Early Breast CancerPhase 3NATALEENCT03701334
A Trial to Evaluate Efficacy and Safety of Ribociclib With Endocrine Therapy as Adjuvant Treatment in Patients With HR+/HER2- Early Breast Cancer
A Phase 3 study testing Ribociclib and Endocrine Therapy (ET) in people with Early Breast Cancer, run by Novartis Pharmaceuticals at 387 sites in 20 countries.
Trial summary
A phase III, multicenter, randomized, open-label trial to evaluate the efficacy and safety of ribociclib with Endocrine Therapy (ET) as an adjuvant treatment in women and men with Hormone Receptor positive (HR+), Human Epidermal Growth Factor Receptor 2 negative (HER2-) Early Breast Cancer (EBC). Read more about this study
- Who is it for?
- Ages 18 to 100 years
- Conditions the study is for
- Early Breast Cancer
- What is being tested?
- Ribociclib and Endocrine Therapy (ET)
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 5,101 participants
- Where
- 387 sitesin 20 countries
- Study dates
- 7 Dec 2018to 29 May 2030
- Phase
- Phase 3
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 100 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Signed and dated Patient Informed Consent Form (PICF) obtained prior to any trial-specific screening procedure.
- Patient is ≥ 18 years-old at the time of PICF signature.
- Patient is female with known menopausal status at the time of randomization or initiation of adjuvant ET (whichever occurs earlier), or male.
- Postmenopausal status is defined as:
- Patient underwent bilateral oophorectomy, or
- Age ≥ 60 years, or
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- Age < 60 years and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene or ovarian suppression) and Follicle-stimulating hormone (FSH) and plasma estradiol are in the postmenopausal ranges per local normal ranges.
- If taking tamoxifen or toremifene and age <60 years, then FSH and plasma estradiol level in postmenopausal ranges.
- Notes
- In women who are premenopausal at the beginning of adjuvant chemotherapy, amenorrhea is not a reliable indicator of menopausal status as ovarian function may still be intact or resume despite anovulation/amenorrhea. For these women with therapy-induced amenorrhea, serial measurements of FSH and/or estradiol per local clinical guidelines are required for determination of postmenopausal status.
- All women who do not meet the criteria for postmenopausal status are considered premenopausal for the purpose of this trial.
- Patient with histologically confirmed unilateral primary invasive adenocarcinoma of the breast with a date of initial cytologic or histologic diagnosis (i.e. date of the pathology report that confirmed the BC diagnosis) within 18 months prior to randomization. Patient with a multicentric and/or multifocal tumor is eligible if all histopathologically examined lesions meet the pathologic criteria in inclusion criteria 5 and 6.
- Patient has breast cancer that is positive for ER and/or PgR according to the local laboratory as determined on the most recently analyzed tissue sample.
- Patient has HER2-negative breast cancer defined as a negative in situ hybridization test or an immunohistochemistry (IHC) status of 0 or 1+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required to confirm the HER2-negative status (based on the most recently analyzed tissue sample tested by a local laboratory).
- Patient (except those enrolled in China) has available archival tumor tissue from the surgical specimen, for submission to a central laboratory (Note: in patients that underwent neoadjuvant systemic therapy and had a pathologic complete response, archival tumor tissue at the time of the initial diagnosis or before the administration of neoadjuvant therapy is mandatory).
- Patient, after surgical resection where tumor was removed completely, with the final surgical specimen microscopic margins free from tumor, and belongs to one of the following categories:
- Anatomic Stage Group III, or
- Anatomic Stage Group IIB, or
- Anatomic Stage Group IIA (subset)
- Notes:
- For patients whose tumors are Anatomic Stage IIA, N0:
- If Grade is 1 or unknown (Gx), patient is not eligible.
- If Grade 2, the gene expression test results (by Oncotype DX, Prosigna/PAM50, MammaPrint or EndoPredict EPclin) or Ki67 levels should be used if obtained as per local practice (i.e. are not mandatory for the purpose of the trial). Results must be available at screening.
- Patients that received neoadjuvant treatment must meet the above criteria (for stage, and if Stage IIA, N0, also for grade and Ki67 or gene expression test) in any presurgical staging/sample and/or in the surgical specimen.
- Categorization into the AJCC 8th edition Anatomic Stage Groups requires determination of the T, N and M categories. ALND is the preferred method for axillary lymph node staging, however SLN dissection can be used to determine the N category in the following cases:
- No metastasis in SLN (patient is considered as pN0).
- Only micrometastasis in SLN (patient is considered as pN1mi).
- Patients with T1-2 and no clinically-evident nodes prior to surgery, no neoadjuvant chemotherapy, at least one macrometastasis in 1 or 2 SLNs, no matted nodes or gross extranodal disease at the time of SLN dissection (patient is considered as pN1).
- In all other cases, ALND is required to determine the N category.
- If indicated, patient has completed adjuvant and/or neoadjuvant chemotherapy according to the institutional guidelines, prior to screening.
- If indicated, patient has completed adjuvant radiotherapy according to the institutional guidelines, prior to screening.
- Patient has no contraindication for the adjuvant ET in the trial and is planned to be treated with ET for 5 years (since randomization date) or more.
- Patient may have already received any standard neoadjuvant and/or adjuvant ET at the time of PICF signature, but randomization should occur within 12 months of the initial start date of ET. Ovarian suppression or short term ET for fertility preservation is not considered neoadjuvant/adjuvant ET. If patient was receiving tamoxifen or toremifene as adjuvant ET, a washout period of 5 half-lives (i.e. 35 days) prior to randomization is required (during that period patient can take AI).
- Patient has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
- Patient has adequate bone marrow and organ function as defined by the following local laboratory values:
- Absolute neutrophil count (ANC) ≥ 1.5 × 109/L
- Platelets ≥ 100 × 109/L
- Hemoglobin ≥ 9.0 g/dL
- Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73m2 according to the Modification of Diet in Renal Disease (MDRD) formula
- Alanine transaminase (ALT) < 2.5 × Upper Limit Normal (ULN)
- Aspartate transaminase (AST) < 2.5 × ULN
- Total serum bilirubin < ULN; or total bilirubin ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 × ULN in patients with well documented Gilbert's Syndrome
- International normalized ratio (INR) ≤ 1.5 (unless the patient is receiving anticoagulants and the INR is within the therapeutic range of intended use for that anticoagulant within 7 days prior to randomization)
- Patient must have the following laboratory values within normal limits or corrected to within normal limits with supplements (the local laboratory value should be documented within normal limits after the correction) before randomization:
- Potassium
- Magnesium
- Total Calcium (corrected for serum albumin)
- Standard 12-lead ECG values assessed by a central laboratory, as:
- QTcF interval (QT interval using Fridericia's correction) at screening < 450 milliseconds (msec)
- Resting heart rate 50-90 beats per minute (determined from the ECG)
- Patient must be willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other trial procedures.
- Women of childbearing potential (CBP), defined as all women physiologically capable of becoming pregnant (see Inclusion Criterion #18 for additional information), must have confirmed negative serum pregnancy test (for β-hCG) within 14 days prior to randomization.
- Women of CBP must be willing to use highly effective methods of contraception. Contraception must continue during the trial treatment and for 21 days after stopping the treatment. Highly effective contraception methods include:
- Total abstinence (when this is in line with the preferred and usual lifestyle of the patient). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
- Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy or tubal ligation at least 6 weeks before taking trial treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
- Male partner sterilization (at least 6 months prior to randomization). For female patients on the trial the vasectomized male partner should be the sole partner for that patient. If vasectomy of the male partner is the highly effective method of contraception chosen, the success of the vasectomy should be medically confirmed according to local practice.
- Placement of an intrauterine device (IUD).
- Notes:
- Use of oral (estrogen and progesterone), transdermal, injected, implanted, hormone containing intrauterine system or any other hormonal method of contraception is not allowed in this trial.
- Women are considered of CBP unless: they have had ≥ 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks prior to randomization. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment she is considered not of CBP.
- After the end of trial treatment, patients should use effective contraception according to local guidelines.
Who cannot join
- Patient has received any CDK4/6 inhibitor.
- Patient has received prior treatment with tamoxifen, raloxifene or AIs for reduction in risk ("chemoprevention") of breast cancer and/or treatment for osteoporosis within the last 2 years prior to randomization. Patient is concurrently using hormone replacement therapy.
- Patient has received prior treatment with anthracyclines at cumulative doses of 450 mg/m² or more for doxorubicin, or 900 mg/m² or more for epirubicin.
- 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 allergy).
- Patient with distant metastases of breast cancer beyond regional lymph nodes (stage IV according to AJCC 8th edition) and/or evidence of recurrence after curative surgery.
- Patient is concurrently using other anti-neoplastic therapy with the exception of adjuvant ET (see Inclusion Criterion #12).
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- Patient has had major surgery, chemotherapy or radiotherapy within 14 days prior to randomization.
- Patient has not recovered from clinical and laboratory acute toxicities related to prior anti-cancer therapies to a NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 4.03 Grade ≤1 at day of randomization. Exceptions to this criterion: patients with any grade of alopecia, amenorrhea, grade 2 neuropathy are allowed to enter the trial or other toxicities not considered a safety risk for the patient as per Investigator's discretion, are allowed to enter the trial.
- 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.
- Patient has known history of human immunodeficiency virus (HIV) infection (testing is not mandatory, unless required by local regulation).
- Patient has known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (testing is not mandatory, unless required by local regulation).
- Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, including any of the following:
- History of documented myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft within 6 months prior to trial entry.
- Documented cardiomyopathy.
- Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) (testing not mandatory)
- 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.
- 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).
- Uncontrolled arterial hypertension with systolic blood pressure > 160 mmHg.
- Patient is currently receiving any of the following substances within 7 days before randomization:
- Concomitant medications, herbal supplements, and/or fruits (e.g. grapefruit, pummellos, starfruit, Seville oranges) and their juices that are known as strong inhibitors or inducers of CYP3A4/5
- Medications that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5
- 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).
- Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the oral trial treatments (e.g. uncontrolled ulcerative diseases, uncontrolled nausea, vomiting or diarrhea, malabsorption syndrome, or small bowel resection).
- 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.
- 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 Medical Monitor is required to establish eligibility.
- Pregnant or breast-feeding (lactating) women or women who plan to become pregnant or breast-feed during the trial.
Trial locations and contacts
387 sites in 20 countries.
387 sites in 20 countries
United States73 sites
University of Michigan Cancer Center
Ann Arbor, Michigan, 48109
Randolph Medical Associates
Asheboro, North Carolina, 27204
Winship Cancer Institute of Emory University
Atlanta, Georgia, 30322
University Of Colorado Hospital
Aurora, Colorado, 80045
Comprehensive Blood and Cancer
Bakersfield, California, 93309
Mercy Medical Center
Baltimore, Maryland, 21202
UCLA Beverly Hills
Beverly Hills, California, 90212
St Vincent Frontier Cancer Center
Billings, Montana, 59102
University of Alabama at Birmingham-Kirklin Clinic
Birmingham, Alabama, 35294-0006
Massachusetts General Hospital
Boston, Massachusetts, 02114
UCLA Burbank
Burbank, California, 91505
Kaiser Permanente NW Region
Clackamas, Oregon, 97015
Baylor Charles A Sammons Cancer Cnt
Dallas, Texas, 75246
Rocky Mountain Cancer Centers
Denver, Colorado, 80218
Encino Research Center
Encino, California, 91436
Virginia Cancer Specialists
Fairfax, Virginia, 22031
Holy Cross Hospital-Ft. Lauderdale
Fort Lauderdale, Florida, 33308
Florida Cancer Specialists
Fort Myers, Florida, 33901
Ctr For Cancer And Blood Disorders
Fort Worth, Texas, 76104
St. Jude Heritage Medical Group
Fullerton, California, 92835
The West Clinic
Germantown, Tennessee, 38138
Cancer Treatment Centers of America
Goodyear, Arizona, 85338
Saint Francis Medical Center
Grand Island, Nebraska, 68803
Cone Health Cancer Center
Greensboro, North Carolina, 27403
Comprehensive Cancer Cntr Of Nevada
Henderson, Nevada, 89052
Penn State Hershey Cancer Institute
Hershey, Pennsylvania, 17033
Memorial Cancer Institute
Hollywood, Florida, 33021
MD Anderson Cancer Center University of Texas
Houston, Texas, 77030
Baptist MD Anderson Cancer Center
Jacksonville, Florida, 32207
St Bernards Medical Center
Jonesboro, Arkansas, 72401
Saint Lukes Hospital of Kansas City
Kansas City, Missouri, 64111
HCA Midwest Division
Kansas City, Missouri, 64132
UCLA Hematology Oncology
Laguna Hills, California, 92653
Saint Barnabas Medical Center
Livingston, New Jersey, 07039
Southern CA Oncology Rsrch Alliance
Los Angeles, California, 90057
Norton Cancer Institute
Louisville, Kentucky, 40202
University of Wisconsin Paul P Carbone Comp Cancer Center
Madison, Wisconsin, 53792-6164
Fairview Health Services
Maple Grove, Minnesota, 55369
University of Miami
Miami, Florida, 33136
Sarah Cannon Research Institute
Nashville, Tennessee, 37203
Cancer Care Center
New Albany, Indiana, 47150
Hospital of Central Connecticut
New Britain, Connecticut, 06052
Yale University School Of Medicine
New Haven, Connecticut, 06520
Perlmutter Cancer Centre
New York, New York, 10016
Southeastern Regional Medical Center
Newnan, Georgia, 30265
Norwalk Hospital
Norwalk, Connecticut, 06856
Eastern Connecticut Hematology and Oncology Associates
Norwich, Connecticut, 06360
Orlando Health Clinical Trials
Orlando, Florida, 32806
Stanford University Medical Center
Palo Alto, California, 94304-1509
UCLA Pasadena HC Hemato Onco
Pasadena, California, 91105
Cancer Treatment Centers of America Eastern Regional Medical Center
Philadelphia, Pennsylvania, 19124
UCLA Porter Ranch Hemato and Onco
Porter Ranch, California, 91326
Cancer Care Associates Medical Grp
Redondo Beach, California, 90277
Virginia Cancer Institute
Richmond, Virginia, 23230
Metro Minnesota CCOP
Saint Louis Park, Minnesota, 55416
Park Nicollet Institute
Saint Louis Park, Minnesota, 55416
Utah Cancer Specialists
Salt Lake City, Utah, 84106
Sharp Memorial Hospital
San Diego, California, 92123
UCSF
San Francisco, California, 94115
Central Coast Medical Oncology Corporation
Santa Maria, California, 93454
UCLA Santa Monica Hematology Oncology
Santa Monica, California, 90404
Fred Hutchinson Cancer Center
Seattle, Washington, 98109
David C Pratt Cancer Center
St Louis, Missouri, 63141
Florida Cancer Specialists-North
St. Petersburg, Florida, 33705
Florida Cancer Specialists Pan
Tallahassee, Florida, 32308
Lundquist Inst BioMed at Harbor
Torrance, California, 90509-2910
UCLA Valencia
Valencia, California, 91355
Valley Breast Care
Van Nuys, California, 91405
Florida Cancer Specialists
West Palm Beach, Florida, 33401
UCLA Cancer Center Westlake Village
Westlake Village, California, 91361
University of Kansas Cancer Center
Westwood, Kansas, 66205
Cancer Center of Kansas
Wichita, Kansas, 67214-3728
Cancer Treatment Centers of America
Zion, Illinois, 60099
Spain44 sites
Novartis Investigative Site
A Coruña, 15006
Novartis Investigative Site
A Coruña, 15009
Novartis Investigative Site
Alicante, Valencia, 03550
Novartis Investigative Site
Badajoz, Extremadura, 06080
Novartis Investigative Site
Badalona, Barcelona, 08916
Novartis Investigative Site
Barcelona, 08035
Novartis Investigative Site
Barcelona, 08036
Novartis Investigative Site
Bilbao, Bizkaia, 48013
Novartis Investigative Site
Burgos, 09006
Novartis Investigative Site
Cáceres, Extremadura, 10003
Novartis Investigative Site
Castellon, 12002
Novartis Investigative Site
Córdoba, 14004
Novartis Investigative Site
Donostia / San Sebastian, Gipuzkoa, 20014
Novartis Investigative Site
El Palmar, Murcia, 30120
Novartis Investigative Site
Elche, Alicante, 03203
Novartis Investigative Site
Fuenlabrada, Madrid, 28942
Novartis Investigative Site
Girona, 17007
Novartis Investigative Site
Granada, Andalusia, 18014
Novartis Investigative Site
Granada, 18016
Novartis Investigative Site
Huelva, Andalusia, 21005
Novartis Investigative Site
Jaén, Andalusia, 23007
Novartis Investigative Site
L'Hospitalet de Llobregat, Barcelona, 08907
Novartis Investigative Site
Las Palmas GC, 35010
Novartis Investigative Site
Lugo, Galicia, 27003
Novartis Investigative Site
Madrid, 28009
Novartis Investigative Site
Madrid, 28033
Novartis Investigative Site
Madrid, 28034
Novartis Investigative Site
Madrid, 28040
Novartis Investigative Site
Madrid, 28222
Novartis Investigative Site
Málaga, 29010
Novartis Investigative Site
Manresa, Barcelona, 08242
Novartis Investigative Site
Murcia, 30008
Novartis Investigative Site
Pamplona, Navarre, 31008
Novartis Investigative Site
Sabadell, Barcelona, 08208
Novartis Investigative Site
Salamanca, 37007
Novartis Investigative Site
San Cristóbal de La Laguna, Santa Cruz De Tenerife, 38320
Novartis Investigative Site
Seville, 41009
Novartis Investigative Site
Seville, 41013
Novartis Investigative Site
Valencia, Valencia, 46009
Novartis Investigative Site
Valencia, 46010
Novartis Investigative Site
Valencia, 46014
Novartis Investigative Site
Vigo, Pontevedra, 36212
Novartis Investigative Site
Vitoria-Gasteiz, Araba, 01009
Novartis Investigative Site
Zaragoza, 50009
France32 sites
Novartis Investigative Site
Amiens, 80000
Novartis Investigative Site
Angers, 49055
Novartis Investigative Site
Argenteuil, 95107
Novartis Investigative Site
Avignon, 84082
Novartis Investigative Site
Besançon, 25030
Novartis Investigative Site
Bordeaux, 33076
Novartis Investigative Site
Bron, 69677
Novartis Investigative Site
Caen, 14021
Novartis Investigative Site
Dijon, Cote D Or, 21034
Novartis Investigative Site
Grenoble, Isere, 38028
Novartis Investigative Site
Le Mans, 72000
Novartis Investigative Site
Limoges, Haute Vienne, 87000
Novartis Investigative Site
Lyon, Rhone, 69004
Novartis Investigative Site
Marseille, 13008
Novartis Investigative Site
Montpellier, 34070
Novartis Investigative Site
Montpellier, 34298
Novartis Investigative Site
Nantes, 44202
Novartis Investigative Site
Nice, Alpes Maritimes, 06189
Novartis Investigative Site
Paris, 75013
Novartis Investigative Site
Paris, 75015
Novartis Investigative Site
Paris, 75231
Novartis Investigative Site
Paris, 75475
Novartis Investigative Site
Paris, 75970
Novartis Investigative Site
Pierre-Bénite, 69495
Novartis Investigative Site
Rennes, Ille Et Vilaine, 35062
Novartis Investigative Site
Rouen, 76038
Novartis Investigative Site
Saint-Cloud, Hauts De Seine, 92210
Novartis Investigative Site
Saint-Herblain, 44805
Novartis Investigative Site
Strasbourg, 67085
Novartis Investigative Site
Toulouse, 31059
Novartis Investigative Site
Vandœuvre-lès-Nancy, 54519
Novartis Investigative Site
Villejuif, 94800
Germany28 sites
Novartis Investigative Site
Augsburg, 86150
Novartis Investigative Site
Bad Liebenwerda, 04924
Novartis Investigative Site
Berlin, 13125
Novartis Investigative Site
Bonn, 53111
Novartis Investigative Site
Bottrop, 46236
Novartis Investigative Site
Cottbus, Brandenburg, 03048
Novartis Investigative Site
Dresden, Saxony, 01307
Novartis Investigative Site
Erlangen, 91054
Novartis Investigative Site
Essen, North Rhine-Westphalia, 45136
Novartis Investigative Site
Essen, 45147
Novartis Investigative Site
Frankfurt am Main, Hesse, 60431
Novartis Investigative Site
Georgsmarienhütte, Lower Saxony, 49124
Novartis Investigative Site
Hamburg, 20357
Novartis Investigative Site
Hanover, Lower Saxony, 30177
Novartis Investigative Site
Kiel, 24105
Novartis Investigative Site
Mainz, 55131
Novartis Investigative Site
Mönchengladbach, North Rhine-Westphalia, 41061
Novartis Investigative Site
Munich, Bavaria, 80637
Novartis Investigative Site
Munich, Bavaria, 81377
Novartis Investigative Site
Munich, Bavaria, 81675
Novartis Investigative Site
Münster, 48149
Novartis Investigative Site
Ravensburg, Baden-Wurttemberg, 88212
Novartis Investigative Site
Regensburg, 93053
Novartis Investigative Site
Schweinfurt, 97422
Novartis Investigative Site
Tübingen, 72076
Novartis Investigative Site
Ulm, 89081
Novartis Investigative Site
Velbert, North Rhine-Westphalia, 42551
Novartis Investigative Site
Würzburg, Bavaria, 97080
Australia24 sites
Novartis Investigative Site
Auchenflower, Queensland, 4066
Novartis Investigative Site
Bedford Park, South Australia, 5041
Novartis Investigative Site
Bendigo, Victoria, 3550
Novartis Investigative Site
Birtinya, Queensland, 4575
Novartis Investigative Site
Campbelltown, New South Wales, 2560
Novartis Investigative Site
Coffs Harbour, New South Wales, 2450
Novartis Investigative Site
Darlinghurst, New South Wales, 2010
Novartis Investigative Site
East Melbourne, Victoria, 3002
Novartis Investigative Site
Epping, Victoria, 3076
Novartis Investigative Site
Fitzroy, Victoria, 3065
Novartis Investigative Site
Franston, Victoria, 3199
Novartis Investigative Site
Heidelberg, Victoria, 3084
Novartis Investigative Site
Kingswood, New South Wales, 2747
Novartis Investigative Site
Kogarah, New South Wales, 2217
Novartis Investigative Site
Liverpool, 2170
Novartis Investigative Site
Melbourne, Victoria, 3000
Novartis Investigative Site
Murdoch, Western Australia, 6150
Novartis Investigative Site
Nedlands, Western Australia, 6009
Novartis Investigative Site
North Ryde, New South Wales, 2109
Novartis Investigative Site
Shepparton, Victoria, 3630
Novartis Investigative Site
St Leonards, New South Wales, 2065
Novartis Investigative Site
Wahroonga, New South Wales, 2076
Novartis Investigative Site
Westmead, New South Wales, 2145
Novartis Investigative Site
Wooloongabba, Queensland, 4102
Canada23 sites
Novartis Investigative Site
Calgary, Alberta, T2N 4N2
Novartis Investigative Site
Edmonton, Alberta, T6G 1Z2
Novartis Investigative Site
Fleurimont, Quebec, J1H 5N4
Novartis Investigative Site
Greater Sudbury, Ontario, P3E 5J1
Novartis Investigative Site
Greenfield Park, Quebec, J4V 2H1
Novartis Investigative Site
Halifax, Nova Scotia, B3H 2Y9
Novartis Investigative Site
Kelowna, British Columbia, V1Y 5L3
Novartis Investigative Site
Kitchener, Ontario, N2G 1G3
Novartis Investigative Site
London, Ontario, N6A 5W9
Novartis Investigative Site
Montreal, Quebec, H2W 1T8
Novartis Investigative Site
Montreal, Quebec, H3T 1E2
Novartis Investigative Site
Montreal, Quebec, H4A 3J1
Novartis Investigative Site
Newmarket, Ontario, J7Y 2P9
Novartis Investigative Site
North Vancouver, British Columbia, V7L 2L7
Novartis Investigative Site
Oshawa, Ontario, L1G 2B9
Novartis Investigative Site
Québec, Quebec, G1S 4L8
Novartis Investigative Site
Saint-Jérôme, Quebec, J7Z 5T3
Novartis Investigative Site
Sault Ste. Marie, Ontario, P6B 0A8
Novartis Investigative Site
Surrey, British Columbia, V3V 1Z2
Novartis Investigative Site
Toronto, Ontario, M4N 3M5
Novartis Investigative Site
Toronto, Ontario, M5G 2M9
Novartis Investigative Site
Vancouver, British Columbia, V5Z 4E6
Novartis Investigative Site
Windsor, Ontario, N8W 2X3
Russia21 sites
Novartis Investigative Site
Chelyabinsk, 454087
Novartis Investigative Site
Kazan', Russian Federation, 420029
Novartis Investigative Site
Kostroma, 156005
Novartis Investigative Site
Krasnoyarsk, 660022
Novartis Investigative Site
Moscow, 111123
Novartis Investigative Site
Moscow, 115522
Novartis Investigative Site
Moscow, 143423
Novartis Investigative Site
Nizhny Novgorod, 603137
Novartis Investigative Site
Novosibirsk, 630000
Novartis Investigative Site
Obninsk, 249036
Novartis Investigative Site
Omsk, 644013
Novartis Investigative Site
Orenburg, 460021
Novartis Investigative Site
Rostov-on-Don, 344037
Novartis Investigative Site
Ryazan, 390011
Novartis Investigative Site
Saint Petersburg, Sankt-Peterburg, 195271
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About this study
Official title: A Phase III Multi-center, Randomized, Open-label Trial to Evaluate Efficacy and Safety of Ribociclib With Endocrine Therapy as an Adjuvant Treatment in Patients With Hormone Receptor-positive, HER2-negative Early Breast Cancer (New Adjuvant TriAl With Ribociclib [LEE011]: NATALEE)
A phase III, multicenter, randomized, open-label trial to evaluate the efficacy and safety of ribociclib with Endocrine Therapy (ET) as an adjuvant treatment in women and men with Hormone Receptor positive (HR+), Human Epidermal Growth Factor Receptor 2 negative (HER2-) Early Breast Cancer (EBC).
Read the detailed description
The trial will include pre and postmenopausal women and men with HR-positive, HER2-negative EBC, with an Anatomic Stage Group III, IIB or a subset of Stage IIA cases, after adequate surgical resection, radiotherapy (if indicated), adjuvant or neoadjuvant chemotherapy (if indicated), and who are deemed to be eligible for adjuvant ET for at least 60 months of duration.
Approximately 5,000 patients will be randomized (using an Interactive Response Technology system [IRT]) into two treatment arms in a 1:1 ratio to:
- Investigational arm:
~ Ribociclib 400 mg by mouth once daily on days 1 to 21 of a 28-day cycle, for 36 months since randomization (approximately 39 cycles).
And
~ ET consisting of:
- For postmenopausal women: letrozole 2.5 mg by mouth once daily continuously or anastrozole 1 mg by mouth once daily continuously.
- For premenopausal women and men: letrozole 2.5 mg by mouth once daily continuously or anastrozole 1 mg by mouth once daily continuously, combined with goserelin 3.6 mg subcutaneously once every 4 weeks.
Duration of ET in the trial will be 60 months from the randomization date.
- Control arm:
~ ET: Same as in the Investigational arm.
In both arms, ET will be administered according to the local clinical guidelines and current local prescribing information. Subsequent ET (or any other anti-cancer treatment) given after the protocol-required 60 months of ET (or after premature discontinuation of ET in the trial) will be administered according to the Investigator's clinical judgment and is not considered a trial treatment.
Randomization will be stratified by the following factors:
- Menopausal status: premenopausal women and men vs. postmenopausal women
- AJCC 8th edition Anatomic Stage Group: Anatomic Stage Group II vs. Anatomic Stage Group III
- Prior neoadjuvant/adjuvant chemotherapy: yes vs. no
- Geographical region: North America/Western Europe/Oceania vs. rest of the world
Enrollment of patients with Anatomic Stage Group II is capped at approximately 2,000 patients.
The trial will include screening, treatment, and follow up phases. The trial includes an exploratory component that requires collection of tumor and blood samples (except for patients enrolled in China).
- Conditions
- Early Breast Cancer
- Being tested
- Ribociclib, Endocrine Therapy (ET)
- Keywords
- adjuvant treatment of Hormone Receptor positive (HR+), Human Epidermal Growth Factor Receptor 2 negative (HER2-), Early Breast Cancer (EBC), HR+/HER2-, adjuvant, Ribociclib (LEE011), CDK4/6 inhibitor
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RibociclibDrug
Also called LEE011
Ribociclib orally taken at 400 mg on days 1 to 21 of a 28-day cycle
Endocrine Therapy (ET)Other
Endocrine Therapy (ET) will be administered according to the local clinical guidelines and current local prescribing information
| Study group | Role | What they receive |
|---|---|---|
| Ribociclib + Endocrine Therapy (ET) | Experimental | Eligible participants will receive Ribociclib 400 mg once daily on days 1 to 21 of a 28-day cycle, followed by 7 days off ribociclib (Days 22 to 28).
And
Endocrine Therapy (ET) consisting of:
* For postmenopausal women:
- Letrozole 2.5 mg by mouth daily continuously or anastrozole 1 mg by mouth daily continuously.
* For premenopausal women and men:
* Letrozole 2.5 mg by mouth daily continuously or anastrozole 1 mg by mouth daily continuously, combined with:
* Goserelin 3.6 mg subcutaneously once every 4 weeks. Receives: Drug: Ribociclib; Other: Endocrine Therapy (ET) |
| Endocrine Therapy (ET) | Active comparator | Eligible participants will receive Endocrine Therapy (ET) consisting of:
* For postmenopausal women:
- Letrozole 2.5 mg by mouth daily continuously or anastrozole 1 mg by mouth daily continuously.
* For premenopausal women and men:
* Letrozole 2.5 mg by mouth daily continuously or anastrozole 1 mg by mouth daily continuously, combined with:
* Goserelin 3.6 mg subcutaneously once every 4 weeks. Receives: Other: Endocrine Therapy (ET) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Invasive Disease-Free Survival (iDFS)
Invasive Disease-Free Survival (iDFS) is defined as the time from the date of randomization to the date of the first event of local invasive breast recurrence, regional invasive recurrence, distant recurrence, death (any cause), contralateral invasive BC, or second primary non-breast invasive cancer (excluding basal and squamous cell carcinomas of the skin). iDFS will be assessed locally using STEEP criteria (Standardized Definitions for Efficacy End Points in Adjuvant Breast Cancer Trials).
Measured: Up to approximately 139 months
Secondary outcomes (6)
Recurrence-free survival (RFS)
Recurrence-free survival (RFS) is defined as the time from date of randomization to date of first event of local invasive breast recurrence, regional invasive recurrence, distant recurrence, or death (any cause) and will be assessed using STEEP criteria (Standardized Definitions for Efficacy End Points in Adjuvant Breast Cancer Trials).
Measured: Up to approximately 139 months
Distant disease-free survival (DDFS)
Distant disease-free survival (DDFS) is defined as the time from date of randomization to date of first event of distant recurrence, death (any cause), or second primary non-breast invasive cancer (excluding basal and squamous cell carcinomas of the skin) and will be assessed using STEEP criteria (Standardized Definitions for Efficacy End Points in Adjuvant Breast Cancer Trials).
Measured: Up to approximately 139 months
Overall Survival (OS)
Overall Survival (OS) is defined as the time from date of randomization to date of death due to any cause.
Measured: Up to approximately 139 months
Change from baseline in the global health status Quality of life scale score as assessed by EORTC QLQ-C30
The EORTC QLQ-C30 contains functional scales, symptom scales, single items scale and a global health status/QoL scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level.
Measured: Up to approximately 139 months
Change from baseline in the physical functioning sub-scale score as assessed by EORTC QLQ-C30
The EORTC QLQ-C30 contains functional scales, symptom scales, single items scale and a global health status/QoL scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level.
Measured: Up to approximately 139 months
Trough Concentration on Day 15 (Ctrough,D1) of ribociclib
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization in a subset of participants. Ctrough,D15 of ribociclib will be listed and summarized using descriptive statistics.
Measured: Cycle 1 Day 15 (0/Pre-dose, 2 and 4 hours post-dose)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Oct 2018
- Study start7 Dec 2018
- Primary completion29 May 2030 (estimated)
- Study completion29 May 2030 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Early Breast CancerStudies of the same condition, open and under way.
- More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 5,101 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Translational Research in Oncology
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03701334
- Sponsor's protocol ID
- CLEE011O12301C
- Other IDs
- 2023-510357-42-00, TRIO033, 2023
- Acronym
- NATALEE
- Status last verified
- Oct 2026
- First submitted
- 21 Sep 2018
- Last updated
- 9 Oct 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
- Expanded access
- Available
Publications
Ji Y, Wang C, Combes FP, Ho YY, Fasching PA, Untch M, Zarate JP, Crown J. Quantitative Pharmacology Justifying Ribociclib Dose in Early Breast Cancer. Clin Pharmacokinet. 2026 Aug;65(8):1217-1228. doi: 10.1007/s40262-026-01643-3. Epub 2026 Jun 23.
PubMed 42334791Fasching PA, Stroyakovskiy D, Yardley DA, Huang CS, Crown J, Bardia A, Chia S, Im SA, Martin M, Xu B, Loi S, Barrios C, Untch M, Moroose R, Visco F, Hortobagyi GN, Slamon DJ, Fresco R, Zarate JP, Li Z, Waters S, Hurvitz SA. Ribociclib Plus Endocrine Therapy in Hormone Receptor-Positive/ERBB2-Negative Early Breast Cancer: 4-Year Outcomes From the NATALEE Randomized Clinical Trial. JAMA Oncol. 2025 Nov 1;11(11):1364-1372. doi: 10.1001/jamaoncol.2025.3700.
PubMed 40996773Slamon D, Lipatov O, Nowecki Z, McAndrew N, Kukielka-Budny B, Stroyakovskiy D, Yardley DA, Huang CS, Fasching PA, Crown J, Bardia A, Chia S, Im SA, Ruiz-Borrego M, Loi S, Xu B, Hurvitz S, Barrios C, Untch M, Moroose R, Visco F, Afenjar K, Fresco R, Severin I, Ji Y, Ghaznawi F, Li Z, Zarate JP, Chakravartty A, Taran T, Hortobagyi G. Ribociclib plus Endocrine Therapy in Early Breast Cancer. N Engl J Med. 2024 Mar 21;390(12):1080-1091. doi: 10.1056/NEJMoa2305488.
PubMed 38507751Slamon DJ, Fasching PA, Hurvitz S, Chia S, Crown J, Martin M, Barrios CH, Bardia A, Im SA, Yardley DA, Untch M, Huang CS, Stroyakovskiy D, Xu B, Moroose RL, Loi S, Visco F, Bee-Munteanu V, Afenjar K, Fresco R, Taran T, Chakravartty A, Zarate JP, Lteif A, Hortobagyi GN. Rationale and trial design of NATALEE: a Phase III trial of adjuvant ribociclib + endocrine therapy versus endocrine therapy alone in patients with HR+/HER2- early breast cancer. Ther Adv Med Oncol. 2023 May 29;15:17588359231178125. doi: 10.1177/17588359231178125. eCollection 2023.
PubMed 37275963