Overview
PREMIERE parallel, non-comparative, two-arm, randomized 1:1, open-label, multicenter, exploratory window of opportunity study in premenopausal women with primary operable HR+/HER2-negative breast cancer with aiming at evaluating the biological effects of elacestrant with or without triptorelin.
Description
PremiÈRe is a 4-week preoperative WOO randomized 2-arms study with a full program in correlative science, including an accurate estradiol measurement to evaluate the efficacy and biological activity of elacestrant in premenopausal patients with and without OFS (elacestrant 400mg per day during 28 days vs elacestrant at 400 mg per day during 28 days plus triptorelin 3.75mg i.m). Biological information (by tumor biopsy and /or blood sample) will be obtained at baseline, on day 14 (only blood) and day 28 post-treatment. Endpoints as rate of CCCA, mean reduction of Ki67 and estrogen-sensitive signature, allowing comparison of elacestrant activity across populations with and without OFS. Regarding the main objective, rate of CCCA, and considering the eligible population (ki67 between 10-35%) and unpublished data from ELIPSE study we estimate around a 20% of CCCA in all randomized patients. It's worthy to mention that a study using triptorelin as GnRH analog and GCMSMS for E2 measurement showed that nearly all women at day 14 (24 of out 26) had E2 levels in the postmenopausal range26, allowing us to compare groups with and without OFS at that early time-point.
Eligibility
Inclusion Criteria:
- Signed informed consent must be obtained prior to any trial-specific procedure.
- Female patients who are at least 35 years of age on the day of signing informed consent.
- Patient is premenopausal at the time of study entry
Premenopausal status is defined as either:
- Patient had last menstrual period within the last 6 months. OR
- Plasma estradiol and FSH in the premenopausal range, according to local laboratory definition.
Note: Patients who have undergone bilateral oophorectomy are not eligible.
4. Histologically confirmed non-metastatic primary invasive adenocarcinoma of the breast
untreated and recently diagnosed, with all the following characteristics:
- Stage I to stage IIB operable breast cancer (7th Edition of the AJCC). Note:
Axillary lymph node status must be assessed by fine needle biopsy or core biopsy.
This procedure at screening will be omitted if there is no suspicion for positive
axillary lymph node(s) radiographically or if a pathological report of suspicious
lymph nodes of the results of a fine needle biopsy or core biopsy is available
prior to the screening period.
- Absence of distant metastasis (i.e., M0) as determined by institutional practice.
- At least 1 lesion that can be accurately and serially measured in at least 1
dimension and for which the longest diameter is ≥ 10 mm as measured by magnetic
resonance imaging (MRI) or ultrasound (US).
- In the case of a multifocal tumor, the largest lesion must be ≥ 10 mm and
designated the "target" lesion for all subsequent tumor evaluations. All biopsied
tumors had to be ER+HER2-negative
5. ER-positive with expression higher than 10% and HER2-negative tumor
- HER2 negativity is defined as either of the following: Immunohistochemistry (IHC)
0, IHC 1+ or IHC2+/in situ hybridization (ISH) negative as per most recent
American Society of Clinical Oncology (ASCO)-College of American Pathologists
Guideline (CAP) guideline according to the local laboratory as determined on the
most recently analyzed tissue sample.
- Documentation of ER positive tumor with ≥ 10% staining by immunohistochemistry of
cells as per most recent ASCO-CAP guideline according to the local laboratory
determined on the most recently analyzed tissue sample, with or without
progesterone receptor positivity.
6. Ki67 expression ≥ 10% and ≤ 35% by local assessment
7. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
8. Breast cancer eligible for primary surgery.
9. Availability of pre-treatment tumor tissue sample of FFPE tumor block from primary
tumor for biomarker analysis. The tumor tissue should be of good quality based on
total and viable tumor content and must be evaluated centrally for quality prior to
enrollment. Archival tumor tissue or ex professo biopsy are acceptable.
10. Adequate hematologic and organ function within 14 days before the first study
treatment on Day 1, defined by the following:
1. Neutrophils (ANC ≥1.000/μL).
2. Hemoglobin ≥ 9.0 g/dL (with no need for transfusions).
3. Platelet count ≥ 75. 000/μL.
4. Serum creatinine ≤1.5 mg/dL or calculated creatinine clearance ≥30 mL/min
(Cockcroft-Gault Equation)
5. International normalized ratio (INR) or prothrombin time (PT) ≤1.5 × ULN and
activated partial thromboplastin time (aPTT) within therapeutic range.
Note: Subjects who are receiving anticoagulation treatment which is monitored by
INR (eg, warfarin) may be allowed to participate if they have a stable INR (ie,
within therapeutic range) for at least 28 days prior to the first dose of study
drug, in the absence of any exclusionary medical conditions, and provided that
elacestrant would be appropriate therapy for the subject
6. Potassium, total Calcium (corrected for serum albumin), and sodium NCI CTCAE v5.0
Grade ≤ 1.
7. Alanine aminotransferase (ALT) ≤ 3x upper limit of normal (ULN)
8. Aspartate aminotransferase (AST) ≤ 3x ULN
9. Total bilirubin ≤ ULN or total bilirubin ≤ 1.5x ULN with direct bilirubin ≤ ULN
of the laboratory in subjects with documented Gilbert's Syndrome
11. Patient must be willing and able to comply with scheduled visits, treatment plans,
laboratory tests, and other trial procedures.
12. Women of childbearing potential (CBP), defined as all women physiologically capable of
becoming pregnant, must have confirmed negative serum pregnancy test within 7 days
prior to randomization.
13. Female subjects must not donate, or retrieve for their own use, oocytes from the time
of screening and throughout the study treatment period, and for at least 120 days
after the time of final study drug administration.
14. Women of CBP must be willing to use highly effective methods of contraception.
Contraception must continue during the trial treatment and after stopping the
treatment received according to protocol. Highly effective contraception methods
include:
- Total abstinence (when this is in line with the preferred and usual lifestyle of
the patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal,
post-ovulation methods) and withdrawal are not acceptable methods of
contraception.
- Placement of a non-hormonal intrauterine device (IUD). Notes: Use of oral
(estrogen and progesterone), transdermal, injected, implanted, hormone containing
intrauterine system, or any other hormonal methods of contraception is not
allowed in this trial. Women are considered of CBP unless: they have had ≥ 12
months of natural (spontaneous) amenorrhea with an appropriate clinical profile
(i.e., age-appropriate history of vasomotor symptoms) or have had surgical
bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or
tubal ligation at least four weeks prior to randomization. In the case of
oophorectomy alone, only when the reproductive status of the woman has been
confirmed by follow-up hormone level assessment, she will be considered not of
CBP. After the end of trial treatment, patients should use effective
contraception at least until 28 days after therapy discontinuation.
15. Patients must have the ability to swallow oral medication.
Exclusion Criteria:
1. Inoperable locally advanced or inflammatory breast cancer (any stage III).
2. Metastatic (Stage IV) breast cancer.
3. Synchronous invasive bilateral or multicentric breast cancer.
4. Patients requiring immediate neoadjuvant chemotherapy or immediate surgical
intervention.
5. Patients who have undergone sentinel lymph node biopsy or tumor excisional biopsy
prior to study treatment.
6. Prior malignancy within 3 years prior to randomization, except curatively treated
non-melanoma skin cancer, in situ cancer or adequately and curatively treated Stage I
or II cancer from which the patient is currently in complete remission.
7. Patients currently on following medications, which cannot be interrupted 7 days prior
treatment start:
- Any prohibited medication as per decapeptyl (triptorelin) label
- Strong inhibitors of CYP3A4, including grapefruit, grapefruit hybrids, pummelos,
starfruit and Seville oranges
- Known strong or moderate inducers or inhibitors of cytochrome P450 (CYP) 3A4
(Refer to http://medicine.iupui.edu/clinpharm/ddis/) within 5 half-life of the
drug prior to initiating trial therapy
- Herbal preparations/medications. These include, but are not limited to, St.
John's wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone
(DHEA), yohimbe, saw palmetto, and ginseng within 5 half-life of the drug prior
to initiating trial therapy
- Vaccination, including but not limited to vaccination against COVID-19, during
the 7 days prior to randomization.
8. Any treatment, local or systemic, including prior chemotherapy, ET, targeted therapy,
and/or radiation therapy for the currently diagnosed BC prior to enrollment.
9. Major surgical procedure or significant traumatic injury within 28 days prior to
randomization.
10. Assessment by the investigator to be unable or unwilling to comply with the
requirements of the protocol.
11. Any of the following within 6 months before enrollment: myocardial infarction,
severe/unstable angina, ongoing cardiac dysrhythmias of NCI CTCAE v5.0 Grade ≥ 2,
prolonged QTcF ≥ Grade 2 (i.e., > 480 msec), uncontrolled atrial fibrillation of any
grade, coronary/peripheral artery bypass graft, heart failure ≥ Class II as defined by
the New York Heart Association guidelines, or cerebrovascular accident including
transient ischemic attack.
12. Child-Pugh Score greater than Class A (i.e., score >6)
13. Coagulopathy or any history of coagulopathy within the past 6 months, including
history of deep vein thrombosis or pulmonary embolism. However, subjects with the
following conditions will be allowed to participate:
1. Adequately treated catheter-related venous thrombosis occurring >28 days prior to
the first dose of study drug
2. Treatment with an anticoagulant, e.g., warfarin or heparin, for a thrombotic
event occurring > 6 months before enrollment, or for an otherwise stable and
allowed medical condition (eg, well controlled atrial fibrillation), provided
dose and coagulation parameters (as defined by local standard of care) are in
therapeutic range prior to the first dose of study drug and provided that an AI
would be an appropriate therapy for the subject
14. Known hypersensitivity to any of the study drugs, including excipients.
15. Known difficulty in tolerating oral medications or conditions which would impair
absorption of oral medications such as: uncontrolled nausea or vomiting (i.e., CTCAE ≥
Grade 3 despite antiemetic therapy), ongoing gastrointestinal obstruction/motility
disorder, malabsorption syndrome, or prior gastric bypass.
16. History of or clinical evidence of significant co-morbidities that, in the judgment of
the investigator, may interfere with the conduction of the study, the evaluation of
response, or with informed consent.
17. Previous hormonal treatments for other indications such as osteoporosis, breast cancer
prevention, hormonal substitutive therapy, such as raloxifene, tamoxifen, estrogen,
progestins must have ended at least 12 months prior to trial registration. If a
patient is on natural products known to contain progestins, they must be stopped 14
days prior to beginning study treatment.
18. Used any prescription medication during the prior 1 month that the investigator judge
is likely to interfere with the study or to pose an additional risk to the patient in
participating.
19. Female subject who is pregnant or breastfeeding or intends to become pregnant during
the study.