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

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ClinicalTrials.gov Identifier: NCT03248427
Recruitment Status : Recruiting
First Posted : August 14, 2017
Last Update Posted : November 16, 2018
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
SOLTI Breast Cancer Research Group

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.

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: Ribociclib Drug: Letrozole 2.5mg Drug: Doxorubicin Drug: Cyclophosphamide Drug: Paclitaxel Phase 2

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


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 94 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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.
Actual Study Start Date : July 13, 2017
Estimated Primary Completion Date : May 2019
Estimated Study Completion Date : May 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Ribociclib + Letrozol
Ribociclib: 600mg, 3-weeks-on/-week-off treatment Letrozole: 2.5mg daily; Six 28 days cycles
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

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
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




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. PEPI Score [ Time Frame: 24 weeks ]
    Preoperative endocrine prognostic index (PEPI) score in the ribociclib plus letrozole treatment arm compared to historical values

  4. Rate of breast conserving surgery (BCS) [ Time Frame: 24 weeks ]
    Rate of breast conserving surgery

  5. Decrease in Ki67 in both treatment arms. [ Time Frame: At baseline, in week 2, and pre-surgery ]
    Decrease in Ki67 in both treatment arms.

  6. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03248427


Contacts
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Contact: Pamela Celiz, PhD +346387844908 pamela.celiz@gruposolti.org

Locations
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Spain
Hospital Clinic de Barcelona Recruiting
Barcelona, Spain
Contact: Montse Muñoz         
Hospital General de Catalunya Recruiting
Barcelona, Spain
Contact: Xavier González Farré         
Hospital Universitari Vall d' Hebron Recruiting
Barcelona, Spain
Contact: Cristina Saura         
Institut Català d'Oncologia l'Hospitalet Not yet recruiting
Barcelona, Spain
Contact: Juan Miguel Gil         
Consorcio Hospitalario Provincial de Castellón Recruiting
Castelló, Spain
Contact: Eduardo Martínez Dueñas         
Hospital San Pedro de Alcántara Recruiting
Cáceres, Spain
Contact: Santiago Gonzalez         
Fundació Privada Hospital Asil de Granollers Not yet recruiting
Granollers, Spain
Contact: Vanesa Ortega         
Centro Integral Oncologico Clara Campal Recruiting
Madrid, Spain
Contact: Laura García Estevez         
Centro Oncológico MD Anderson International España Recruiting
Madrid, Spain
Contact: Raquel Bratos Lorenzo         
Hospital Quirón Madrid Recruiting
Madrid, Spain
Contact: Lucía González Cortijo         
Hospital Rey Juan Carlos Recruiting
Madrid, Spain
Contact: Sergio Hoyos Simón         
Hospital Universitario 12 de octubre Recruiting
Madrid, Spain
Contact: Eva Ciruelos         
Hospital Universitario Fundación de Alcorcón Recruiting
Madrid, Spain
Contact: Carlos Jara Sánchez         
Hospital Universitario Fundación Jiménez Díaz Recruiting
Madrid, Spain
Contact: Yann Izarzugaza         
Hospital Universitari Son Espases Recruiting
Palma, Spain
Contact: Neus Ferrer Tur         
Complexo Hospitalario Universitario de Santiago Recruiting
Santiago de Compostela, Spain
Contact: Rafael Lopez Lopez         
Hospital Virgen del Rocío Recruiting
Sevilla, Spain
Contact: Alvaro Montaño         
Hospital Virgen Macarena Recruiting
Sevilla, Spain
Contact: Juan Antonio Virizuela Echaburu         
Fundación Instituto Valenciano de Oncología Recruiting
Valencia, Spain
Contact: Joaquin Gavilá         
Hospital Clínico Universitario de Valencia Recruiting
Valencia, Spain
Contact: Begonia Bermejo         
Hospital Universitari Arnau de Vilanova de València Recruiting
Valencia, Spain
Contact: Antonio Llombart Cussac         
Sponsors and Collaborators
SOLTI Breast Cancer Research Group
Novartis
Investigators
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Principal Investigator: Aleix Prat, PhD H.Clinic de Barcelona/
Principal Investigator: Joaquin Gavilá, MD Fundación Instituto Valenciano de Oncología

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Responsible Party: SOLTI Breast Cancer Research Group
ClinicalTrials.gov Identifier: NCT03248427     History of Changes
Other Study ID Numbers: SOLTI1402
First Posted: August 14, 2017    Key Record Dates
Last Update Posted: November 16, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Keywords provided by SOLTI Breast Cancer Research Group:
Breast Cancer
Neoadjuvant
Luminal B tumors
Ribociclib
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Paclitaxel
Cyclophosphamide
Doxorubicin
Liposomal doxorubicin
Letrozole
Phenobarbital
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Aromatase Inhibitors
Steroid Synthesis Inhibitors