assignment

Not Recruiting

Evaluation of Ribociclib Combined with Endocrine Therapy in Hormone Receptor-Positive, HER2-Negative Early Breast Cancer: A Phase III Randomized Trial

Trial ID: 2023-510357-42-00
Protocol: CLEE011O12301C
Sponsor: Novartis Pharma AG

Trial statistics

science

test molecules

location_city

152

research sites

public

countries

medical_information

diseases

person_search

135

investigators

handshake

vendors

Diseases & Conditions

Breast cancer Hormone receptor positive breast cancer

Objectives

The primary objective of this phase III, multicenter, randomized, open-label trial is to compare the **invasive disease-free survival (iDFS)** for ribociclib combined with endocrine therapy (ET) versus ET alone in patients with hormone receptor (HR)-positive, HER2-negative, early breast cancer (EBC). This objective is clinically relevant as it aims to determine the efficacy of ribociclib in preventing disease recurrence, which is crucial for improving long-term outcomes in this patient population.

Secondary objectives include:

Evaluating the two treatment arms with respect to **recurrence-free survival (RFS)**.
Assessing the two treatment arms concerning **distant disease-free survival (DDFS)**.
Comparing the two treatment arms in terms of **overall survival (OS)**.
Evaluating patient-reported outcomes (PRO) for health-related **quality of life (QoL)** in the two treatment arms.
Assessing the **safety and tolerability** of the treatment regimen.
Characterizing the **pharmacokinetics (PK)** of ribociclib when given in combination with non-steroidal aromatase inhibitors (NSAI) and goserelin if applicable.

These secondary objectives are essential for providing a comprehensive understanding of the treatment's impact on survival, quality of life, safety, and pharmacokinetics, thereby informing clinical decision-making and optimizing patient care.

Participants

The clinical trial involves a total of **2598 participants** diagnosed with **hormone receptor (HR)-positive, HER2-negative, early breast cancer (EBC)**. The study population includes both male and female subjects, aged 18 years and older, with a focus on individuals who have completed necessary adjuvant therapies and have no contraindications for the trial's endocrine therapy (ET). Participants were selected based on their health status, including adequate bone marrow and organ function, and an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. The trial includes individuals who have undergone surgical resection with tumor-free margins and meet specific pathological criteria. Lifestyle considerations such as the use of effective contraception methods are required for women of childbearing potential. The trial population is diverse, including vulnerable groups, and is characterized by a commitment to comply with scheduled visits and trial procedures.

Plans and Procedures

The clinical trial is a **phase III**, multicenter, randomized, open-label study designed to evaluate the efficacy and safety of **ribociclib** in combination with endocrine therapy as an adjuvant treatment for patients with hormone receptor-positive, HER2-negative, early breast cancer. The trial aims to compare invasive disease-free survival (iDFS) for ribociclib plus endocrine therapy versus endocrine therapy alone. The study is expected to run from June 2019 to April 2026, with a maximum treatment period of 60 months for participants.

Participants will be randomly assigned to receive either ribociclib with endocrine therapy or endocrine therapy alone. The trial will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. The screening visit will ensure that participants meet all inclusion criteria, such as having completed any necessary adjuvant radiotherapy and having no contraindications for the trial's endocrine therapy. Follow-up visits will occur at predetermined intervals to evaluate the primary and secondary endpoints, including recurrence-free survival (RFS), distant disease-free survival (DDFS), overall survival (OS), and changes in quality of life.

The expected length of participant involvement is up to 60 months, depending on individual treatment response and adherence to the protocol. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with the study protocol. Participants will be monitored for safety through regular laboratory tests, electrocardiograms, and assessments of adverse events. The trial will adhere to rigorous scientific standards to ensure the reliability and validity of the results, contributing valuable data to the understanding of adjuvant treatments in early breast cancer.

Treatment

The clinical trial involves the administration of several **experimental medications** to evaluate their efficacy and safety in patients with hormone receptor-positive, HER2-negative, early breast cancer. **Letrozole** is administered in the form of a tablet, with a maximum daily dose of 2.5 mg. The route of administration is oral, and the treatment period extends up to 60 days. The packaging and labeling of letrozole have been modified for clinical use. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.

**Anastrozole** is also administered as a tablet, with a maximum daily dose of 1 mg. The route of administration is oral, and the treatment period is up to 60 days. Anastrozole has been relabeled for clinical use, and participant compliance is similarly monitored to ensure adherence to the prescribed dosing regimen.

**Goserelin** is provided as an implant with a maximum daily dose of 3.6 mg. The route of administration is subcutaneous, and the treatment period is up to 60 days. The goserelin implant is delivered via a pre-filled syringe that is integral with the approved medicinal product. The product has been relabeled for clinical use, and compliance is monitored through scheduled follow-ups.

**Ribociclib** is administered as a film-coated tablet, with a maximum daily dose of 400 mg. The route of administration is oral, and the treatment period is up to 36 days. The clinical drug product is packaged in HDPE bottles, differing from the commercial packaging in blisters, and has an extended shelf-life based on stability data. Participant compliance is monitored to ensure adherence to the dosing schedule, with regular assessments conducted throughout the trial.

In addition to the experimental medications, standard-of-care therapy may be used as a comparator treatment in the study. The trial is designed to compare the invasive disease-free survival (iDFS) for ribociclib combined with endocrine therapy versus endocrine therapy alone. Compliance monitoring is a critical component of the study to ensure accurate evaluation of the treatment efficacy and safety.

Efficacy

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the invasive Disease-Free Survival (**iDFS**) as assessed by the Investigator using the STEEP criteria. Secondary endpoints include Recurrence-Free Survival (**RFS**), Distant Disease-Free Survival (**DDFS**), and Overall Survival (**OS**), which is defined as the time from the date of randomization to the date of death due to any cause. Additionally, changes from baseline in the physical functioning sub-scale score and global health status/Quality of Life (QoL) scale score will be evaluated using the EORTC QLQ-C30. The frequency and severity of adverse events (AEs), laboratory abnormalities, and Electrocardiogram (ECG) abnormalities will also be monitored. Pharmacokinetic (PK) parameters such as Ctrough and other applicable parameters for ribociclib will be measured.

Inclusion and Exclusion Criteria

check_circle

Inclusion Criteria

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 • 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.
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
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 that is either: • N1, or • N0, with: • Grade 3, or • Grade 2, with any of the following criteria: • Ki67 ≥ 20%, or • Oncotype DX Breast Recurrence Score ≥ 26, or • Prosigna/PAM50 categorized as high risk, or • MammaPrint categorized as high risk, or • EndoPredict EPclin Risk Score categorized as high risk
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).

cancel

Exclusion Criteria

Patient has received any CDK4/6 inhibitor
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).
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).
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 tria l
Patient has a concurrent invasive malignancy or a prior invasive malignancy whose treatment was completed within 2 years before randomization.
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.
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 antibacterial 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 Status by Country

Country	Status	Start of Recruitment	Planned Patients
Austria	Not Recruiting	14 Jun 2019	44
Belgium	Not Recruiting	14 Jun 2019	155
France	Not Recruiting	14 Jun 2019	435
Germany	Not Recruiting	14 Jun 2019	238
Hungary	Not Recruiting	14 Jun 2019	82
Ireland	Not Recruiting	14 Jun 2019	129
Italy	Not Recruiting	14 Jun 2019	86
Poland	Not Recruiting	14 Jun 2019	424
Romania	Not Recruiting	14 Jun 2019	61
Spain	Not Recruiting	14 Jun 2019	740

Sites & Investigators

Research sites

Sejtterapia Kozpont Kft.Clinique de l'Europe Institut Jules Bordet Institut De Cancerologie De Lorraine

Investigators

Michael B.Helmut F.Zsofia D.Anne K.

Investigational Products

Details about the medicinal products being studied in this clinical trial.

Product Name	Role in Trial	Formulation	Administration	Max Daily Dose	Treatment Duration	EU MP Number
ANASTROZOLE	Test	—	ORAL USE	1	60	SUB05502MIG
GOSERELIN	Test	—	SUBCUTANEOUS USE	3.6	60	SUB07962MIG
RIBOCICLIB	Test	—	ORAL USE	400	36	SUB180246
LETROZOLE	Test	—	ORAL	2.5	60	SUB08444MIG