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.
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.
Female or male patients ≥ 18 years of age at the time of signing ICF.
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.
Age ≥ 60 years;
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).
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.
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.
ECOG performance status of 0-1.
Parallel
Everolimus
DrugPatients will receive 7.5 mg of everolimus orally once daily.
Elacestrant
DrugPatients will receive elacestrant 345 mg orally once daily
Placebo
DrugPatients will receive placebo orally once daily
Auxiliary Medicinal Product - Dexamethasone
Drug10 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.
Auxiliary Medicinal Product - Luteinizing hormone-releasing hormone (LHRH) analogues
DrugAccording to clinical practice (for premenopausal/perimenopausal patients and male patients in both treatment arms). Used to suppress estrogen production.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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MedSIR
Lead sponsor
Stemline Therapeutics, Inc.
Collaborator