Study of Efficacy and Safety in Premenopausal Women With Hormone Receptor Positive, HER2-negative Advanced Breast Cancer

Study Overview
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Brief Summary
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This is a multi-center, randomized, double-blinded, placebo controlled trial in pre-menopausal women with advanced breast cancer. The purpose of this study is to assess the efficacy of Ribociclib (LEE011), as measured by progression free survival (PFS), in premenopausal women with HR positive, HER2 negative advanced breast cancer

Official Title
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A Phase III Randomized, Double-blind, Placebo-controlled Study of LEE011 or Placebo in Combination With Tamoxifen and Goserelin or a Non-steroidal Aromatase Inhibitor (NSAI) and Goserelin for the Treatment of Premenopausal Women With Hormone Receptor Positive, HER2-negative, Advanced Breast Cancer

Conditions
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Advanced Metastatic Breast Cancer

Intervention / Treatment
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* Drug: LEE011
* Drug: Tamoxifen
* Drug: Letrozole
* Drug: Anastrozole
* Drug: Goserelin
* Drug: LEE011 Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient has advanced (locoregionally recurrent or metastatic) breast cancer not amenable to curative therapy Patient is premenopausal or perimenopausal at the time of study entry Patients who received (neo) adjuvant therapy for breast cancer are eligible Patient has a histologically and/or cytologically confirmed diagnosis of estrogen-receptor positive and/or progesterone receptor positive breast cancer Patient has HER2-negative breast cancer Patient must have either measurable disease or If no measurable disease is present, then at least one predominantly lytic bone lesion Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Patient has adequate bone marrow and organ function Exclusion Criteria: Patient who has received a prior CDK4/6 inhibitor Patient is postmenopausal Patients who currently have inflammatory breast cancer at screening. Patients who received any prior hormonal anti-cancer therapy for advanced breast cancer, except for ≤ 14 days of tamoxifen or NSAI ± goserelin for advanced breast cancer prior to randomization. Patient has a concurrent malignancy or malignancy within 3 years of randomization, with the exception of adequately treated basal cell skin carcinoma, squamous cell skin carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer. Patient with CNS metastases. Patient has active cardiac disease or a history of cardiac dysfunction Patient is currently using other antineoplastic agents Patient is pregnant or nursing or physiologically capable of becoming pregnant and not using highly effective contraception Other protocol-defined Inclusion/Exclusion may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 59 Years

Sexes Eligible for Study
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Female

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ribociclib (LEE011) + NSAI/tamoxifen + goserelin<br>LEE011 600 mg daily oral (3 weeks on/ 1 week off) in combination with NSAI or tamoxifen (tamoxifen 20 mg daily oral or letrozole 2.5 mg daily oral or anastrozole 1 mg daily oral) and goserelin 3.6 mg subcutaneous injection (once every 28 days) | Drug: LEE011<br>* LEE011 600 mg daily oral<br>Drug: Tamoxifen<br>* tamoxifen 20 mg daily oral<br>Drug: Letrozole<br>* letrozole 2.5 mg daily oral<br>Drug: Anastrozole<br>* anastrozole 1 mg daily oral<br>Drug: Goserelin<br>* Goserelin 3.6 mg subcutaneous injection<br>|
| Placebo Comparator: LEE011 placebo+NSAI/tamoxifen+goserelin<br>LEE011 Placebo 600 mg daily oral (3 weeks on/ 1 week off) in combination with NSAI or tamoxifen (tamoxifen 20 mg daily oral or letrozole 2.5 mg daily oral or anastrozole 1 mg daily oral) and goserelin 3.6 mg subcutaneous injection (once every 28 days) | Drug: Tamoxifen<br>* tamoxifen 20 mg daily oral<br>Drug: Letrozole<br>* letrozole 2.5 mg daily oral<br>Drug: Anastrozole<br>* anastrozole 1 mg daily oral<br>Drug: Goserelin<br>* Goserelin 3.6 mg subcutaneous injection<br>Drug: LEE011 Placebo<br>* LEE011 placebo 600 mg daily oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) Per Investigator's Assessment | PFS, defined as the time from the date of randomization to the date of the first documented progression or death due to any cause and assessed according to Response Evaluation Criteria In Solid Tumors (RECIST) v1.1]. PFS was assessed via a local radiology assessment according to RECIST 1.1 | Up to approximatley 25 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Time from date of randomization to the date of death from any cause | Up to approximately 69 months | 
| Overall Response Rate (ORR) Per Local Assessment | ORR is the percentage of participants with the best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1. CR = Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; PR = At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. | Up to approximately 25 months | 
| Clinical Benefit Rate (CBR) | Percentage of participants with complete response (CR) or partial response (PR) or stable disease (SD) lasting 24 weeks or longer as defined in RECIST 1.1.CR = Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; PR = At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters; SD = Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for progressive disease: PD = At least a 20% increase in the sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline. In addition to the relative increase of 20% the sum must also demonstrate an absolute increase of at least 5 mm. | Up to approximately 25 months | 
| Safety and Tolerability of LEE011 | Safety and tolerability will be determined by type, frequency and severity of adverse events and laboratory abnormalities per Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 | Up to approximately 26 months | 
| Time to Response (TTR) Per Local Investigator's Assessment | Time to response is the time from the date of randomization to the first documented response (CR or PR, which must be confirmed subsequently) according to RECIST 1.1. All patients will be included in time to response calculations. Patients who do not achieve a confirmed response will be censored at the maximum follow-up time (i.e. first patient first visit to last patient last visit used for the analysis) for patients who had a PFS event (i.e. either progressed or died due to any cause) or at the date of last adequate tumor assessment otherwise. | Up to approximately 25 months | 
| Duration of Response (DOR) Per Investigator's Assessment - Patients With Confirmed Complete Response (CR) or Partial Response (PR) | Time from the first documented response (CR or PR) to the first documented progression or death due to underlying cancer | Up to approximately 25 months | 
| Time to Definitive Deterioration of the ECOG PS From Baseline | Time to deterioration of Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) | Baseline, up to approximately 25 months | 
| Time to 10% Deterioration in the Global Health Status/QOL Scale Score of the EORTC QLQ-C30 | Patient reported outcomes for health related quality of life | Up to approximately 25 months | 
| Change From Baseline in the Global Health Status/QOL Scale Score of the EORTC QLQ-C30 | Patient reported outcomes for health related quality of life | Up to approximately 25 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LEE011, ribociclib, HR-positive, HER2-negative, Advanced breast cancer, Letrozole, Anastrozole, Tamoxifen, Goserelin, CDK, CDK4, CDK6, CDK4/6, Phase III, ER-positive, PR-positive, Premenopausal