A Trial to Evaluate Efficacy and Safety of Ribociclib With Endocrine Therapy as Adjuvant Treatment in Patients With HR+/HER2- Early Breast Cancer

Study Overview
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Brief Summary
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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 (EBC)

Detailed Description
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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. The trial will include screening, treatment, and follow up phases.

Official Title
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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)

Conditions
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Early Breast Cancer

Intervention / Treatment
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* Drug: Ribociclib
* Other: Endocrine Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Patient with histologically confirmed unilateral primary invasive adenocarcinoma of the breast with a date of initial cytologic or histologic diagnosis within 18 months prior to randomization. Patient has breast cancer that is positive for ER and/or PgR Patient has HER2-negative breast cancer Patient has available archival tumor tissue from the surgical specimen 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 II or III If indicated, patient has completed adjuvant and/or neoadjuvant chemotherapy according to the institutional guidelines If indicated, patient has completed adjuvant radiotherapy according to the institutional guidelines Patient has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. Patient has no contraindication for the adjuvant ET in the trial and is planned to be treated with ET for 5 years Exclusion Criteria: 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 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 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 Patient has a concurrent invasive malignancy or a prior invasive malignancy whose treatment was completed within 2 years before randomization Patient has known HIV infection, Hepatitis B or C infection Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality Patient is currently receiving any of the following substances within 7 days before randomization - Concomitant medications, herbal supplements, and/or fruits that are known as strong inhibitors or inducers of CYP3A4/5 or Medications that have a narrow therapeutic window and are predominantly metabolized through CYP3A4/5 is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting trial treatment Patient has impairment of GI function or GI disease that may significantly alter the absorption of the oral trial treatments 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 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. Pregnant or breast-feeding (lactating) women or women who plan to become pregnant or breast-feed during the trial

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ribociclib + Endocrine Therapy<br>Participants will receive ribociclib 400 mg once daily on days 1-21 of a 28-day cycle and endocrine therapy once daily continuously | Drug: Ribociclib<br>* Ribociclib orally taken at 400 mg on days 1 to 21 of a 28-day cycle<br>Other: Endocrine Therapy<br>* ET will be administered according to the local clinical guidelines and current local prescribing information<br>|
| Active Comparator: Endocrine Therapy<br>Participants will receive endocrine therapy only once daily continuously | Other: Endocrine Therapy<br>* ET will be administered according to the local clinical guidelines and current local prescribing information<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Invasive Disease-Free Survival (iDFS) | iDFS using STEEP criteria (Standardized Definitions for Efficacy End Points in Adjuvant Breast Cancer Trials), as assessed by Investigator. iDFS is defined as 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). | Up to approximately 91 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence-free survival (RFS) | RFS using STEEP criteria (Standardized Definitions for Efficacy End Points in Adjuvant Breast Cancer Trials). 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 (any cause). | Up to approximately 91 months | 
| Distant disease-free survival (DDFS) | DDFS using STEEP criteria. DDFS is defined as the time from date of randomization to date of first event of distant recurrence, death (any cause), or second primary non-breast invasive cancer (excluding basal and squamous cell carcinomas of the skin). | Up to approximately 91 months | 
| Overall Survival (OS) | OS is defined as the time from date of randomization to date of death due to any cause. | Up to approximately 91 months | 
| Change from baseline in the global health status Quality of life scale score as assessed by EORTC QLQ-C30 | The EORTC QLQ-C30 contains functional scales, symptom scales, single items scale and a global health status/QoL scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. | Up to approximately 91 months | 
| Change from baseline in the physical functioning sub-scale score as assessed by EORTC QLQ-C30 | The EORTC QLQ-C30 contains functional scales, symptom scales, single items scale and a global health status/QoL scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. | Up to approximately 91 months | 
| PK parameters: Ctrough and other applicable parameters for ribociclib | Pharmacokinetics of ribociclib: Ctrough and other applicable parameters | Cycle 1 Day 15 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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early breast cancer (EBC), HR+/HER2-, adjuvant, LEE011, ribociclib, CDK4/6 inhibitor