A randomized phase 3, double-blind, placebo-controlled study of elacestrant plus everolimus versus elacestrant in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative, ESR1-mutated, advanced breast cancer progressing to endocrine therapy and CDK4/6 inhibitors - The ADELA study-

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Medica Scientia Innovation Research S.L., Medica Scientia Innovation Research S.L., Stemline Therapeutics Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

12 Dec 2024 → ongoing

Decision date (initial)

2024-12-02

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Berlin-Chemie AG

External identifiers

EU CT number

2024-512926-27-00

ClinicalTrials.gov

NCT06382948

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To demonstrate that elacestrant plus everolimus compared with elacestrant
plus placebo is superior in prolonging progression-free survival (PFS) based
on a Blinded Imaging Review Committee (BIRC) in patients with
ER[+]/HER2[-], ESR1-mutated, ABC that have previously received
endocrine therapy in combination with a CDK4/6 inhibitor (all patients).

Secondary objectives 6

1. To compare Investigator-assessed PFS based on local assessment between treatment groups in all patients.
2. To compare overall survival (OS) between treatment groups in all patients.
3. To compare objective response rate (ORR), clinical benefit rate (CBR), time to response (TTR), duration of response (DoR), and best percentage of change in tumor burden based on a BIRC between treatment groups in all patients.
4. To compare ORR, CBR, TTR, DoR, and best percentage of change in tumor burden based on local Investigator assessment between treatment groups in all patients.
5. To compare the safety profile and tolerability between treatment groups in all patients.
6. To describe the changes in health-related quality-of-life (HRQoL) assessments from baseline using the EuroQoL 5 Dimension 5 Level (EQ5D-5L), the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and EORTC Breast Cancer–Specific Quality of Life Questionnaire (EORTC QLQ-BR42) between treatment groups in all patients.

Conditions and MedDRA coding

patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative, ESR1-mutated, advanced breast cancer progressing to endocrine therapy and CDK4/6 inhibitors.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 19

1. Patient or his/her legal representative 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 postmenopausal 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: o Age ≥ 60 years; o 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; o 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 mutation determined before randomization using Guardant360® CDx-CGP panel (Guardant Health) test. Note: Patients with previously determined ESR1 mutation using appropriately validated tests (such as 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, PROTAC, CERAN, or novel SERM, and/or PI3K/AKT/mTOR inhibitors, including everolimus, for advanced disease are permitted. Note: Fulvestrant is permitted if treatment was 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 lyticblastic 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: o 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. o 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). o Renal: Serum creatinine ≤ 1.5 x ULN or estimated creatinine clearance ≥ 50 mL/min as calculated by Cockcroft- Gault equation. o 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/freezing 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 21

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 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 anti-convulsants 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, nonmelanoma 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: o 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 QTcF (> 480 msec).
14. Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited, to any of the following: o Massive lung metastatic involvement (e.g., pleural effusion, lymphangitic carcinomatosis, etc.). o Any underlying pulmonary disorder (e.g., severe asthma, severe chronic obstructive pulmonary disease [COPD], restrictive lung disease, post COVID-19 pulmonary fibrosis, etc.). o Any autoimmune, connective tissue, or inflammatory disorders with pulmonary involvement (e.g., rheumatoid arthritis, Sjogren's syndrome, sarcoidosis, etc.). o 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: o Adequately treated catheter-related venous thrombosis occurring more than 28 days prior to randomization. o 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 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 halflives 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 antigen [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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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 BIRC through the use of RECIST v.1.1.

Secondary endpoints 9

1. 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 through the use of RECIST v.1.1.
2. OS, defined as the period from randomization to death from any cause, as determined locally by the Investigator.
3. ORR, 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.
4. CBR, 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.
5. TTR, defined as the period from 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.
6. 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, based on a BIRC and local Investigator assessment through the use of RECIST v.1.1.
7. 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, based on a BIRC and local Investigator assessment through the use of RECIST v.1.1.
8. Safety and tolerability, assessed by adverse events (AEs), treatmentemergent adverse events (TEAEs), serious adverse events (SAEs), dose modifications, clinical laboratory parameters (i. e., hematology, chemistry, lipid panel, and coagulation), electrocardiograms (ECGs), performance status, and vital signs.
9. Changes from baseline in EuroQoL 5 Dimension 5 Level (EQ-5D-5L), the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the EORTC Breast Cancer-Specific Quality of Life Questionnaire (EORTC QLQ-BR42) scales, and symptoms scores

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Placebo 1

Auxiliary 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Medica Scientia Innovation Research S.L.

Sponsor organisation

Medica Scientia Innovation Research S.L.

Address

Carrer De Pere IV 128 3rd Floor

City

Barcelona

Postcode

08005

Country

Spain

Medica Scientia Innovation Research S.L.

Sponsor organisation

Medica Scientia Innovation Research S.L.

Address

Carrer De Pere IV 128 3rd Floor

City

Barcelona

Postcode

08005

Country

Spain

Scientific contact point

Organisation

Medica Scientia Innovation Research S.L.

Contact name

Chief Scientific Oficcer

Public contact point

Organisation

Medica Scientia Innovation Research S.L.

Contact name

Trial & Client

Third parties 1

Stemline Therapeutics Inc.

Sponsor organisation

Stemline Therapeutics Inc.

Address

750 Lexington Avenue

City

New York

Postcode

10022-1200

Country

United States

Scientific contact point

Organisation

Stemline Therapeutics Inc.

Contact name

Leo Nicacio, MD

Public contact point

Organisation

Stemline Therapeutics Inc.

Contact name

Clinical team and Clinical Development

Locations

7 EU/EEA countries · 97 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 59 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

9 submissions — initial application plus substantial / non-substantial modifications