Adjuvant Ribociclib With Endocrine Therapy in Hormone Receptor+/HER2- Intermediate Risk Early Breast Cancer

Study Overview
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Brief Summary
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This is an international, multi-center, randomized, double-blinded, placebo-controlled clinical study evaluating the efficacy and safety of ribociclib with endocrine therapy as an adjuvant treatment in patients with hormone receptor-positive, HER2-negative, intermediate risk breast cancer.

Detailed Description
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While adjuvant endocrine therapy (ET) is effective in reducing risk of recurrence in patients with hormone receptor (HR)-positive early breast cancer (EBC), recurrences are still common, especially in patients with unfavorable clinical, pathological and/or molecular features. Ribociclib, a CDK4/6 inhibitor, demonstrated clinical efficacy with tolerable toxicity when added to ET in patients with HR-positive, HER2-negative advanced breast cancer. The purpose of this study is to evaluate the effect of addition of ribociclib to standard adjuvant ET on invasive disease-free survival in patients with HR+, HER2- intermediate-risk EBC.

Official Title
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A Phase III, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate Efficacy and Safety of Ribociclib With Endocrine Therapy as an Adjuvant Treatment in Patients With Hormone Receptor-positive, HER2-negative, Intermediate Risk Early Breast Cancer

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Ribociclib
* Drug: Placebo
* Drug: Adjuvant endocrine therapy


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Histologically confirmed unilateral primary invasive adenocarcinoma of the breast Estrogen receptor-positive and/or progesterone receptor-positive, HER2-negative breast cancer Patient is after surgical resection of the tumor where tumor was removed completely with surgical specimen microscopic margins free from tumor and with available archival tumor tissue from the surgical specimen Patient who have AJCC 8th edition Prognostic Stage Group II Patient has completed adjuvant radiotherapy (if indicated) according to the institutional guidelines prior to screening Patient may already have initiated adjuvant endocrine therapy (ET) at the time of randomization, but randomization must take place within 52 weeks of date of initial histological diagnosis of breast cancer and within 12 weeks of initiating ET ECOG Performance Status 0 or 1 Adequate bone marrow and organ function Sodium, potassium, phosphorus, magnesium and total calcium laboratory values within normal limits QTcF interval < 450 msec and mean resting heart rate 50-90 bpm Key Exclusion Criteria: Prior neoadjuvant therapy (endocrine therapy or chemotherapy) or CDK4/6 inhibitor Prior treatment with tamoxifen, raloxifen or aromatase inhibitors for reduction in risk (chemoprevention) of breast cancer and/or treatment for osteoporosis within last 2 years Patient with inflammatory breast cancer Prior treatment with anthracyclines at cumulative doses of 450 mg/m² or more for doxorubicin or 900 mg/m² or more for epirubicin Distant metastases of breast cancer beyond regional lymph nodes Patient has not recovered from clinical and laboratory acute toxicities of chemotherapy, radiotherapy and surgery Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality, or clinically significant cardiac arrhythmias Uncontrolled hypertension with systolic blood pressure >160 mmHg Patient is currently receiving any of the prohibited substances that cannot be discontinued 7 days prior to Cycle 1 Day 1: concomitant medications, herbal supplements, and/or fruits 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; systemic corticosteroids ≤ 2 weeks prior to starting study drug, or who have not fully recovered from side effects of such treatment; concomitant medications with a known risk to prolong the QT interval and/or known to cause torsades de points that cannot be discontinued or replaced by safe alternative medication. Pregnant or breast-feeding (lactating) women or women who plan to become pregnant or breast-feed during the study Women of child-bearing potential unless they are using highly effective methods of contraception during the study treatment and for 21 days after stopping the study treatment.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ribociclib + adjuvant endocrine therapy<br>Ribociclib in combination with standard adjuvant endocrine therapy | Drug: Ribociclib<br>* Ribociclib 600 mg daily on days 1 to 21 of a 28-day cycle for 26 cycles (approximately 24 months). Ribociclib will be supplied in the form of 200 mg tablets.<br>* Other names: LEE011;Drug: Adjuvant endocrine therapy<br>* Tamoxifen 20 mg daily, or letrozole 2.5 mg daily, or anastrozole 1 mg daily, or exemestane 25 mg daily (male patients will be treated with tamoxifen 20 mg daily) for a total duration of at least 60 months. In premenopausal women, adjuvant endocrine therapy may include GnRH agonist administered every 28 days.<br>|
| Active Comparator: Placebo + adjuvant endocrine therapy<br>Placebo in combination with standard adjuvant endocrine therapy | Drug: Placebo<br>* Placebo 600 mg daily on days 1 to 21 of a 28-day cycle for 26 cycles (approximately 24 months). Placebo will be supplied in the form of 200 mg tablets.<br>Drug: Adjuvant endocrine therapy<br>* Tamoxifen 20 mg daily, or letrozole 2.5 mg daily, or anastrozole 1 mg daily, or exemestane 25 mg daily (male patients will be treated with tamoxifen 20 mg daily) for a total duration of at least 60 months. In premenopausal women, adjuvant endocrine therapy may include GnRH agonist administered every 28 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Invasive disease-free survival (iDFS) using STEEP criteria | 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, contralateral invasive breast cancer, or second primary non-breast invasive cancer, and is assessed locally by investigators. | up to 90 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence-free survival (RFS) using STEEP criteria | 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. | up to 90 months | 
| Distant disease-free survival (DDFS) using STEEP criteria | DDFS is defined as the time from date of randomization to date of first event of distant recurrence, death, or second primary non-breast invasive cancer | up to 90 months | 
| Overall survival (OS) | OS is defined as the time from date of randomization to date of death due to any cause. | up to 90 months | 
| Quality of Life (QOL) | Change from baseline in the physical functioning sub-scale score and global health status/QOL scale score as assessed by EORTC QLQ-C30 | Baseline, 90 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hormone receptor-positive, Estrogen and/or progesterone receptor-positive, HER2-negative, Intermediate risk early breast cancer, Adjuvant, Ribociclib, LEE011, CDK4/6 inhibitor, Endocrine therapy, Phase III, breast carcinoma, breast cancer