IRB Study Number 25-212
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objective:
• Evaluate the efficacy of elacestrant relative to standard endocrine therapy in terms of IBCFS in participants with node-positive, estrogen receptor-positive, HER2-negative early breast cancer with high risk of recurrence.
Key Secondary Objectives:
• Evaluate the efficacy of elacestrant relative to standard of care (SoC) in terms of distant relapse-free survival (DRFS).
• Evaluate the efficacy of elacestrant relative to SoC in terms of overall survival (OS).
Secondary Objectives:
• Evaluate the efficacy of elacestrant relative to SoC in terms of invasive disease-free survival (IDFS).
• Characterize the safety of elacestrant in the trial patient population.
• Evaluate the effect of elacestrant relative to SoC on patient-reported outcomes (PROs).
• Characterize elacestrant steady-state pharmacokinetics (PK) and exposure-response relationships (efficacy and safety) in a subset of participants enrolled in the elacestrant arm at United States (US) clinical sites.
Inclusion Criteria
Participant has signed the informed consent before any study-specific activities according to local guidelines and is able to follow the study schedule during treatment and follow-up.
Adult women or men aged ≥18 years old, or older if required by local regulations, at the time of informed consent signature.
Histopathologically or cytologically confirmed ER-positive (≥ 10% by immunohistochemistry [IHC]), HER2-negative [IHC = 0 or 1, or (IHC = 2 and ISH-negative)] on tumor biopsy or final surgical pathology specimen early stage resected invasive breast cancer without evidence of recurrence or distant metastases, per local laboratory, according to the ASCO/College of American Pathologists (CAP) guidelines (Allison et al, 2020, Wolff et al, 2018).
Participants considered at high risk of recurrence defined, at initial staging, as:
a. ≥ 4 positive axillary lymph nodes or
b. 1-3 positive axillary lymph nodes and
▪ Histologic grade 3 disease or
▪ Tumor size ≥ 5 cm.
- Participants who have received at least 24 months but not more than 60 months of endocrine therapy (AIs or tamoxifen) with or without a CDK4/6i and with or without an LHRH agonist. Participants who received prior CDK4/6i or a poly ADP-ribose polymerase (PARP) inhibitor must have already completed or discontinued these treatments. Notes:
▪ Toxicity from prior therapy must be resolved to NCI CTCAE v5.0 Grade ≤ 1. Grade < 2 peripheral neuropathy, arthralgia, or other toxicities not considered a safety risk for the participant per the investigator's judgment will also be deemed eligible for the study.
▪ A washout period prior to randomization is not required as the likelihood of drug-drug interaction between elacestrant and anastrozole, letrozole, exemestane or tamoxifen is low.
▪ A washout period prior to randomization of 7 days is recommended for CDK4/6i or poly(ADP-ribose) polymerase (PARP) inhibitor therapies.
- Participants are to be between 2 to 6 years from the date of curative surgical resection.
Note: Participants who were diagnosed with multicentric and/or bilateral breast cancer either simultaneously or with 6 months of each other are allowed and the date of curative surgery will be the date of removal of the most recent tumor. However, all tumors need to meet the ER-positive/HER2-negative histopathological criteria, per inclusion criterion #3.
• The participant must have undergone adequate definitive surgery of the primary breast tumor(s). If more than one surgery was performed, the date of the most recent surgery will be considered the date of ‘curative’ surgery. Participants with no primary tumor identified (Tx) are eligible as long as other inclusion criteria including positive axillary lymph nodes (inclusion criterion #4) are present with full axillary dissection complete (radiation therapy as per local guidelines).
• Except for the situations described below, the margins of the resected specimen must have been histologically free of invasive tumor and/or a component of ductal carcinoma in situ (DCIS) as determined by the local pathologist. If pathologic examination demonstrated tumor at the line of resection, additional excisions performed to obtain clear margins are acceptable. If tumor was still present at the resected margin after re-excision(s), the participant must have undergone mastectomy to be eligible. Of note, participants with margins positive for lobular carcinoma in situ (LCIS) are eligible without additional resection.
• For participants who have undergone mastectomy or wide local excision where a deep margin abuts the pectoralis fascia, participants with microscopic positive margins are eligible if radiation therapy of the chest wall was administered prior to study entry. Participants with positive anterior margins may be eligible if no gross disease was left behind (radiation therapy as per local guidelines).
• Where surgical excision of involved supraclavicular or internal mammary nodes was not feasible, residual nodes should have been irradiated in accordance with standard guidelines.
• If given, radiation therapy (for example, post-mastectomy or post-lumpectomy) should have been administered according to standard guidelines.
- Female participants may be either postmenopausal, premenopausal, or perimenopausal. Postmenopausal status is defined by:
a. Age ≥ 60 years
b. Age < 60 years and amenorrhea for 12 or more months (without an alternative cause, including current LHRH agonist therapy) and follicle-stimulating hormone (FSH) value and an estradiol value in the postmenopausal ranges per local reference ranges.
c. Documentation of bilateral oophorectomy or ovarian ablation, at least 1 month before first dose of study therapy.
Premenopausal women, perimenopausal women, and men will be administered a LHRH agonist. If a participant is not currently receiving LHRH agonist, then LHRH agonist will need to be administered at least 28 days prior to the start of study treatment. See the Schedule of Assessments (Table 12, Section 3.11.1) for more details. Subsequent LHRH administration will be according to local prescribing information.
Notes:
▪ Monthly LHRH agonist formulation is preferred. If a 3-monthly LHRH agonist formulation is used, FSH must be within postmenopausal levels at baseline and monitored every 3 months after randomization while the participant is receiving study therapy.
▪ For premenopausal and perimenopausal women, a negative serum pregnancy test must be documented within 7 days prior to randomization. There is no need to repeat the test on Day 1 of Cycle 1 if performed within 72 hours of that visit.
Male participants receiving treatment with an AI or with elacestrant must receive an LHRH agonist. If the participant is not currently on LHRH agonist, LHRH agonist will need to be administered at least 28 days prior to the start of study treatment.
Participant is considered a candidate for an additional 5 years of endocrine therapy.
Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
Participant has adequate bone marrow and organ function, as defined by the following laboratory values:
a. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L
b. Platelets ≥ 100 × 109/L
c. Hemoglobin ≥ 9.0 g/dL
d. Potassium, sodium, and calcium (corrected for serum albumin) of CTCAE Grade ≤ 1
e. Serum creatinine below the local institutional upper limit of normal OR
Cockcroft-Gault based creatinine clearance ≥ 30 mL/min:
▪ Creatinine clearance (male) = ([140-age in years] × weight in kg)/([serum creatinine in mg/dL] × 72)
▪ Creatinine clearance (female) = (0.85 × [140-age in years] × weight in kg)/([serum creatinine in mg/dL] × 72)
▪ For participants ≤ 50 kg, urine creatinine value ≥ 500 mg/day (4,420 mmol/day), based on a 24-hour collection is acceptable.
f. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 1.5× upper limit of normal (ULN).
g. Total serum bilirubin < 1.5 × ULN, except for participants with Gilbert’s syndrome who may be included if the total serum bilirubin is ≤ 2.5 × ULN.
The participant is able and willing to adhere to the study visit schedule and other protocol requirements.
The participant is able to swallow oral medications.
Exclusion Criteria
Participants with inflammatory breast cancer.
Participants with stage IV metastatic breast cancer.
History of any prior (ipsilateral and/or contralateral) invasive breast cancer with the exception of ipsilateral DCIS treated by local regional therapy alone ≥ 5 years ago or contralateral DCIS treated by local regional therapy at any time.
Participant with history of malignancy within 3 years of the date of randomization, except for adequately treated basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix.
Participants who have had more than a 6-month continuous interruption of prior SoC adjuvant endocrine therapy or who discontinued adjuvant endocrine therapy more than 6 months prior to randomization.
Uncontrolled significant active infections that in the opinion of the investigator would prevent the participant from participating in this study.
Major surgery within 4 weeks of starting study therapy.
Pregnant and breastfeeding women are excluded from the study. In addition, women of childbearing potential are excluded who:
• Within 28 days before starting study therapy did not use a highly effective method of contraception.
• Do not agree to use a highly effective method of contraception (Appendix E) or abstain from heterosexual intercourse throughout the entire study period and for 120 days after study therapy discontinuation.
Participants who do not agree to abstain from donating or freezing sperm or ova, or who do not use a highly effective method of contraception (Appendix E), during the treatment period and for 120 days thereafter the last dose of study treatment.
Known intolerance to any of the study drugs or any of the excipients.
Participant has received, or is currently receiving any of the following medications prior to the first dose of study therapy:
a. Investigational anticancer therapy within 28 days prior to initiation of study treatment or is currently enrolled in any other type of medical research judged by the Sponsor not to be scientifically or medically compatible with the study.
b. Known strong or moderate inducers or inhibitors of cytochrome P450 (CYP) 3A4 (including foods and herbal preparations) within 14 days or 5 half-lives, whichever is shorter, prior to initiating study therapy (refer to Section 5.8.3).
c. Herbal preparations/medications (which are not strong or moderate inducers or inhibitors of CYP3A4). These include, but are not limited to, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng within 7 days prior to initiating study therapy.
- Any preexisting or current medical or other condition (including alcohol or drug abuse) that in the opinion of the investigator(s) would preclude the participant from participating in this study.
