临床试验/NCT03701334

NCT03701334进行中（未招募）3 期

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)

Novartis Pharmaceuticals479 个研究点分布在 1 个国家目标入组 5,101 人开始时间: 2018年12月7日最近更新: 2026年9月18日

适应症

干预措施

试验速览

阶段: 3 期
状态: 进行中（未招募）
发起方: Novartis Pharmaceuticals
入组人数: 5,101
试验地点: 479
主要终点: Invasive Disease-Free Survival (iDFS)

研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验相关资讯

研究概览

简要总结

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).

详细描述

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

研究设计

研究类型: Interventional
分配方式: Randomized
干预模型: Parallel
主要目的: Treatment
盲法: None

入排标准

年龄范围: 18 Years 至 100 Years（Adult, Older Adult）
性别: All
接受健康志愿者: 否

入选标准

•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.
•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
•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)
•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
•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.
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排除标准

•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).
•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.

研究组 & 干预措施

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.

干预措施: Endocrine Therapy (ET) (Other)

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.

干预措施: Ribociclib (Drug)

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.

干预措施: Endocrine Therapy (ET) (Other)

结局指标

主要结局

Invasive Disease-Free Survival (iDFS)

时间窗: Up to approximately 139 months

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).

次要结局

Recurrence-free survival (RFS)(Up to approximately 139 months)
Distant disease-free survival (DDFS)(Up to approximately 139 months)
Overall Survival (OS)(Up to approximately 139 months)
Change from baseline in the global health status Quality of life scale score as assessed by EORTC QLQ-C30(Up to approximately 139 months)
Change from baseline in the physical functioning sub-scale score as assessed by EORTC QLQ-C30(Up to approximately 139 months)
Trough Concentration on Day 15 (Ctrough,D1) of ribociclib(Cycle 1 Day 15 (0/Pre-dose, 2 and 4 hours post-dose))

研究者

发起方

Novartis Pharmaceuticals

申办方类型

Industry

责任方

Sponsor

研究点 (479)

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