Breast Cancer Clinical Trials

⁃ All patients, independent from gender

⁃ Patient must be ≥18 years at diagnosis

⁃ The patient must be capable of giving informed consent and be willing and able to comply with the requirements and restrictions in this protocol and accessible for treatment and follow-up

⁃ Sign informed consent prior to any study-specific procedures.

⁃ Histologically confirmed unilateral, primary invasive carcinoma of the breast Note: bilateral, multicentric, or multifocal carcinoma may only be included after consultation of Sponsor.

⁃ Histologically confirmed diagnosis of primary hormone-receptor-positive (HR+) (i.e., oestrogen-receptor (ER) ≥ 10% and progesterone-receptor PR ≥ 10%) early breast cancer by local laboratory Note: ER positive according to ASCO / AGO Guidelines, ER 1-10% (low) is not defined as HR+.

⁃ Patient has HER2-negative breast cancer defined as a negative in-situ hybridization test or an IHC status of 0, 1+, or 2+, if IHC is 2+, a negative in-situ hybridization (FISH, CISH, or SISH) test is required (based on the most recently analysed tissue sample and all tested by a local laboratory).

⁃ No evidence of distant metastasis (confirmed by CT thorax / abdomen, X-ray chest, ultrasound liver, bone scan, or PET-CT, respectively, performed within clinical routine).

⁃ High genomic risk assessment within clinical routine (Oncotype DX® preferred; In those cases, where Oncotype Dx® is not possible in clinical routine, Oncotype Dx® should be assessed retrospectively after inclusion of the patient and as a study specific measure, provided sufficient tumour tissue from primary diagnosis is available.)

‣ 10\. Completed 2-6 weeks of endocrine induction treatment and Ki-67 response assessment Note: 2-4 weeks recommended, up to 6 weeks allowed. Endocrine induction is highly recommended, but if endocrine induction therapy could not be performed or ET response is not representative, clinical factors should be used.

‣ 11\. Completed (neo)adjuvant chemotherapy, if applicable

‣ Completed radiotherapy, if applicable

‣ Patient meets any of the following three conditions at end of primary treatment (including endocrine induction treatment, biopsy/surgery, and if necessary, chemotherapy and radiotherapy and up to 12 months standard-of-care endocrine treatment, excluding previous treatment \> 4 weeks with any SERD):

‣ Pathological Stage \* Genomical High-Risk (Oncotype Dx®)\*\* Age Clinical High-Risk Factors Stage I T1 N0

‣ RS\>25 Any age High risk (≤ 1 factor applies):

∙ ET non-response (post ET Ki-67 \>10%)\*\*\*

∙ No Chemotherapy

∙ G3 or PR negative and Ki-67 \>25%\*\*\*

∙ Non-pCR after NACT\*

‣ RS 16-25 Age \<50 High risk (≤ 1 factor applies):

∙ ET non-response (post ET Ki-67 \>10%)\*\*\*

∙ No Chemotherapy

∙ G3 or PR negative and Ki-67 \>25%\*\*\*

∙ Non-pCR after NACT\* Any genomic risk Any age G3 and Ki-67\>40%

‣ Stage IIa with T2 N0

‣ RS 0-25 Age\>50 High risk (≤ 1 factor applies):

∙ ET non-response (post ET Ki-67 \>10%)\*\*\*

∙ G3 and Ki-67\>40%

∙ G3 or PR negative and Ki-67 \>25%\*\*\*

∙ Non-pCR after NACT\*

‣ RS 0-15 Age\<50 No chemotherapy AND high risk (≤ 1 factor applies):

∙ ET non-response (post ET Ki-67 \>10%)\*\*\*

∙ G3 and Ki-67\>40%

∙ G3 or PR negative and Ki-67 \>25%\*\*\*

∙ Non-pCR after NACT\*

‣ RS 16-25 Age\<50 No chemotherapy, AND/OR high risk (≤ 1 factor applies):

∙ ET non-response (post ET Ki-67 \>10%)\*\*\*

∙ G3 and Ki-67\>40%

∙ G3 or PR negative and Ki-67 \>25%\*\*\*

∙ Non-pCR after NACT\*

‣ RS \>25 Any age Any clinical risk

‣ Any genomic risk Any age G3 and Ki-67 \>40%

‣ Stage IIa with T1 N1, G1-2

‣ RS 0-25 Age\>50 High risk (≤ 1 factor applies):

∙ ET non-response (post ET Ki-67 \>10%)\*\*\*

∙ PR negative and Ki-67 \>25%\*\*\*

∙ Non-pCR after NACT\*

∙ 3 positive LN

‣ RS 0-25 Age \<50 No chemotherapy, AND/OR high risk (≤ 1 factor applies):

∙ ET non-response (post ET Ki-67 \>10%)\*\*\*

∙ PR negative and Ki-67 \>25%\*\*\*

∙ Non-pCR after NACT\*

∙ 3 positive LN

‣ RS\>25 Any age Any clinical risk

‣ Stage IIb with T3 N0 or T2 N1, G1-2 Any genomic risk Any age Any clinical risk

‣ \* In patients treated by neoadjuvant chemotherapy, clinical stage should be used for inclusion

‣ \*\* In stage I-IIa and N0 patients with unknown genomic risk prior to inclusion, Oncotype Dx® Test should be performed on untreated tumour tissue within clinical routine.

‣ Results of other genomic tests, if already performed within the clinical routine, may be considered. In such cases, inclusion is only possible if clinical high-risk criteria apply and after consultation with sponsor.

‣ In those cases, where Oncotype Dx® is missing from clinical routine and in the N1-situation, Oncotype Dx® should be assessed retrospectively after inclusion of the patient and as a study specific measure, provided sufficient tumour tissue from primary diagnosis is available.

‣ \*\*\* Use of clinical factors is recommended in patients with unknown or not representative ET response.

‣ No contraindication for adjuvant SoC endocrine treatment

‣ No contraindication for elacestrant treatment

‣ No contraindication for ribociclib treatment, if medically indicated, and adequate washout time for CYP3A4 inducers/inhibitors and QT time-prolonging drugs is given

‣ Tumour block for central pathology review (core biopsy of initial diagnosis and biopsy/surgery sample of definite surgery), if available

‣ Performance Status ECOG ≤ 1 or Karnofsky Index ≥ 80%

‣ Laboratory requirements (female and male patients, not older than 14 days prior to date of informed consent)

• absolute neutrophil count ≥ 1.5 × 109/L,

∙ platelets ≥ 100 × 109/L,

∙ haemoglobin ≥ 9.0 g/dL,

∙ INR ≤ 1.5,

∙ serum creatinine \< 1.5 × ULN OR clearance ≥30 mL/min for participant with creatinine levels \>1.5 × institutional ULN

∙ total bilirubin \< ULN, except for patients with Gilbert's Syndrome who may only be included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN,

∙ aspartate transaminase (AST) \< 2.5 × ULN,

∙ alanine transaminase (ALT) \< 2.5 × ULN,

∙ Screening lipid panel fasting levels: total cholesterol ≤400 mg/dL AND/OR triglycerides \<500 mg/dL.

‣ Note: Patients with lipid panel fasting levels NOT meeting the above criteria may consider initiating therapy for lipid management per local guidelines and will be allowed to be included once the lipid levels meet the inclusion criteria.

‣ Clinical assessments:

‣ • normal electrocardiogram within 6 weeks prior to randomization (QTcF interval at screening \<450msec using Fridericia's correction, mean resting heart rate 50-90 bpm)

‣ Ability to swallow tablets

‣ Contraception

⁃ A. Female patients of childbearing potential at inclusion must have a negative pregnancy test (serum) and additionally fulfil either one of the following conditions:

• surgically sterile,

• or carry a non-hormone releasing intrauterine device (combined with a barrier method),

• or having received tubal ligation/occlusion (combined with a barrier method),

• or using a highly effective contraceptive method from the time they sign consent, during participation in the study until end of study, at least 4 months (120 days) after the last dose of ELA, and for at least 21 days after the last dose of RIBO) to prevent pregnancy; ova donation or preservation is also not allowed within this time frame

• Total/true abstinence: When the patient refrains from any form of sexual intercourse and this is in line with their usual and/or preferred lifestyle; this must continue from the time they sign consent, during participation in the study until end of study, at least 4 months (120 days) after the last dose of ELA, and for at least 21 days after the last dose of RIBO) to prevent pregnancy;

• Vasectomised sexual partner (with participant assurance that partner received post-vasectomy confirmation of azoospermia) combined with a barrier method or sexual partner with bilateral orchiectomy.

• Hormonal contraception is not acceptable. B. Male patients must either be

• surgically sterile

• or using a highly effective method of contraception from the time they sign consent, during participation in the study until end of study, at least 4 months (120 days) after the last dose of ELA, and for at least 21 days after the last dose of RIBO) to prevent pregnancy in a partner; sperm donation or preservation is also not allowed within this time frame

• Male patients who intend to be sexually active with a woman of childbearing potential, must use a condom plus spermicide from the time they sign consent, during participation in the study until end of study, at least 4 months (120 days) after the last dose of ELA, and for at least 21 days after the last dose of RIBO) to prevent pregnancy in a partner;

• Highly effective methods of contraception should be considered in female partners of men taking elacestrant and/or ribociclib who are of childbearing potential.