EMBER4

EMBER-4 Etude de Phase 3, randomisée en ouvert, comparant l’imlunestrant à l’hormonothérapie standard en adjuvant chez des patients ayant précédemment reçu 2 à 5 années d’hormonothérapie adjuvante pour un cancer du sein précoce ER+ et HER2- avec un risque accru de récidive.

Critères d'inclusion :

1. Participants must be 18 years of age, or of an acceptable age according to local regulations, whichever is older, at the time of signing the informed consent.

2. Have a diagnosis of ER+, HER2- early-stage, resected, invasive breast cancer without evidence of distant metastasis

a. to fulfill the requirement for ER+ disease, by local testing on primary disease specimen, tumor must express the ER by IHC, as defined in the relevant ASCO/CAP Guidelines (Allison et al. 2020)
b. to fulfill the requirement of HER2- disease by local testing on primary disease specimen, tumor must be HER2- according to ASCO/CAP guidelines for HER2 testing (Wolff et al. 2018).

3. Patients with bilateral breast cancer (diagnosis of invasive tumors in both breasts simultaneously or within 6 months of each other) can be eligible if all lesions tested on both sides are ER+, HER2- (as defined in Inclusion Criterion #2) and adequate surgery has been performed in both breasts. The Lilly CRP/CRS must be consulted for all cases of bilateral breast cancer.

4. The patients must have undergone definitive loco-regional therapy (surgery, with or without, radiation therapy where appropriate/per guidelines) of the primary breast tumor(s).

a. With the exception of the situations described below, the margins of the resected specimen must be histologically free of invasive tumor and/or a component of DCIS as determined by the local pathologist.

i. for patients who undergo mastectomy or wide local excision where deep margin abuts the pectoralis fascia, patients with microscopic positive margins are eligible as long as radiotherapy of the chest wall was administered. Patients with positive anterior margins may be eligible if there is no gross disease left behind (radiotherapy as per local guidelines).

b. Where surgical excision of supraclavicular or internal mammary nodes is not feasible, residual nodes should have been irradiated in accordance with standard guidelines.

c. If given, radiation therapy, for example, post-mastectomy or post-lumpectomy, should have been administered according to standard guidelines.

5. Patients must have received at least 24 months but not more than 60 months of any adjuvant ET, from time of adjuvant ET initiation. See Exclusion Criteria 22 and 23.

6. Patients may have received (neo) adjuvant chemotherapy and/or targeted therapy with a CDK4/6- or PARP- inhibitor.

7. If patients have received either or all of the therapies indicated below (a,b), they must have completed them and have recovered (CTCAE Version 5, Grade ≤1) from the acute effects (except for residual alopecia or Grade 2 peripheral neuropathy) prior to Visit 1, with the following washout periods:

a. myelosuppressive agents, for example, CDK4/6 inhibitors: At least 21 days between the last targeted therapy dose and Day 1 of treatment

b. investigational agents: 28 days or 5 half-lives between the last dose of therapy and Day 1 treatment.

8. Patients must have an increased risk of disease recurrence based on clin-path risk features as defined by any of the following (a-c):

a. ≥N2: ≥4 positive ALN
b. N1: 1-3 positive ALN and one of the following criteria must also be present:
i. tumor size ≥5 cm
ii. histologic Grade 3 tumor
iii. tumor size >2 cm but <5 cm and histologic Grade 2
c. N0: no positive ALN and one of the following criteria must also be present:
iv. tumor size ≥5 cm
v. tumor size >2 cm but <5 cm and histologic Grade 3
Note 1: Positive ALN= Pathological tumor involvement in axillary lymph nodes
Note 2: For patients who received neoadjuvant therapy, cytological tumor involvement in 1 to 3 ALNs at time of initial diagnosis is allowed, and primary tumor size based on breast imaging is allowed.
Note 3: If tumor size is needed to meet eligibility criteria, patients with multifocal or multicentric tumors may be eligible based on the addition of diameters of the individual lesions following discussion with the Lilly CRP/CRS.

9. For female participants: both pre-/peri- and postmenopausal status is allowed.
a. postmenopausal due to surgical or natural menopause requires at least 1 of the following:
i. prior bilateral oophorectomy
ii. age ≥60 years
iii. age <60 years, amenorrheic for at least 12 months [in the absence of chemotherapy, tamoxifen, toremifene, or ovarian function suppression (OFS)], and FSH and estradiol levels in the postmenopausal range
b. pre-/peri-menopausal patients must agree to the following:
i. have a negative serum pregnancy test at baseline, within 14 days prior to Visit 1
ii. agree to use OFS with a GnRH agonist such as goserelin or leuprolide (received monthly and initiated at least 28 days prior to Visit 1) if receiving study treatment with imlunestrant or an AI. Note: Participants established on a less frequent (that is, 3-month) GnRH agonist administration schedule will be permitted, if considered by the investigator to have adequate OFS based on serial estradiol and FSH assessments.
iii. agree to use highly effective, medically approved precautions to prevent pregnancy (see Section 10.4 Appendix 4) during the study and for 6 months following the last dose of study treatment.

10. If male, must agree to use the following:
a. hormone suppression (initiated at least 28 days prior to Visit 1) with a GnRH agonist such as goserelin or leuprolide if receiving study treatment with imlunestrant or an AI
b. highly effective methods of birth control and to not donate sperm during the study and for at least 6 months following the last dose of study drug(s), or for the duration specified in country requirements, whichever is longer

11. Have a Performance Status of 0 or 1 on the Eastern Cooperative Oncology Group scale (Oken et al. 1982).

12. Have adequate organ function as defined in table below. System Laboratory Value Renal Serum creatinine or <1.5× ULN OR calculateda creatinine clearance ≥50 mL/min Hematologic ANC ≥1.5 × 109/L Platelets ≥100 × 109/L Hemoglobin ≥9 g/dL Note: transfusions to increase a participant’s hemoglobin level or initiation of erythropoietin or G-CSF therapy to meet enrollment criteria are not allowed in the 14 days preceding the first dose of study drug. Hepatic Total bilirubin ≤1.5× ULN, participants with Gilbert’s syndrome with a total bilirubin ≤2.0 times ULN and direct bilirubin within normal limits are permitted ALT and AST ≤3× ULN
Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; G-CSF = granulocyte-colony stimulating factor; ULN = upper limit of normal.
a See Section 10.12, Appendix 12

13. Participants must be able to swallow capsules or tablets

14. Capable of giving signed informed consent as described in Section 10.1.3 Appendix 1, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

Critères de non inclusion :

15. Have any evidence of
a. metastatic disease (including contralateral ALN) or inflammatory breast cancer at primary breast cancer diagnosis
i. inflammatory carcinoma should not apply to a patient with neglected locally advanced breast cancer presenting late in the course of their disease (American Joint Committee on Cancer [AJCC] staging system for breast cancer 8th edition, Hortobagyi et al. 2017). The investigator should consult with the Lilly CRP/CRS regarding eligibility of patients with neglected inflammatory disease
b. breast cancer recurrence (local or distant)
c. a different primary breast cancer.

16. Patients with more than a 6-month consecutive gap in therapy during the course of prior adjuvant ET.

17. Patients who have completed or discontinued prior adjuvant ET >6 months prior to screening.

18. Patients with a history of previous breast cancer are excluded, with the exception of ipsilateral DCIS treated by locoregional therapy alone ≥5 years ago.

19. Pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 180 days after the last dose of study intervention.

20. The patient is receiving concurrent exogenous reproductive hormone therapy, for example, birth control pills, hormone replacement therapy, or megestrol acetate. Appropriate washout period between last dose of exogenous hormone therapy and randomization is up to the investigator’s medical judgment, for example, applying 5 times the half-life elimination rule. Note: topical vaginal estrogen therapy is permitted if all other non-hormonal options are exhausted.

21. The patient has previously received ET of any duration for breast cancer prevention (tamoxifen or AIs) or raloxifene.

22. The patient has received an experimental treatment in a clinical trial within the last 30 days or 5 half-lives, whichever is longer, prior to randomization, or is currently enrolled in any other type of medical research (for example: medical device) judged by the Sponsor not to be scientifically or medically compatible with this study. Co-enrollment to other studies may be allowed following consultation with the Sponsor medical monitor.

23. Patients with a history of any other cancer (except non-melanoma skin cancer, Stage I uterine cancer, or carcinoma in situ of the cervix or other in-situ cancer), unless in complete remission with no therapy for a minimum of 5 years from the date of randomization. For patients with a history of other non-breast cancers within 5 years from the date of randomization and considered of very low risk of recurrence per investigator’s judgment (for example, papillary thyroid cancer treated with surgery), eligibility is to be discussed with the Sponsor medical monitor.

24. Have serious preexisting medical conditions that, in the judgment of the investigator, would preclude participation in this study (such as preexisting medical condition of ILD/pneumonitis, severe dyspnea at rest or requiring oxygen therapy, history of major surgical resection involving the stomach or small bowel, preexisting Crohn’s disease or ulcerative colitis, or a preexisting chronic condition resulting in clinically significant diarrhea).

25. Have had major surgery within 14 days prior to randomization.

26. Have a serious cardiac condition, such as
a. congestive heart failure
b. New York Heart Association Class III/IV heart disease
c. unstable angina pectoris
d. myocardial infarction within the last 3 months
e. valvulopathy that is severe or moderate, or deemed clinically significant
f. arrhythmias that are symptomatic or require treatment, not including patients with rate-controlled atrial fibrillation
g. cerebrovascular accident (stroke) within the last 3 months
h. a mean QT interval corrected for heart rate of ≥470 msec on screening ECG, as calculated using the Fridericia’s formula at several consecutive days of assessment
i. baseline bradycardia with resting heart rate <60 bpm
j. history of VTE, for example, DVT of the leg or arm and/or PE, will be excluded. Patients with a history of venous catheter occlusion by thrombus that did NOT surround the catheter, and the lumen could be made patent by appropriate measures, for example, saline or thrombolytic agent, are not excluded.

27. Have serious preexisting medical conditions that, in the judgment of the investigator, would preclude participation in this study

28. Have received an autologous or allogeneic stem cell transplant

29. Have active bacterial or fungal infection, or detectable viral infection, for example, HIV or viral hepatitis. Screening is required for enrollment

30. Known allergic reaction against any of the components of the study treatment.