Trial Title:
Elacestrant + Everolimus in Patients ER+/HER2-, ESR1mut, Advanced Breast Cancer Progressing to ET and CDK4/6i.
NCT ID:
NCT06382948
Condition:
Advanced Breast Cancer
ER-positive Breast Cancer
HER2-negative Breast Cancer
ESR1 Gene Mutation
Conditions: Official terms:
Breast Neoplasms
Dexamethasone
Everolimus
Hormones
Prolactin Release-Inhibiting Factors
Estrogens
Selective Estrogen Receptor Modulators
Estrogen Receptor Modulators
Conditions: Keywords:
ER-positive
HER22-negative
ESR1-mutation
CDK4/6-inhibitor
Selective endocrine receptor degrader (SERD)
Study type:
Interventional
Study phase:
Phase 3
Overall status:
Not yet recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Intervention model description:
Double-blind, parallel group (two arms: elacestrant plus everolimus, and elacestrant plus
placebo).
Primary purpose:
Treatment
Masking:
Double (Participant, Investigator)
Masking description:
A blinded, independent IRC will perform a review of radiographic images and clinical
information collected on study to determine the protocol-defined endpoints of disease
response and progression. Further information on the independent review process will be
provided in the BIRC Charter.
Intervention:
Intervention type:
Drug
Intervention name:
Everolimus
Description:
Patients will receive 7.5 mg of everolimus orally once daily.
Arm group label:
Interventional Arm 1
Other name:
Zortress
Other name:
Votubia
Other name:
RAD001
Other name:
Certican
Other name:
Afinitor
Intervention type:
Drug
Intervention name:
Elacestrant
Description:
Patients will receive elacestrant 345 mg orally once daily
Arm group label:
Control Arm 2
Arm group label:
Interventional Arm 1
Other name:
ER-306323
Other name:
RAD1901
Other name:
Selective estrogen receptor degrader/selective estrogen receptor modulator (SERD/SERM) RAD1901
Intervention type:
Drug
Intervention name:
Placebo
Description:
Patients will receive placebo orally once daily
Arm group label:
Control Arm 2
Intervention type:
Drug
Intervention name:
Auxiliary Medicinal Product - Dexamethasone
Description:
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.
Arm group label:
Control Arm 2
Arm group label:
Interventional Arm 1
Intervention type:
Drug
Intervention name:
Auxiliary Medicinal Product - Luteinizing hormone-releasing hormone (LHRH) analogues
Description:
According to clinical practice (for premenopausal/perimenopausal patients and male
patients in both treatment arms). Used to suppress estrogen production.
Arm group label:
Control Arm 2
Arm group label:
Interventional Arm 1
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.
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.
Criteria for 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 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.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Start date:
September 1, 2024
Completion date:
April 2028
Lead sponsor:
Agency:
MedSIR
Agency class:
Other
Collaborator:
Agency:
Stemline Therapeutics, Inc.
Agency class:
Other
Source:
MedSIR
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06382948
