Adj. Marker-adjusted Personalized Therapy Comparing ET+Ribociclib vs Chemotherapy in Intermediate Risk, HR+/HER2- EBC

Adjuvant Dynamic Marker - Adjusted Personalized Therapy Comparing Endocrine Therapy Plus Ribociclib Versus Chemotherapy in Intermediate Risk, HR+/HER2- Early Breast Cancer

The study investigates, whether the patient group with intermediate-risk early breast cancer benefits from treatment with ribociclib in combination with endocrine therapy compared to standard-of-care chemotherapy (followed by adjuvant endocrine therapy).

The WSG ADAPT trial program is one of the first new generation trials addressing the issue of individualization of (neo)-adjuvant decision-making in early breast cancer (EBC) in a subtype-specific manner. The first WSG ADAPT umbrella trial (NCT01779206) aimed to establish early predictive molecular surrogate markers for response after a short 3-week induction treatment.

The goals of the WSG ADAPT trial program - early response assessment and subtype-specific therapy tailoring to those patients who are most likely to benefit - have contributed to the very positive national and international feedback to the ADAPT concept as a whole.

The aim of this ADAPTcycle phase-III-trial is to investigate whether the intermediate-risk patient group identified during the screening phase derives additional benefit from treatment with ribociclib in combination with ET compared to chemotherapy (followed by adjuvant ET).

Inclusion Criteria:

Patients eligible for inclusion in this study have to meet all of the following criteria:

A. Prior to REGISTRATION in the study:

1. Written informed consent prior to any screening procedures. 2. Female. 3. ≥ 18 years of age. 4a. EITHER: (Post)menopausal status at the time of initiation of (neo)adjuvant study medication

• patient underwent bilateral oophorectomy, or

• age ≥ 60, or

• age < 60 and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) and/or FSH and estradiol in the postmenopausal range per local normal range.

  4b. OR: Pre-menopausal patients:

• confirmed negative serum pregnancy test (β-hCG) before starting study treatment, or

• patient has had a hysterectomy. 5. Histologically confirmed diagnosis of primary estrogen-receptor positive and/or progesterone-receptor positive (> 1%) early breast cancer by local laboratory.

  6. 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 analyzed tissue sample and all tested by a local laboratory).

  7. Local therapy of breast cancer (if adjuvant treatment or planned if neoadjuvant treatment) according to current guidelines.

Note: This may include radiotherapy of breast cancer.

B. Prior to RANDOMIZATION in the study 8. No evidence of distant metastasis (confirmed prior to randomization by, preferentially, CT thorax / abdomen, X-ray chest, ultrasound liver, bone scan, or PET-CT).

9. Patient has available tumor tissue from diagnostic biopsy. 10. Patient is classified as intermediate risk according to the ADAPT intermediate-risk definition (i) (as follows), or (only in case of missing Oncotype DX or Ki-67 response data), according to the clinical intermediate-risk definition (ii) (as follows).

(i). ADAPT intermediate-risk definition: Patient meets one of the following criteria:

• c/pN0, RS ≤ 25 with luminal-B-like (Ki-67 ≥20% or G3) or c/pT2-4 without endocrine response (post-endocrine Ki-67 > 10 %)
• c/pN1, RS ≤ 25 without endocrine response (post-endocrine Ki-67 > 10 %)
• c/pN0, RS > 25 with luminal-B-like (Ki-67 ≥20% or G3) or c/pT2-4 with endocrine response (Ki-67 ≤ 10 %)
• c/pN1, RS > 25 with endocrine response (Ki-67 ≤ 10 %)
• c/pN2-3, RS ≤ 25 with endocrine response (Ki-67 ≤ 10 %). Note: Postmenopausal patients with pT1-2/pN0 disease and RS < 25, as well as premenopausal patients with pT1-2/pN0 disease and RS<16, are recommended to be treated by endocrine therapy alone and not to be randomized (at investigator´s discretion).

(ii). Clinical intermediate-risk definition (ascertained by investigator): Clinical intermediate risk may be ascertained by the investigator prior to randomization if at maximum two of the following three risk factors are present (according to primary diagnosis / 1st sample):

1. cT2-4
2. c/pN positive
3. G3 and / or Ki-67 ≥ 20% Note: Inclusion of a patient according to "clinical intermediate risk" is permitted only in case of missing baseline Oncotype DX® or Ki-67 decrease. In this case, investigators will follow a risk-based, step-wise assessment process.

11. No contraindication for (neo)-adjuvant ET. 12. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. 13. Patient has adequate bone marrow and organ function as defined by the following laboratory values:

• absolute neutrophil count ≥ 1.5 × 109/L,

• platelets ≥ 100 × 109/L,

• hemoglobin ≥ 9.0 g/dL,

• estimated glomerular filtration rate (eGFR) ≥ 30 mL/min by a Cockcroft-Gault formula,

• INR ≤ 1.5,

• serum creatinine < 1.5 mg/dL,

• 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. 14. 2-lead-ECG (CANKADO) with:

• QTcF interval at screening < 450 msec (using Fridericia's correction),

• mean resting heart rate 50-90 bpm (determined from the ECG). 15. Ability to swallow ribociclib tablets or to administer other study medication, respectively.

  16. Ability to communicate with the investigator and comply with study procedures.

  17. Willing to remain during therapy at the clinical site, as required by the protocol.

Exclusion Criteria:

Patients eligible for inclusion in this study must not meet any of the following criteria:

1. Patient with distant metastases of breast cancer beyond regional lymph nodes.

2. Patient has received prior (neo)-adjuvant treatment with chemotherapy, ET, or any CDK4/6 inhibitor for breast cancer.

3. Patient has received tamoxifen, raloxifene, or aromatase inhibitors (AIs) for reduction in risk ("chemoprevention") of breast cancer and/or treatment for osteoporosis within last 2 years prior to screening.

4. Patient has received prior neoadjuvant/adjuvant treatment with anthracyclines at cumulative doses of 450 mg/m² or more for doxorubicin or 900 mg/m² or more for epirubicin.

5. Patient with a known hypersensitivity to any of the excipients of ribociclib, ET, or standard-of-care chemotherapy.

6. Patient with inflammatory breast cancer at screening.

7. Patient is concurrently using other anti-cancer therapy.

8. Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major side effects.

9. Patient is currently receiving warfarin or other coumarin-derived anti-coagulant for treatment, prophylaxis, or otherwise.

10. Patient has not recovered from clinical and laboratory acute toxicities related to prior anticancer therapies to NCI CTCAE version 5.0 Grade ≤ 1.

11. Patient has a concurrent malignancy, or malignancy within 5 years of randomization, or known history of invasive breast cancer.

12. Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., uncontrolled ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small-bowel resection).

13. Patient has a known history of HIV infection.

14. Patient has known active hepatitis-B-virus (HBV) or hepatitis-C-virus (HCV) infection.

15. Patient has any other concurrent severe and/or uncontrolled medical condition that would, in the investigator´s judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study, or compromise compliance with the protocol (e.g., chronic pancreatitis, chronic active hepatitis, active untreated or uncontrolled fungal, bacterial, or viral infections, etc.).

16. Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, including any of the following:

    • history of myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to study entry,

    • documented cardiomyopathy,

    • left ventricular ejection fraction (LVEF) < 50 % as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO),

    • long QT syndrome, family history of idiopathic sudden death, congenital long QT syndrome, or any of the following:

      • risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/ symptomatic bradycardia,
      • concomitant medications with a known risk to prolong the QT interval and/or known to cause Torsades de Pointe that cannot be discontinued or replaced by safe alternative medication (e.g., within 5 half-lives or 7 days prior to starting study drug),
      • inability to determine the QTcF interval,
      • clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left-bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II, and 3rd-degree AV block),
      • systolic blood pressure (SBP) > 160 or < 90 mmHg.

17. Patient is currently receiving any of the following substances, which cannot be discontinued 7 days prior to Cycle 1 Day 1:

    • concomitant medications, herbal supplements, fruits (e.g. grapefruit, pomegranates, pomelos, star fruit, Seville oranges) and their juices that are strong inducers or inhibitors of CYP3A4/5,
    • medications that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5.

18. Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting study drug, or who have not fully recovered from side effects of such treatment.

19. Participation in a prior investigational study within 30 days prior to enrollment or within five half-lives of the investigational product, whichever is longer.

20. Not able to understand and to comply with study instructions and requirements.

21. Pregnant or nursing (lactating) woman.

22. Woman of child-bearing potential defined as woman physiologically capable of becoming pregnant, unless she is using highly effective methods of contraception during the study treatment and for 21 days after stopping the treatment:

    • total abstinence (when this is in line with the preferred and usual lifestyle of the patient).
    • female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks before taking study treatment.
    • male partner sterilization (at least 6 months prior to study screening). For female patients on the study, the vasectomized male partner should be the sole partner for that patient.
    • placement of an intrauterine device (IUD).

23. Use of oral (estrogen and progesterone), transdermal, injected, or implanted hormonal methods of contraception as well as hormonal replacement therapy.