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Neadjuvant Multi-agent Chemotherapy or Letrozole Plus Ribociclib in Luminal B/HER2-negative Breast Cancer.



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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:



Phase 2

Trial Eligibility



  • Brief Title: Neadjuvant Multi-agent Chemotherapy or Letrozole Plus Ribociclib in Luminal B/HER2-negative Breast Cancer.
  • Official Title: CORALLEEN: A Phase 2 Clinical Trial of Multi-agent Chemotherapy or Letrozole Plus Ribociclib (LEE011) as Neoadjuvant Treatment for Postmenopausal Patients With Luminal B/HER2-negative Breast Cancer.

Clinical Trial IDs

  • NCT ID: NCT03248427


  • Breast Cancer


RibociclibLEE011Ribociclib + Letrozol
Letrozole 2.5mgRibociclib + Letrozol


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.

Detailed Description

      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 evaluate the ability of each treatment strategy to provide
      ROR-low score at surgery.

      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, Rate of ROR-low (at surgery) after neoadjuvant treatment, according to
      the Prosigna test 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

Trial Arms

Ribociclib + LetrozolExperimentalRibociclib: 600mg, 3-weeks-on/-week-off treatment Letrozole: 2.5mg daily; Six 28 days cycles
  • Ribociclib
  • Letrozole 2.5mg
ChemotherapyOtherChemotherapy treatment will consist of four cycles of AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 21 days) followed by weekly paclitaxel during 12 weeks.
  • Doxorubicin
  • Cyclophosphamide
  • Paclitaxel

Eligibility Criteria

        Inclusion Criteria

          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
             assessed locally.

          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.

        Exclusion criteria

          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
                  QT syndrome.

               -  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
             treatment complications.

         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
             treatment start:

               -  Any prohibited medication as per letrozole, doxorubicin, cyclophosphamide, or
                  paclitaxel label.

               -  Herbal preparations/medications, dietary supplements.

               -  Medications that have a known risk to prolong the QT interval or cause Torsades
                  de Pointe.

               -  Medications with a narrow therapeutic window and predominantly metabolized
                  through CYP3A4/5.

               -  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
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Rate of ROR-low according to the Prosigna test.
Time Frame:24 weeks
Safety Issue:
Description:Rate of ROR-low after neoadjuvant treatment at surgery, according to the Prosigna test,as per central assessment

Secondary Outcome Measures

Measure:Tumor Overall response rate (ORR)
Time Frame:24 weeks
Safety Issue:
Description:Tumor overall objective response rate (ORR), defined as the sum of Partial Responses (PR) and Complete Responses (CR) according to RECIST v1.1, as per Investigator's assessments by breast MRI.
Measure:pCR in the breast and axillary lymph nodes
Time Frame:24 weeks
Safety Issue:
Description:pCR is defined as the complete absence of invasive carcinoma in the breast and axillary lymph nodes on histological examination.
Measure:PEPI Score
Time Frame:24 weeks
Safety Issue:
Description:Preoperative endocrine prognostic index (PEPI) score in the ribociclib plus letrozole treatment arm compared to historical values
Measure:Residual Cancer Burden (RCB)
Time Frame:24 weeks
Safety Issue:
Description:Rate of residual cancer burden (RCB) score 0 or 1 (RCB0/1) after neoadjuvant treatment, according to the MD Anderson Cancer Center procedures, as per central assessment.
Measure:Rate of breast conserving surgery (BCS)
Time Frame:24 weeks
Safety Issue:
Description:Rate of breast conserving surgery
Measure:Decrease in Ki67 in both treatment arms.
Time Frame:At baseline, in week 2, and pre-surgery
Safety Issue:
Description:Decrease in Ki67 in both treatment arms.
Measure:Incidence, duration and severity of Adverse Events (AEs)
Time Frame:Up to 24 weeks
Safety Issue:
Description:Incidence, duration and severity of Adverse Events (AEs) assessed by the NCI Common Terminology for Classification of Adverse Events (CTCAE) version 4.


Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:SOLTI Breast Cancer Research Group

Trial Keywords

  • Breast Cancer
  • Neoadjuvant
  • Luminal B tumors
  • Ribociclib

Last Updated

March 17, 2021