CORALLEEN is a two-arm, randomized, multicentric study in postmenopausal women with primary
HR+/HER2 negative Luminal B breast cancer that will explore if the combination of ribociclib
with letrozole offers clinical benefit at least comparable to that of standard chemotherapy.
This is a parallel, two-arm, randomized 1:1, stratified by tumor size and nodal involvement,
open-label, multicenter, exploratory study in postmenopausal women with primary operable
HR+/HER2-negative Luminal B breast cancer according to PAM50 intrinsic subtype to evaluate
the clinical benefit and biological effects of ribociclib combined with letrozole.
The primary trial objective is to explore the clinical benefit of ribociclib plus letrozole
Luminal B patients will be randomized 1:1 to either letrozole plus ribociclib or
chemotherapy.Two weeks after the first administration of the assigned treatment, patients
will undergo a biopsy to assess early biological response to treatment, at Ki67 protein and
gene expression level. After finalization of the assigned neoadjuvant treatment, patients
will undergo surgery.
The primary endpoint, Residual Cancer Burden, will be centrally assessed. Baseline, Day 15
and post-treatment (surgical) primary breast tumor tissue samples should be available for
each patient for molecular characterization A post-surgery visit will be performed within 28
days (7 days) from surgery, and will mark the end of the study for that patient
1. Signed Informed Consent Form prior to any study-specific procedure.
2. Female patients.
3. Post-menopausal status and age ≥18 years.
4. Histologically confirmed invasive breast carcinoma, with all the following
- Primary tumor ≥ 2cm in largest diameter as measured by breast MRI
- Stage I to stage IIIA breast cancer
- No evidence of distant metastasis (M0)
5. Breast cancer eligible for primary surgery.
6. Available pre-treatment FFPE core (Tru-cut) biopsy evaluable for PAM50 or possibility
to obtain one. Minimal sample requirements are to have at least 2 tumor cylinders with
a minimal tissue surface of 10 mm2 tissue, containing at least 10% tumor cells and
having enough tissue to do at least 2 cuts of 10 micrometers each.
7. Luminal B subtype as per PAM50 analysis of pre-treatment sample.
8. ER-positive and/or PgR-positive and HER2-negative tumor by ASCO/CAP guidelines
9. In the case of a multifocal tumor (defined as the presence of two or more foci of
cancer within the same breast quadrant), the largest lesion must be ≥ 2 cm and
designated the "target" lesion for all subsequent tumor evaluations and
HR+/HER2-negative status must be documented in all the tumor foci.
10. ECOG performance status of 0 or 1.
11. Adequate hematological, renal and hepatic function.
12. Ability and willingness to comply with study visits, treatment, testing and to comply
with the protocol.
1. Any prior treatment for primary invasive breast cancer.
2. Inoperable locally advanced or inflammatory (i.e., inoperable Stage III) breast
3. Metastatic (Stage IV) breast cancer.
4. Bilateral invasive breast cancer.
5. Multicentric breast cancer, defined as the presence of two or more foci of cancer in
different quadrants of the same breast.
6. Patients who have undergone sentinel lymph node biopsy prior to study treatment.
7. Inability or unwillingness to swallow pills.
8. Malabsorption syndrome or other condition that would interfere with enteric absorption
of study drugs.
9. Participation in a prior investigational study within 30 days prior to enrollment or
within 5 half-lives of the investigational product, whichever is longer.
10. Patient with a Child-Pugh score B or C.
11. Patient has active cardiac disease or a history of cardiac dysfunction including any
of the following:
- History of acute coronary syndromes (including myocardial infarction, unstable
angina, coronary artery bypass grafting, coronary angioplasty or stenting) or
symptomatic pericarditis within 12 months prior to screening.
- History of documented congestive heart failure (New York Heart Association
functional classification III-IV).
- Documented cardiomyopathy.
- Patient has a Left Ventricular Ejection Fraction (LVEF) < 50% as determined by
Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO).
- Clinical significant cardiac arrhythmias (e.g. ventricular tachycardia), complete
left bundle branch block, high-grade AV block (e.g. bifascicular block, Mobitz
type II and third-degree AV block)
- Long QT Syndrome or family history of idiopathic sudden death or congenital long
- On screening 12-lead ECG, any of the following cardiac parameters (defined as the
mean of triplicate ECGs: bradycardia (resting heart rate < 50), tachycardia
(resting heart rate > 90), PR interval > 220 msec, QRS interval >109 msec, or
QTcF interval ≥450 msec (using Fridericia's correction).
12. Uncontrolled hypertension (Systolic blood pressure >160 mmHg or <90 mmHg and/or
diastolic >100 mmHg).
13. Active infection requiring intravenous (IV) antibiotics.
14. Symptomatic hypercalcemia despite adequate management.
15. Clinically significant history of liver disease, including viral or other hepatitis,
current alcohol abuse, or cirrhosis.
16. Known human immunodeficiency virus (HIV) infection.
17. Any other diseases, active or uncontrolled pulmonary dysfunction, metabolic
dysfunction, physical examination finding, or clinical laboratory finding giving
reasonable suspicion of a disease or condition that contraindicates the use of an
investigational drug, that may compromise compliance with the protocol, that may
affect the interpretation of the results, or renders the patients at high risk from
18. Significant traumatic injury within 3 weeks prior to initiation of study treatment.
19. Major surgical procedure (not including minor procedures such as lymph node biopsy,
tumor core biopsy, fine needle aspiration) within 4 weeks prior to initiation of study
treatment or not fully recovered from any side effects of previous procedures.
20. Any psychological, familial, sociological, or geographical condition potentially
hampering compliance with the study protocol and follow-up schedule.
21. History of other malignancy within 5 years prior to screening, except for
appropriately treated basal or squamous cell carcinoma, carcinoma in situ of the
cervix, non-melanoma skin carcinoma, or Stage I uterine cancer.
22. Hormone replacement therapy stopped less than 2 weeks before treatment start.
23. Currently receiving or has received systemic corticosteroids until 2 weeks before
treatment start or who have not fully recovered from side effects of such treatment.
Following corticosteroid uses are permitted: single doses, topical applications (e.g.
for rash), inhaled sprays (e.g. for obstructive airways diseases), eye drops or local
injections (e.g. intra-articular)
24. Known hypersensitivity to any of the excipients of ribociclib, letrozole, doxorubicin,
cyclophosphamide or paclitaxel.
25. Patients currently on following medications, which cannot be interrupted 7 days prior
- Any prohibited medication as per letrozole, doxorubicin, cyclophosphamide, or
- Herbal preparations/medications, dietary supplements.
- Medications that have a known risk to prolong the QT interval or cause Torsades
- Medications with a narrow therapeutic window and predominantly metabolized
- Strong inducers or inhibitors of CYP3A4/5, including grapefruit, grapefruit
hybrids, pummelos, star-fruit and Seville oranges.
- Warfarin or other coumarin-derived anticoagulant for treatment, prophylaxis or
otherwise. Therapy with heparin, low molecular weight heparin or fondaparinux is