A phase III multi-center, randomized, open-label trial to evaluate efficacy and safety of ribociclib with endocrine therapy as adjuvant treatment in patients with HR+/HER2- Early Breast Cancer
- Conditions
- hormone receptor (HR)-positive, HER2-negative, early breast cancer (EBC).
- Registration Number
- 2023-510357-42-00
- Lead Sponsor
- Novartis Pharma AG
- Brief Summary
To compare iDFS for ribociclib + ET versus ET in patients with HR-positive,
HER2-negative, EBC
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Ongoing, recruitment ended
- Sex
- Not specified
- Target Recruitment
- 2394
Signed and dated Patient Informed Consent Form (PICF) obtained prior to any trial-specific screening procedure.
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).
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.
Patient has received any CDK4/6 inhibitor
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.
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.
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method iDFS using STEEP criteria, as assessed by Investigator iDFS using STEEP criteria, as assessed by Investigator
- Secondary Outcome Measures
Name Time Method RFS using STEEP criteria RFS using STEEP criteria
DDFS using STEEP criteria DDFS using STEEP criteria
OS defined as time from date of randomization to date of death due to any cause OS defined as time from date of randomization to date of death due to any cause
Change from baseline in the physical functioning sub-scale score and global health status/ QoL scale score as assessed by EORTC QLQ-C30 Change from baseline in the physical functioning sub-scale score and global health status/ QoL scale score as assessed by EORTC QLQ-C30
Frequency and severity of AEs, laboratory and Electrocardiogram (ECG) abnormalities Frequency and severity of AEs, laboratory and Electrocardiogram (ECG) abnormalities
PK parameters such as Ctrough and other applicable parameters for ribociclib PK parameters such as Ctrough and other applicable parameters for ribociclib
Trial Locations
- Locations (166)
Centre Hospitalier Regional De La Citadelle
🇧🇪Liege, Belgium
Jessa Ziekenhuis
🇧🇪Hasselt, Belgium
Centre Hospitalier Universitaire Dinant Godinne Sainte-Elisabeth-UCL-Namur
🇧🇪Namur, Belgium
GasthuisZusters Antwerpen
🇧🇪Antwerp, Belgium
Grand Hopital De Charleroi
🇧🇪Charleroi, Belgium
Cliniques Universitaires Saint-Luc
🇧🇪Sint-Lambrechts-Woluwe, Belgium
Institut Jules Bordet
🇧🇪Anderlecht, Belgium
Centre hospitalier universitaire de Liege
🇧🇪Liege, Belgium
Antwerp University Hospital
🇧🇪Edegem, Belgium
Hopital De Libramont
🇧🇪Libramont-Chevigny, Belgium
Scroll for more (156 remaining)Centre Hospitalier Regional De La Citadelle🇧🇪Liege, BelgiumJean-Paul SalmonSite contact42257165JeanPaul.Salmon@chrcitadelle.be