Phase II, multicenter, randomized, open-label study of premenopausal women with luminal breast cancer investigating the effect of elacestrant (oral selective estrogen receptor degrader) with/without triptorelin on the estrogen receptor functional pathway and Ki67 proliferation. Preoperative trial - PremiÈRe.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Solti Group

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Therapeutics [E02], Diseases [C] - Neoplasms [C04]

Trial duration

11 Sep 2023 → ongoing

Decision date (initial)

2023-07-28

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Menarini Group - Stemline Therapeutics, Inc

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy

Part A: To evaluate the biological activity of elacestrant with or without OFS in premenopausal women with ER+/HER2- operable EBC.
Part B: To evaluate the biological activity of elacestrant monotherapy versus tamoxifen in premenopausal women with ER+/HER2- operable EBC.

Secondary objectives 7

1. To evaluate the biological activity of: • Part A: elacestrant with orwithout OFS • Part B: elacestrant monotherapy and tamoxifen in premenopausal women withER+/HER2- operable EBC according to baseline researchbased PAM50 subtype.
2. To evaluate the antiproliferative activity after treatment of: • Part A: elacestrant with or without OFS • Part B: elacestrant monotherapy and tamoxifen
3. To identify changes in the research-based PAM50 subtypes pre- and post-treatment samples after treatment
4. To evaluate the impact of E2 levels on the rate of CCCA.
5. To evaluate dynamics of E2 and FSH in blood
6. To evaluate the safety and tolerability of the treatments when administered in pre-menopausal patient population.
7. To evaluate the expression ofestrogen receptor (ER) andprogesterone receptor (PgR) intumor tissue before and after study treatment.

Conditions and MedDRA coding

Premenopausal women with early luminal breast cancer

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. Signed informed consent must be obtained prior to any trial-specific procedure.
2. Patient must be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other trial procedures.
3. 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.
4. 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.
5. 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.
6. Patients must have the ability to swallow oral medication.
7. 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.
8. 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).
9. In the case of a multifocal tumor, the largest lesion must be ≥ 10 mm and designated the “target” lesion for all subsequent tumor evaluations. ER-positive with expression higher than 10% and HER2-negative tumor by local assessment. • 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.
10. Ki67 expression ≥ 10% and ≤ 35% by local assessment.
11. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
12. Breast cancer eligible for primary surgery.
13. 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 randomization. Archival tumor tissue or ex professo biopsy are acceptable
14. Adequate hematologic and organ function, defined by the following: a. Neutrophils (ANC ≥1.000/μL). b. Hemoglobin ≥ 9.0 g/dL (with no need for transfusions). c. Platelet count ≥ 75. 000/μL. d. Serum creatinine ≤1.5 mg/dL or calculated creatinine clearance ≥30 mL/min (Cockcroft-Gault Equation) e. International normalized ratio (INR) or prothrombin time (PT) ≤1.5 × ULN and activated partial thromboplastin time (aPTT) within therapeutic rangeNote: 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 f. Potassium, total Calcium (corrected for serum albumin), and sodium NCI CTCAE v5.0 Grade ≤ 1. g. Alanine aminotransferase (ALT) ≤ 3x upper limit of normal (ULN) h. Aspartate aminotransferase (AST) ≤ 3x ULN i. Total bilirubin ≤ ULN or total bilirubin ≤ 1.5x ULN with direct bilirubin ≤ ULN of the laboratory in subjects with documented Gilbert’s Syndrome
15. Female patients who are at least 35 years of age on the day of signing informed consent.

Exclusion criteria 19

1. Inoperable locally advanced or inflammatory breast cancer (any stage III).
2. Assessment by the investigator to be unable or unwilling to comply with the requirements of the protocol.
3. Any of the following within 6 months before randomization: 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.
4. Metastatic (Stage IV) breast cancer.
5. Synchronous invasive bilateral or multicentric breast cancer.
6. Patients requiring immediate neoadjuvant chemotherapy or immediate surgical intervention.
7. Patients who have undergone sentinel lymph node biopsy or tumor excisional biopsy prior to study treatment.
8. 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.
9. 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-lives of the drug prior to initiating trial therapy. • Potent CYP2D6 inhibitors (Part B only), e.g., paroxetine, fluoxetine, quinidine, cinacalcet, or bupropion. Following randomization, if the patient is assigned to the elacestrant arm and treatment with a potent CYP2D6 inhibitor is considered medically necessary, its use may be permitted upon consultation and approval by the Medical Monitor. • Herbal preparations/medications. • Vaccination, including but not limited to vaccination against COVID-19, during the 7 days prior to randomization.
10. Any treatment, local or systemic, including prior chemotherapy, ET, targeted therapy, and/or radiation therapy for the currently diagnosed BC prior to randomization.
11. Major surgical procedure or significant traumatic injury within 28 days prior to randomization.
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: a. Adequately treated catheter-related venous thrombosis occurring <28 days prior to randomization. b. Treatment with an anticoagulant, e.g., warfarin or heparin, for a thrombotic event occurring < 6 months before randomization, 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 must be appropriately documented (indication, dose, duration of use, and date of discontinuation). The following washout periods prior to C1D1 apply, according to the type of hormonal treatment: a. Selective estrogen receptor modulators (e.g., tamoxifen, raloxifene) and systemic estrogen- or progestin-based therapies used for osteoporosis, breast cancer prevention, or hormone replacement therapy: ≥ 12 months. b. Hormonal treatments used for contraception or other benign conditions (e.g., endometriosis): ≥ 28 days, unless otherwise specified. c. Intramuscular depot medroxyprogesterone acetate: ≥ 12 months. d. Etonogestrel depot implant: removal ≥ 4 months. e. Hormonal intrauterine device (IUD): removal ≥ 14 days. f. Natural products known to contain progestins: ≥ 14 days.
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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Rate of CCCA determined by central assessment by IHC Ki67 (% Ki67 ≤ 2.7%) after short-term elacestrant therapy with or without OFS.

Secondary endpoints 9

1. Rate of CCCA defined as centrally assessed Ki67 ≤ 2.7% by IHC, after 4 weeks of therapy, evaluated separately in patients with Luminal A and non–Luminal A disease.
2. Mean change in Ki67 measured by IHC Ki67 expression between pre- and post-treatment samples.
3. Differences in differential expression (mean suppression = 100 - [geometric mean (post treatment / pre-treatment · 100)]) of proliferative genes (BIRC5, CCNB1, CDC20, CDCA1, CEP55, KNTC2, MKI67, PTTG1, RRM2, TYMS and UBE2C).
4. Proportion of patients switching subtype between pre- and post-treatment samples
5. Mean change in Ki67 expression and CCCA rate (Ki67 ≤ 2.7%) according to post-treatment estradiol (E2) levels
6. Mean change of E2 and FSH levels between pre- and on- treatment (D14) and posttreatment samples.
7. Incidence and severity of adverse events, with severity, determined according to NCI CTAE v.5.0.
8. Change from baseline in targeted clinical laboratory test results, including ECGs
9. Immunohistochemical (IHC) assessment of E) and PgR expression in pre-treatment and post-treatment tumor samples.

Investigational products

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

Test 1

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Solti Group

Sponsor organisation

Solti Group

Address

Calle Balmes 89 Planta 1 Puerta 2

City

Barcelona

Postcode

08008

Country

Spain

Scientific contact point

Organisation

Solti Group

Contact name

SOLTI START UP GROUP

Public contact point

Organisation

Solti Group

Contact name

SOLTI START UP GROUP

Third parties 5

Locations

1 EU/EEA country · 15 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 13 files

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

Application history

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