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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03248427
Recruitment Status : Recruiting
First Posted : August 14, 2017
Last Update Posted : November 16, 2018
Information provided by (Responsible Party):
SOLTI Breast Cancer Research Group

Tracking Information
First Submitted Date  ICMJE July 3, 2017
First Posted Date  ICMJE August 14, 2017
Last Update Posted Date November 16, 2018
Actual Study Start Date  ICMJE July 13, 2017
Estimated Primary Completion Date May 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 9, 2017)
Rate of Residual Cancer Burden (RCB) [ Time Frame: 24 weeks ]
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
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03248427 on Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 9, 2017)
  • Tumor Overall response rate (ORR) [ Time Frame: 24 weeks ]
    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.
  • pCR in the breast and axillary lymph nodes [ Time Frame: 24 weeks ]
    pCR is defined as the complete absence of invasive carcinoma in the breast and axillary lymph nodes on histological examination.
  • PEPI Score [ Time Frame: 24 weeks ]
    Preoperative endocrine prognostic index (PEPI) score in the ribociclib plus letrozole treatment arm compared to historical values
  • Rate of breast conserving surgery (BCS) [ Time Frame: 24 weeks ]
    Rate of breast conserving surgery
  • Decrease in Ki67 in both treatment arms. [ Time Frame: At baseline, in week 2, and pre-surgery ]
    Decrease in Ki67 in both treatment arms.
  • Incidence, duration and severity of Adverse Events (AEs) [ Time Frame: Up to 24 weeks ]
    Incidence, duration and severity of Adverse Events (AEs) assessed by the NCI Common Terminology for Classification of Adverse Events (CTCAE) version 4.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Neadjuvant Multi-agent Chemotherapy or Letrozole Plus Ribociclib in Luminal B/HER2-negative Breast Cancer.
Official Title  ICMJE 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.
Brief Summary 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 explore the clinical benefit of ribociclib plus letrozole versus chemotherapy.

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

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Breast Cancer
Intervention  ICMJE
  • Drug: Ribociclib
    Ribociclib flat-fixed dose of 600 mg daily (three 200-mg capsules), days 1 to 21 of a 28-days cycle.
    Other Name: LEE011
  • Drug: Letrozole 2.5mg
    Daily continuous
  • Drug: Doxorubicin
    60 mg/m2 as a continuous IV perfusion
  • Drug: Cyclophosphamide
    600 MG/M2 in a 30 minutes IV infusion
  • Drug: Paclitaxel
    80 mg/m2, in one hour IV infusion
Study Arms  ICMJE
  • Experimental: Ribociclib + Letrozol
    Ribociclib: 600mg, 3-weeks-on/-week-off treatment Letrozole: 2.5mg daily; Six 28 days cycles
    • Drug: Ribociclib
    • Drug: Letrozole 2.5mg
  • Chemotherapy
    Chemotherapy 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.
    • Drug: Doxorubicin
    • Drug: Cyclophosphamide
    • Drug: Paclitaxel
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 9, 2017)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 2019
Estimated Primary Completion Date May 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 characteristics:

    • 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 cancer.
  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 allowed.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Pamela Celiz, PhD +346387844908
Listed Location Countries  ICMJE Spain
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT03248427
Other Study ID Numbers  ICMJE SOLTI1402
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party SOLTI Breast Cancer Research Group
Study Sponsor  ICMJE SOLTI Breast Cancer Research Group
Collaborators  ICMJE Novartis
Investigators  ICMJE
Principal Investigator: Aleix Prat, PhD H.Clinic de Barcelona/
Principal Investigator: Joaquin Gavilá, MD Fundación Instituto Valenciano de Oncología
PRS Account SOLTI Breast Cancer Research Group
Verification Date November 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP