Chemotherapy De-escalation in HR +, HER2-, Intermediate-risk Early Breast Cancer Treated With Adjuvant Ribociclib (NoLEEta)

No Chemotherapy in Intermediate-risk HR+ HER2- Early Breast Cancer Treated With Ribociclib (LEE-011) in the Adjuvant Setting, a Non-inferiority Phase III Trial

The advent of CDK4/6 inhibitors (drugs designed to block the action of CDK4/6 proteins, which play a key role in cell proliferation) has improved treatment prospects for patients with metastatic breast cancer whose tumour cells express hormone receptors but not the HER2 protein (HR+/HER2-). The NATALEE study showed that the addition of ribociclib for three years to conventional adjuvant hormone therapy (i.e. after surgery) prolonged survival free of invasive disease (i.e. extending to surrounding tissues) in patients with early HR breast cancer+ /HER2-. Unlike other studies, NATALEE included a group of patients at intermediate risk of recurrence, usually treated with adjuvant chemotherapy before receiving hormone therapy. However, the benefit of adjuvant chemotherapy in these patients is uncertain. The hypothesis of the NoLEEta study is that by using the CDK 4/6 inhibitor, patients could avoid adjuvant chemotherapy and therefore be spared the side-effects associated with this chemotherapy, without reducing the efficacy of the treatment.

Study Overview

• Status: Recruiting
• Conditions: Breast Cancer
• Intervention / Treatment: Other: De-escalation; Drug: Chemotherapy followed by endocrine therapy and ribociclib treatment

Detailed Description

The advent of CDK4/6 inhibitors has changed the outlook of patients with metastatic hormone receptor-positive (HR+) HER2- breast cancer. Moreover, including CDK4/6 inhibitors in the adjuvant treatment regimens strategies has led to significant gains in disease-free survival.

The phase III NATALEE trial demonstrated the efficacy of an adjuvant three-year treatment with ribociclib in prolonging invasive disease-free survival (iDFS) in patients with intermediate and high-risk HR+ HER2- early breast cancer.

Contrarily to similar studies of CDK4/6 inhibitors in this setting, NATALEE included a group of patients with intermediate clinical risk (pT1-2 pN1, pT3-4 pN0 or pT2 pN0 with histological grade 3 or grade 2 with Ki67≥ 20%). These patients are usually considered for adjuvant chemotherapy based on their clinicopathological conditions or the results of a genomic signature (e.g. Oncotype Dx). Nevertheless, the benefit of adjuvant chemotherapy in these patients is uncertain (and likely small) in the context of an adjuvant treatment strategy that includes a CDK 4/6 inhibitor.

As such, a de-escalation trial could demonstrate that patients with intermediate-risk breast cancer treated with CDK4/6 inhibitors could be spared the dreaded chemotherapy side effects while ensuring similar survival outcomes.

In order to be generalizable and practice changing, a trial in this setting should aim to be as pragmatic as possible, particularly in inclusion criteria, with the required resources for patient inclusion and delivery of care being as similar as possible to those employed in usual care. As such, chemotherapy eligibility should be defined similarly to routine clinical practice in the participating centers (i.e. using routine clinicopathological parameters and/or genomic signatures).

While single-arm designs could help address non-inferiority in the previously mentioned setting, they are usually compared to historical controls and lack external validation. Moreover, in some settings, like early breast cancer, the standard of care may change relatively quickly (e.g. Oncotype Dx-based chemotherapy de-escalation or adjuvant CDK4/6 inhibitors use), rendering the comparison to historical controls challenging, limiting the study conclusions and their impact on clinical practice. Finally, there is no consensus on the optimal non-inferiority threshold in single-arm trials using historical controls as a comparator. As such, randomized controlled non-inferiority trials with a strict non-inferiority margin remain the gold standard design to prove that a de-escalated treatment regimen is safe and advantageous, and the only ones capable of producing level IA evidence according to ESMO (Trapani et al., Annals of Oncology 2022).

• Study Type: Interventional
• Enrollment (Estimated): 3902
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Sandrine Marques; Phone Number: +33 (0) 6 17 90 00 54; Email: s-marques@unicancer.fr

Study Locations

• France
  • Amiens, France, 80090
    • Not yet recruiting
    • Clinique de l'Europe
  • Angers, France, 49055
    • Not yet recruiting
    • Institut de Cancérologie de l'Ouest - Site Paul Papin
  • Argenteuil, France, 95107
    • Not yet recruiting
    • CH Victor Dupouy
  • Aurillac, France, 15000
    • Active, not recruiting
    • CH Henri Mondor
  • Auxerre, France
    • Not yet recruiting
    • Centre Hospitalier d'Auxerre
  • Avignon, France, 84918
    • Recruiting
    • Sainte Catherine - Institut du Cancer Avignon Provence
  • Bayonne, France, 64100
    • Active, not recruiting
    • Centre Hospitalier de la Cote Basque
  • Beauvais, France, 60021
    • Active, not recruiting
    • Centre Hospitalier Simone Veil de Beauvais
  • Besançon, France, 25000
    • Not yet recruiting
    • CENTRE HOSPITALIER UNIVERSITAIRE de BESANCON
  • Bordeaux, France, 33076
    • Not yet recruiting
    • Institut Bergonié
  • Bordeaux, France
    • Not yet recruiting
    • Clinique Tivoli
  • Caen, France, 14000
    • Not yet recruiting
    • Centre Francois Baclesse
  • Carcassonne, France, 11000
    • Not yet recruiting
    • Centre Hospitalier de Carcassonne
  • Chalon-sur-Saône, France
    • Active, not recruiting
    • Centre Hospitalier William Morey
  • Chambray-lès-Tours, France, 37170
    • Not yet recruiting
    • Centre d'Oncologie et de Radiothérapie 37
  • Chambéry, France, 73000
    • Active, not recruiting
    • Centre Hospitalier Métropole de Savoie
  • Cholet, France, 49300
    • Not yet recruiting
    • CH Cholet
  • Clermont-Ferrand, France, 63011
    • Not yet recruiting
    • Centre Jean Perrin
  • Colmar, France, 68000
    • Active, not recruiting
    • Hospices Civils de Colmar
  • Compiègne, France, 60200
    • Not yet recruiting
    • Polyclinique Saint Côme
  • Coudekerque-Branche, France, 59210
    • Not yet recruiting
    • Clinique de Flandre
  • Dijon, France, 21000
    • Not yet recruiting
    • Institut de Cancérologie de Bourgogne
  • Fréjus, France
    • Active, not recruiting
    • CHI Fréjus St-Raphaël
  • La Chaussée-Saint-Victor, France, 41260
    • Not yet recruiting
    • Polyclinique de Blois
  • La Roche-sur-Yon, France, 85925
    • Not yet recruiting
    • Centre Hospitalier Départemental de Vendée
  • La Tronche, France
    • Not yet recruiting
    • CHU Grenoble
  • Le Chesnay, France, 78150
    • Not yet recruiting
    • Centre Hospitalier De Versailles
  • Le Mans, France, 72000
    • Not yet recruiting
    • Clinique Victor Hugo
  • Le Mans, France, 72000
    • Not yet recruiting
    • Centre Hospitalier Le Mans
  • Limoges, France, 87039
    • Not yet recruiting
    • Polyclinique de Limoges - Site Cinique Chénieux
  • Limoges, France, 87042
    • Active, not recruiting
    • Centre Hospitalier Universitaire de Limoges
  • Lyon, France, 69008
    • Recruiting
    • Centre Leon Berard
  • Lyon, France, 69008
    • Active, not recruiting
    • Hopital Prive Jean Mermoz
  • Marseille, France
    • Not yet recruiting
    • Institut Paoli Calmettes
  • Metz-Tessy, France
    • Not yet recruiting
    • Centre Hospitalier Annecy Genevois
  • Montpellier, France, 34070
    • Recruiting
    • Centre de Cancerologie du Grand Montpellier
  • Mulhouse, France, 68100
    • Recruiting
    • Groupe Hospitalier De La Region De Mulhouse Et Sud Alsace (GHRMSA)
  • Nantes, France
    • Not yet recruiting
    • Hôpital Privé du Confluent
  • Nice, France, 06189
    • Recruiting
    • Centre Antoine Lacassagne
  • Nîmes, France, 30029
    • Not yet recruiting
    • CHU de NÎMES - Institut de Cancérologie du Gard
  • Orléans, France
    • Active, not recruiting
    • CHU Orléans
  • Paris, France, 75010
    • Not yet recruiting
    • Hopital Saint Louis
  • Paris, France, 75020
    • Not yet recruiting
    • Hôpital Tenon APHP
  • Paris, France, 75020
    • Active, not recruiting
    • Hopital Diaconesses-Croix Saint Simon
  • Pau, France, 64046
    • Active, not recruiting
    • Centre Hospitalier de Pau
  • Pierre-Bénite, France
    • Not yet recruiting
    • Hospices Civils de Lyon - Centre principal: Hôpital Lyon Sud
  • Plérin, France
    • Active, not recruiting
    • CARIO - Centre Armoricain Radiothérapie Imagerie Médicale et Oncologie
  • Poitiers, France, 86180
    • Not yet recruiting
    • CHU Poitiers
  • Pontoise, France, 95300
    • Not yet recruiting
    • Hôpital NOVO - Site PONTOISE
  • Quimper, France, 29000
    • Not yet recruiting
    • Centre Hospitalier de Quimper
  • Quint-Fonsegrives, France, 31130
    • Not yet recruiting
    • Clinique de la Croix du Sud
  • Reims, France, 51100
    • Recruiting
    • Institut Jean Godinot
  • Rennes, France, 35042
    • Active, not recruiting
    • Centre Eugène Marquis
  • Rouen, France
    • Not yet recruiting
    • Centre Henri Becquerel
  • Saint-Cloud, France, 92219
    • Recruiting
    • Institut Curie
  • Saint-Etienne, France, 42100
    • Active, not recruiting
    • Hôpital Privé de la Loire
  • Saint-Etienne, France, 42270
    • Recruiting
    • CHU de Saint Etienne
  • Saint-Herblain, France, 44800
    • Not yet recruiting
    • Institut de Cancérologie de l'Ouest - Site René Gauducheau
  • Saint-Nazaire, France, 44600
    • Active, not recruiting
    • Clinique Mutualiste de l'Estuaire
  • Sarcelles, France, 95200
    • Not yet recruiting
    • Institut de Cancérologie Paris Nord - GCS RISSA
  • St-Malo, France, 35400
    • Not yet recruiting
    • Groupe Hospitalier Rance Emeraude (GHRE)
  • Strasbourg, France
    • Active, not recruiting
    • Centre Paul Stauss
  • Thonon-les-Bains, France, 74200
    • Active, not recruiting
    • Hopitaux du Leman
  • Toulouse, France, 31059
    • Recruiting
    • Institut Claudius Regaud
  • Tours, France, 37000
    • Not yet recruiting
    • Chu Bretonneau
  • Valence, France, 26000
    • Not yet recruiting
    • Centre Hospitalier de Valence
  • Vandœuvre-lès-Nancy, France
    • Recruiting
    • Institut de Cancerologie de Lorraine
  • Villejuif, France
    • Active, not recruiting
    • Gustave Roussy
  • Île-de-France Region
    • Marseille, Île-de-France Region, France, 13009
      • Not yet recruiting
      • Institut Paoli Calmettes
    • Paris, Île-de-France Region, France, 75005
      • Recruiting
      • Institut Curie
• Germany
  • Aachen, Germany, 52074
    • Not yet recruiting
    • Universitätsklinikum Aachen AöR
  • Augsburg, Germany, 86150
    • Not yet recruiting
    • Hämatologie-Onkologie im Zentrum MVZ GmbH
  • Bad Nauheim, Germany, 61231
    • Not yet recruiting
    • GZW Hochwaldkrankenhaus
  • Berlin, Germany, 13125
    • Not yet recruiting
    • HELIOS Klinikum Berlin Buch
  • Berlin, Germany, 10367
    • Not yet recruiting
    • Praxisklinik Krebsheilkunde für Frauen / Brustzentrum
  • Bremen, Germany, 28209
    • Not yet recruiting
    • Hämato-Onklogische Praxis im Medicum
  • Cottbus, Germany, 03048
    • Not yet recruiting
    • Medizinische Universität Lausitz - Carl-Thiem
  • Dresden, Germany, 01307
    • Not yet recruiting
    • Universitatsklinikum Carl Gustav Carus An Der Technischen Universitat Dresden
  • Düsseldorf, Germany, 40235
    • Not yet recruiting
    • MVZ Medical Center Düsseldorf GmbH
  • Düsseldorf, Germany, 40225
    • Not yet recruiting
    • Universitätsklinikum Düsseldorf AöR
  • Eschweiler, Germany, 52249
    • Not yet recruiting
    • St.-Antonius-Hospital
  • Esslingen am Neckar, Germany, 73730
    • Not yet recruiting
    • Klinikum Esslingen GmbH
  • Frankfurt, Germany, 60431
    • Not yet recruiting
    • Agaplesion Markus Krankenhaus
  • Gelsenkirchen, Germany, 45879
    • Not yet recruiting
    • Evangelisches Klinikum Gelsenkirchen
  • Hamburg, Germany, 20357
    • Not yet recruiting
    • Mammazentrum HH am Krankenhaus Jerusalem
  • Heidelberg, Germany, 69120
    • Not yet recruiting
    • Nationales Centrum für Tumorerkrankungen
  • Kassel, Germany, 34117
    • Not yet recruiting
    • Elisabeth Krankenhaus Kassel
  • Koblenz, Germany, 56068
    • Not yet recruiting
    • InVO - Institut für Versorgungsforschung in der Onkologie
  • Leipzig, Germany, 04103
    • Not yet recruiting
    • Universitätsklinikum Leipzig
  • Mannheim, Germany, 68167
    • Not yet recruiting
    • Universitätsmedizin Mannheim
  • Münster, Germany, 48149
    • Not yet recruiting
    • University Hospital Münster
  • Münster, Germany, 48145
    • Not yet recruiting
    • St. Franziskus-Hospital Münster
  • Offenbach, Germany, 63069
    • Not yet recruiting
    • Sana Klinikum Offenbach
  • Ravensburg, Germany, 88212
    • Not yet recruiting
    • MVZ für Hämatologie und Onkologie Ravensburg GmbH
  • Rostock, Germany, 18059
    • Not yet recruiting
    • University of Rostock
  • Tübingen, Germany, 72076
    • Not yet recruiting
    • Universitätsklinikum Tübingen AöR
  • Ulm, Germany, 89075
    • Not yet recruiting
    • Universitatsklinikum Ulm
  • Worms, Germany, 67550
    • Not yet recruiting
    • Klinikum Worms gGmbH
• Italy
  • Aviano, Italy, 33081
    • Not yet recruiting
    • IRCCS Centro di Riferimento Oncologico
  • Caserta, Italy, 81100
    • Not yet recruiting
    • AORN Sant'Anna e San Sebastiano
  • Genova, Italy, 16132
    • Not yet recruiting
    • IRCCS Ospedale Policlinico San Martino - Università di Genova
  • Naples, Italy, 80131
    • Not yet recruiting
    • Azienda Ospedaliero-Universitaria Federico II
  • Naples, Italy, 80131
    • Not yet recruiting
    • IRCCS Istituto Nazionale dei Tumori Fondazione "G. Pascale"
  • Padova, Italy, 32128
    • Not yet recruiting
    • IRCCS Istituto Oncologico Veneto
  • Pisa, Italy, 56100
    • Not yet recruiting
    • Azienda Ospedaliero Universitaria Pisana
  • Pontedera, Italy, 56125
    • Not yet recruiting
    • Ospedale F. Lotti Pontedera e Volterra, AUSL Toscana Nord Ovest
  • Roma, Italy, 00168
    • Not yet recruiting
    • IRCCS Fondazione Policlinico Universitaria "A. Gemelli"
• Netherlands
  • Arnhem, Netherlands, 6815 AD
    • Not yet recruiting
    • Rijnstate Ziekenhuis Stichting
  • Hilversum, Netherlands, 1212 VG
    • Not yet recruiting
    • Tergooiziekenhuizen
  • Hoofddorp, Netherlands, 2134 TM
    • Not yet recruiting
    • Spaarne Gasthuis Stichting
  • Leeuwarden, Netherlands, 8934 AD
    • Not yet recruiting
    • Frisius MC
  • Leiden, Netherlands, 2333 ZA
    • Not yet recruiting
    • Leids Universitair Medisch Centrum (LUMC)
  • Venlo, Netherlands, 5912 BL
    • Not yet recruiting
    • Stichting Viecuri Medisch Centrum voor Noord-Limburg
• Spain
  • Badajoz, Spain, 06006
    • Recruiting
    • Hospital Universitario de Badajoz
  • Barcelona, Spain, 08036
    • Recruiting
    • Hospital Clinic De Barcelona
  • Barcelona, Spain, 08035
    • Recruiting
    • Hospital Vall d'Hebron
  • Barcelona, Spain, 08003
    • Not yet recruiting
    • Hospital del Mar
  • Bilbao, Spain, 48013
    • Not yet recruiting
    • Hospital Universitario de Basurto
  • Fuenlabrada, Spain, 28942
    • Not yet recruiting
    • Hospital Universitario de Fuenlabrada
  • Granada, Spain, 18016
    • Recruiting
    • Hospital Universitario Clínico San Cecilio
  • Jaén, Spain, 23007
    • Recruiting
    • Hospital Universitario de Jaén
  • Jerez de la Frontera, Spain, 11405
    • Recruiting
    • Hospital Universitario de Jerez
  • L'Hospitalet de Llobregat, Spain, 08908
    • Recruiting
    • ICO Hospitalet
  • Las Palmas de Gran Canaria, Spain, 35016
    • Recruiting
    • Complejo Hospitalario Insular Materno-Infantil
  • Leganés, Spain, 28911
    • Not yet recruiting
    • Hospital Severo Ochoa
  • Lleida, Spain, 25198
    • Recruiting
    • Hospital Universitario Arnau de Vilanova de Lleida
  • Madrid, Spain, 28041
    • Not yet recruiting
    • Hospital Universitario 12 Octubre
  • Mataró, Spain, 08304
    • Recruiting
    • Hospital de Mataró
  • Murcia, Spain, 30120
    • Recruiting
    • Hospital Universitario Virgen de La Arrixaca
  • Málaga, Spain, 29011
    • Recruiting
    • Hospital Materno-Infantil Málaga
  • Móstoles, Spain, 28933
    • Not yet recruiting
    • Hospital Universitario Rey Juan Carlos
  • Palma de Mallorca, Spain, 07120
    • Recruiting
    • Hospital Universitario Son Espases
  • Palma de Mallorca, Spain, 07198
    • Recruiting
    • Hospital Son Universitario Son Llatzer
  • Reus, Spain, 43204
    • Recruiting
    • Hospital Universitari Sant Joan de Reus
  • Sabadell, Spain, 08208
    • Recruiting
    • Hospital Universitari Parc Tauli
  • Santander, Spain, 39008
    • Recruiting
    • Hospital Universitario Marques de Valdecilla
  • Seville, Spain, 41013
    • Not yet recruiting
    • Hospital Universitario Virgen del Rocio
  • Valencia, Spain, 46026
    • Recruiting
    • Hospital la Fé

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patient must have signed a written informed consent prior to any trial-specific screening procedure.

   Note: When the patient is physically unable to give their written consent, an impartial witness of their choice, independent from the investigator or the sponsor, can confirm in writing the patient's consent.

2. Patient is ≥ 18 years old.

3. Patient is female with known menopausal status at the time of randomization.

   Post-menopausal status is defined as:

   1. Patient underwent bilateral oophorectomy, or
   2. Age ≥ 60 years, or
   3. Age < 60 years and either amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene or ovarian suppression) or Follicle-stimulating hormone (FSH) and plasma estradiol are in the postmenopausal ranges per local normal ranges.
   4. If taking tamoxifen or toremifene and age <60 years, then FSH and plasma estradiol level in postmenopausal ranges.

4. The following criteria must be met for histologically confirmed invasive breast carcinoma, as determined by the local pathologist:

   1. Pathological stage (8th edition of the AJCC), including pT2 pN0 Grade 3 or pT2 pN0 Grade 2 with Ki67≥20% or pT0-2 pN1 or pT3-4 pN0
   2. ER-positive (with tumor cells showing ≥10% ER staining) and HER2-negative according to the most recent ASCO/CAP guidelines.

   Note: Multifocal and multicentric tumors are allowed if they meet the clinical stage II criteria of the 8th Edition of the AJCC. All tumors must be ER-positive and HER2-negative. Patients with bilateral invasive breast cancer (diagnosed simultaneously or within 6 months of each other) are eligible if all lesions tested on both sides are ER+ (ie, ≥10% positive stained cells) and HER2- AND adequate surgery has been performed in both breasts.

5. Chemotherapy eligible per investigator decision, based on clinicopathological findings or the results of any genomic signature.
6. Patient has no contraindication for the adjuvant endocrine therapy (ET) or chemotherapy in the trial and is planned to be treated with ET for 5 years (after randomization date) or more.
7. Curative surgery for the invasive disease must have been performed with negative surgical margins within 12 weeks before randomization. If positive surgical margins, patients are eligible if revision surgery or other adequate local treatment (i.e local radiotherapy) is planned.
8. Women of childbearing potential (CBP) must have a confirmed negative serum pregnancy test (β-hCG) before starting study treatment.
9. Women of childbearing potential must agree to use one effective form of contraception during trial treatment and up to 21 days after the last dose of study drugs or longer, if required per standard of care;
10. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 within 28 days prior to randomization.

11. Adequate hematological, renal, and hepatic function, as outlined below:

    1. Absolute neutrophil count (ANC) ≥1.5 x 10⁹/L
    2. Platelet count ≥100 x 10⁹/L
    3. Hemoglobin ≥9 g/dL
    4. Total bilirubin < ULN. Patients with known Gilbert syndrome may be enrolled with total bilirubin ≤3 x ULN or direct bilirubin ≤1.5 x ULN
    5. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2.5 x ULN
    6. Serum creatinine ≤1.5 mg/dL or calculated creatinine clearance ≥60 mL/min/1.73m² (CKD-EPI equation (2021))
    7. Potassium, total calcium (corrected for serum albumin), and magnesium should be within institutional normal limits or corrected to within normal limits using supplements before the first dose of study medication.

12. Standard 12-lead ECG values assessed, as:

    1. QTcF interval (QT interval using Fridericia's correction) at screening < 450 milliseconds (msec)
    2. Resting heart rate 50-100 beats per minute (determined from the ECG)
13. Patient must be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other trial procedures.
14. Absence of any psychological, familial or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.
15. Patients must be affiliated to a Social Security System (or equivalent) based on local regulations.

Exclusion Criteria:

1. Patient has received any neoadjuvant chemotherapy since her breast cancer diagnosis or has received any prior CDK4/6 inhibitor.
2. Breast cancer diagnosed while patient was receiving tamoxifen, raloxifene or aromatase inhibitors (AIs) for reduction in risk ("chemoprevention") of breast cancer and/or treatment for osteoporosis within the last 2 years prior to randomization.
3. Patient with a known hypersensitivity to any of the excipients of ribociclib and/or ET (e.g. rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption, and soy or peanut allergy).
4. Patient with evidence or history of distant metastases of breast cancer beyond regional lymph nodes (stage IV according to AJCC 8th edition), inflammatory breast cancer, breast cancer recurrence (local or distant) or a different primary breast cancer.
5. Patient has a concurrent invasive malignancy or a prior invasive malignancy whose treatment was completed within 2 years before randomization. Note: Patients with adequately treated basal or squamous cell skin carcinoma or curatively resected cervical cancer in situ are eligible.
6. Patients whose breast cancer is considered as endocrine therapy insensitive, as determined by investigator's opinion; this may include (but is not limited to) breast cancer classified as " basal like " by molecular signatures (if available in the patient file) and/or breast cancer with persistently high proliferation after pre-operative endocrine therapy.
7. Patient has had major surgery within 14 days prior to study treatment initiation.

8. Patient has known history of human immunodeficiency virus (HIV) infection (testing is not mandatory) whose antiretroviral therapy (ART) has a known strong CYP3A4 inhibitor with potential for DDI with ribociclib. Patients with HIV may be enrolled if they fulfil the criteria recommended by FDA and ASCO guidelines (FDA Guidance, Uldrick et al. 2017):

   1. CD4+ T-cell (CD4+) counts ≥ 350 cells/µL, AND
   2. No history of AIDS-defining opportunistic infections within the past 12 months (prophylactic antimicrobials allowed if no drug-drug interactions or overlapping toxicities), AND
   3. On established ART which is not a strong CYP3A4 inhibitor, for at least 4 weeks and have an HIV viral load less than 400 copies/mL prior to enrolment. Effective ART is defined as a drug, dosage, and schedule associated with reduction and control of the viral load.
9. Patient has known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (testing is not mandatory).

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

    1. History of documented myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft within 6 months prior to trial entry.
    2. Documented cardiomyopathy.
    3. Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) (testing not mandatory)

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

       • Risk factors for Torsades de Pointes (TdP) including uncorrected hypocalcemia, hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia.
       • Concomitant medication(s) with a known risk to prolong the QT interval and/or known to cause TdP that cannot be discontinued or replaced by safe alternative medication (e.g. within 5 half-lives or 7 days prior to starting trial treatment).
       • Inability to determine the QTcF interval.
    5. Clinically significant cardiac arrhythmias (e.g. ventricular tachycardia), complete left bundle branch block, high-grade Atrioventricular (AV) block (e.g. bifascicular block, Mobitz type II and third degree AV block).
    6. Uncontrolled arterial hypertension with systolic blood pressure >160 mmHg.
11. Presence of any other medical conditions, including respiratory or metabolic dysfunction, physical examination findings, or laboratory results that raise reasonable suspicion of a contraindication to the use of an experimental drug, potential impact on compliance with the study protocol, influence on result interpretation, or increased risk of treatment complications for the patients (such as severe dyspnea at rest or requiring oxygen therapy, history of major surgical resection involving the stomach or small bowel, preexisting Crohn's disease or ulcerative colitis, or a preexisting chronic condition resulting in clinically significant diarrhea).
12. Previous history of pneumonitis, regardless of cause.

13. Patient is currently receiving any of the following substances within 7 days before randomization and which cannot be stopped within seven days prior to the start of treatment:

    1. Concomitant medications, herbal supplements, and/or fruits (e.g. grapefruit, pummelos, starfruit, Seville oranges) and their juices that are known as strong inhibitors or inducers of CYP3A4/5
    2. Medications that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5
    3. Any medication prohibited according to the instructions for goserelin, leuprolide or triptorelin (pre-menopausal patients), anastrozole, exemestane, letrozole, or ribociclib.
    4. Medications known to have a risk of prolonging the QT interval or causing Torsades de Pointes.
14. Patient is concurrently using hormone replacement therapy. Estrogen replacement therapy discontinued less than two weeks prior to the start of treatment.

15. Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting trial treatment, or has not fully recovered from side effects of such treatment.

    Note: The following uses of corticosteroids are permitted: a short duration (<5 days) of systemic corticosteroids; any duration of topical applications (e.g. for rash), inhaled sprays (e.g. for obstructive airways diseases), eye drops or local injections (e.g. intra-articular).

16. 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 trial or compromise compliance with the protocol (e.g. chronic pancreatitis, chronic active hepatitis, liver cirrhosis or any other significant liver disease, active untreated or uncontrolled fungal, bacterial or viral infections, active infection requiring systemic anti-bacterial therapy, etc.) or limit life expectancy to ≤5 years.
17. Participation in other studies involving investigational drug(s) within 30 days prior to randomization or within 5 half-lives of the investigational drug(s) (whichever is longer), or participation in any other type of medical research judged not to be scientifically or medically compatible with this trial. If the patient is enrolled or planned to be enrolled in another study that does not involve an investigational drug, the agreement of the sponsor is required to establish eligibility.
18. Inability or unwillingness to swallow oral pills.
19. Presence of malabsorption syndrome or any other condition that could hinder the absorption of study drugs in the gastrointestinal tract.
20. Any psychological, familial, sociological, or geographical factors that may impede adherence to the study protocol and follow-up schedule.
21. Pregnant or breast-feeding (lactating) women or women who plan to become pregnant or breast-feed during the first 48 months of adjuvant therapy.
22. Persons deprived of their liberty or under protective custody or guardianship.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Investigational arm (Arm A); Ribociclib and endocrine therapy (ET)	Other: De-escalation; De-escalation of the chemotherapy in the adjuvant setting; Other Names: Ribociclib; Adjuvant hormonotherapy
Other: Control arm (Arm B); Chemotherapy followed by ribociclib and endocrine therapy	Drug: Chemotherapy followed by endocrine therapy and ribociclib treatment; Endocrine therapy and ribociclib treatment; Other Names: Ribociclib; Adjuvant hormonotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Invasive breast cancer-free survival (iBCFS)	iBCFS is defined as the time from the date of randomization to the date of the first event of invasive ipsilateral breast tumor recurrence, local-regional invasive recurrence, distant recurrence, death (any cause) or invasive contralateral breast cancer as assessed by investigator.	From ramdomization to iBCFS, up to 12 years.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Invasive disease-free survival (iDFS)	iDFS is defined as the time from date of randomization to the date of the first iDFS event that is: i) same event as IBCFS, or ii) secondary invasive non breast cancer.	From ramdomization to iDFS event, up to 12 years.
Distance disease-free survival (DDFS)	DDFS is defined as the time from the date of randomization to the date of the first event of distant recurrence, death (any cause), or second primary non-breast invasive cancer (excluding basal and squamous cell carcinomas of the skin).	From ramdomization to DDFS event, up to 12 years.
Overall survival (OS)	OS is defined as the time from the date of randomization to the date of death due to any cause	From ramdomization to death from any cause, up to 12 years.
Type of iBCFS event	To evaluate the rate of the different types of iBCFS events in each treatment arm	From ramdomization to iBCFS event, up to 12 years.
Acute and late toxicity during the study focusing on grade ≥2	The National Cancer Institute-Common Terminology Criteria for Adverse Events version 5 (NCI-CTCAE v5) is widely accepted in the community of oncology research as the leading rating scale for adverse events. This scale, divided into 5 grades (1 = "mild", 2 = "moderate", 3 = "severe", 4 = "life-threatening", and 5 = "death")	Throughout study completion, up to 8.5 years.
Quality of life questionnaire - Core 30 (QLQ-C30)	Developed by the EORTC, this self-reported questionnaire assesses the health-related quality of life of cancer patients in clinical trials. The questionnaire includes five functional scales (physical, everyday activity, cognitive, emotional, and social), three symptom scales (fatigue, pain, nausea and vomiting), a health/quality of life overall scale, and a number of additional elements assessing common symptoms (including dyspnea, loss of appetite, insomnia, constipation, and diarrhea), as well as, the perceived financial impact of the disease. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level.	At baseline, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, 8.5 years from randomization.
Quality of Life Questionnaire - Breast cancer module (QLQ-BR42)	This EORTC breast cancer specific questionnaire is intended to supplement the QLQ-C30. The QLQ-BR42 incorporates nine multi-item scales to assess body image, sexual functioning, breast satisfaction, systemic therapy side effects, arm symptoms, breast symptoms, endocrine therapy symptoms, skin mucosis symptoms, endocrine sexual symptoms. In addition, single items assess sexual enjoyment, future perspective and being upset by hair loss. All items are rated on a four-point Likert-type scale (1 = "not at all", 2 = "a little", 3 = "quite a bit", and 4 = "very much"), and are linearly transformed to a 0-100 scale. Higher scores indicate more severe symptoms or problems for all items.	At baseline, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, 8.5 years from randomization.

Collaborators and Investigators

• Sponsor: UNICANCER
• Collaborators: Novartis; Latin American Cooperative Oncology Group; Canadian Cancer Trials Group; SOLTI Breast Cancer Research Group; BOOG Study Center; Gruppo Italiano Mammella (GIM); Menarini Silicon Biosystems, INC; GBG Forschungs GmbH; Swiss Cancer Institute
• Investigators: Principal Investigator: François-Clément BIDARD, PhD, Institut Curie

Study record dates

Study Major Dates

• Study Start (Actual): December 18, 2025
• Primary Completion (Estimated): November 30, 2033
• Study Completion (Estimated): December 31, 2037

Study Registration Dates

• First Submitted: November 14, 2025
• First Submitted That Met QC Criteria: November 14, 2025
• First Posted (Actual): November 19, 2025

Study Record Updates

• Last Update Posted (Actual): May 26, 2026
• Last Update Submitted That Met QC Criteria: May 22, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Chemotherapy; De-escalation
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Breast Neoplasms; Therapeutics; ribociclib
• Other Study ID Numbers: UC-BCG-2501; 2025-520979-13-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual Participant Data will not be shared at an individual level. Those data will be part of the study database including all enrolled patients.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No