Bento Gonçalves, Brazil
• Hospital Cachoeiro de Itapemirim, Cachoeiro de Itapemirim, Brazil
• Catarina Pesquisa Clínica - Neoplasias Litoral, Itajaí, Brazil
• UPCO - Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil
• NOB Ondina, Salvador, Brazil
• Masaryk Memorial Cancer Institute, Brno, Czechia
• ...and 10 more locations

Frequently Asked Questions

Related Conditions

• Advanced Breast Cancer
• ER-positive Breast Cancer
• HER2-negative Breast Cancer
• Hormone Receptor-Positive Breast Cancer
• Metastatic Breast Cancer
• Endocrine Therapy Resistance
• CDK4/6 Inhibitor Resistance
• ESR1 Gene Mutations in Cancer
• Oncology
• Targeted Cancer Therapy

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