NoLEEta - Phase III non-inferiority trial of chemotherapy de-escalation in hormone receptorpositive, Her2-negative, intermediate-risk early breast cancer treated with Ribociclib (LEE-011) in the adjuvant setting

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Unicancer

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

18 Dec 2025 → ongoing

Decision date (initial)

2025-11-17

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Novartis

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

To demonstrate the non-inferiority of an adjuvant treatment regimen including ribociclib and ET (Arm A) as compared to the same regimen preceded by adjuvant chemotherapy (Arm B) in intermediate-risk HR+ HER2- EBC, with respect to iBCFS.

Secondary objectives 4

1. To evaluate the efficacy in the two treatment arms according to other metrics: Invasive disease-free survival (iDFS), distance diseasefree survival (DDFS), and overall survival (OS) rates at 5, 8, and 10 years and iBCFS by subgroups
2. To evaluate the rate of the different types of iBCFS events in each treatment arm at 3, 5, 8, and 10 years
3. To evaluate safety and tolerability in the two treatment arms with respect to the frequency and severity of AE
4. To evaluate the health-related quality of life trajectories in both arms

Conditions and MedDRA coding

Patients with HR+ HER2- early breast cancer at intermediate risk of recurrence and eligible for adjuvant chemotherapy

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. Patient must have signed a written informed consent prior to any trial-specific screening procedure.
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: a. Patient underwent bilateral oophorectomy, or b. Age ≥ 60 years, or c. 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. d. 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: a. 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 b. ER-positive (with tumor cells showing ≥10% ER staining) and HER2-negative according to the most recent ASCO/CAP guidelines.
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: a. Absolute neutrophil count (ANC) ≥1.5 x 109/L b. Platelet count ≥100 x 109/L c. Hemoglobin ≥9 g/dL d. Total bilirubin < ULN. Patients with known Gilbert syndrome may be enrolled with total bilirubin ≤3 x ULN or direct bilirubin ≤1.5 x ULN e. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2.5 x ULN f. Serum creatinine ≤1.5 mg/dL or calculated creatinine clearance ≥60 mL/min/1.73m2 (CKD-EPI equation (2021)) g. 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: a. QTcF interval (QT interval using Fridericia’s correction) at screening < 450 milliseconds (msec) b. 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 22

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): a. CD4+ T-cell (CD4+) counts ≥ 350 cells/μL, AND b. No history of AIDS-defining opportunistic infections within the past 12 months (prophylactic antimicrobials allowed if no drug-drug interactions or overlapping toxicities), AND c. 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: a. History of documented myocardial infarction (MI), angina pectoris, symptomatic pericarditis, or coronary artery bypass graft within 6 months prior to trial entry. b. Documented cardiomyopathy. c. Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated acquisition (MUGA) scan or echocardiogram (ECHO) (testing not mandatory) d. 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. e. 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). f. 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: a. 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 b. Medications that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5 c. Any medication prohibited according to the instructions for goserelin, leuprolide or triptorelin (pre-menopausal patients), anastrozole, exemestane, letrozole, or ribociclib. d. 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.
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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Invasive breast cancer-free survival according to the STEEP criteria 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. iBCFS will be censored if no iBCFS event is observed prior to the analysis cut-off date.

Secondary endpoints 4

1. iDFS, DDFS, and OS according to STEEP criteria (Tolaney et al., JCO 2021).
2. Type of iBCFS event
3. AEs (adverse events) focusing on grade ≥2 according to NCI CTCAE v5.0.
4. Change from baseline in EORTC QLQ-C30 and EORTC QLQ-BR42 questionnaires scores.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 10

Auxiliary 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Unicancer

Sponsor organisation

Unicancer

Address

101 Rue De Tolbiac

City

Paris

Postcode

75013

Country

France

Scientific contact point

Organisation

Unicancer

Contact name

Nourredine AIT RAHMOUNE

Public contact point

Organisation

Unicancer

Contact name

Nourredine AIT RAHMOUNE

Locations

5 EU/EEA countries · 142 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 55 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications