Study of 2 Ribociclib Doses in Combination With Aromatase Inhibitors in Women With HR+, HER2- Advanced Breast Cancer

Study Overview
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Brief Summary
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QT interval prolongation and neutropenia are considered to be important identified risks for ribociclib. The approved dosing regimen of ribociclib is 600 mg daily (QD) on a 3 weeks on/1 week off schedule. The purpose of the study is to explore whether a reduced dosing regimen of 400 mg ribociclib orally QD 3 weeks on/1 week off may decrease the risk of QTc prolongation without compromising the efficacy of ribociclib in combination with an NSAI in pre- and postmenopausal women with HR-positive, HER2-negative aBC who have received no prior therapy for advanced disease. The risks of other AEs of special interest, such as neutropenia and hepatobiliary toxicity will be evaluated in this study as well. Approximately 350 patients will be randomly assigned to one of the below treatment arms in a 1:1 ratio: Experimental arm (Arm 1) - Ribociclib 400 mg QD 3 weeks on/1 week off + NSAI (+ goserelin in premenopausal women): 175 patients Control arm (Arm 2) - Ribociclib 600 mg QD 3 weeks on/1 week off + NSAI (+ goserelin in premenopausal women): 175 patients Randomization will be stratified by the presence of lung and/or liver metastases (yes versus no).

Official Title
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A Phase II, Multicenter, Randomized, Open-label Study to Evaluate the Safety and Efficacy of 400 mg of Ribociclib in Combination With Non-steroidal Aromatase Inhibitors for the Treatment of Pre- and Postmenopausal Women With Hormone Receptor-positive, HER2-negative Advanced Breast Cancer Who Received no Prior Therapy for Advanced Disease

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: Ribociclib
* Drug: Letrozole or Anastrozole
* Drug: Goserelin


Participation Criteria
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Eligibility Criteria
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Key Inclusion criteria: Patient has advanced (loco-regionally recurrent or metastatic) breast cancer not amenable to curative therapy. Patient has a histologically and/or cytologically confirmed diagnosis of ER-positive and/or PgR-positive breast cancer based on the most recently analyzed tissue sample, and all tested by local laboratory. Patient has HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization (FISH, CISH, or SISH) test is required by local laboratory testing and based on the most recently analyzed tissue sample. Patient must have measurable disease, i.e., at least one measurable lesion according to RECIST version 1.1. (a lesion in a previously irradiated site may only be counted as a target lesion if there is clear evidence of progression since the irradiation). Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Standard 12-lead ECG values defined as the mean of the triplicate ECGs and assessed by the central laboratory: QTcF interval at screening < 450 ms (QT interval using Fridericia's correction) Mean resting heart rate 50 to 90 bpm (determined from the ECG) Women of childbearing potential (CBP), defined as all women physiologically capable of becoming pregnant, 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. Key Exclusion Criteria: Patient with symptomatic visceral disease or any disease burden that makes the patient ineligible for endocrine therapy per the investigator's judgment. Patient who received any prior systemic anti-cancer therapy(including endocrine therapy, chemotherapy, prior CDK4/6 inhibitors) for aBC. Patients who received neo-/adjuvant therapy for breast cancer are eligible. Patient is concurrently using other anti-cancer therapy. Patient has had major surgery within 14 days prior to starting study drug or has not recovered from major toxicities. Patient has received extended-field radiotherapy ≤ 4 weeks or limited field radiotherapy ≤ 2 weeks prior to randomization, and has not recovered to grade 1 or better from related side effects of such therapy (with the exception of alopecia or other toxicities not considered a safety risk for the patient at investigator's discretion). Patients in whom ≥ 25% of the bone marrow has been previously irradiated are also excluded. Patient has a concurrent malignancy or malignancy within 3 years of the randomization date, with the exception of adequately treated basal or squamous cell skin carcinoma, or curatively resected cervical carcinoma in situ. Patients with central nervous system (CNS) involvement unless they meet specific stability criteria. Patient has clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality. Patient is currently receiving or has received systemic corticosteroids ≤ 2 weeks prior to starting study drug, and has not fully recovered from side effects of such treatment. Other protocol-defined Inclusion/Exclusion may apply.

Ages Eligible for Study
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Minimum Age: 18 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ribociclib 400 mg<br>Ribociclib 400 mg QD 3 weeks on/1 week off + letrozole or anastrozole (+goserelin in premenopausal women) | Drug: Ribociclib<br>* Ribociclib will be supplied as 200 mg tablets as individual patient supply packaged bottles taken by mouth.<br>* Other names: LEE011;Drug: Letrozole or Anastrozole<br>* Letrozole 2.5 mg by mouth QD continuously or anastrozole 1 mg by mouth QD continuously (investigator choice)<br>Drug: Goserelin<br>* Goserelin 3.6 mg subcutaneously once every 4 weeks (pre-menopausal women only)<br>|
| Active Comparator: Ribociclib 600 mg<br>Ribociclib 600 mg QD 3 weeks on/1 week off + letrozole or anastrozole (+ goserelin in premenopausal women) | Drug: Ribociclib<br>* Ribociclib will be supplied as 200 mg tablets as individual patient supply packaged bottles taken by mouth.<br>* Other names: LEE011;Drug: Letrozole or Anastrozole<br>* Letrozole 2.5 mg by mouth QD continuously or anastrozole 1 mg by mouth QD continuously (investigator choice)<br>Drug: Goserelin<br>* Goserelin 3.6 mg subcutaneously once every 4 weeks (pre-menopausal women only)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR is based on local tumor assessments (RECIST version 1.1) for all patients that have been treated for at least 6 months or have discontinued the study treatment. | At least 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Δ QTcF at Cycle 1 Day 15 (at 2h post-dose) (Key Secondary Endpoint) | To evaluate QTc (with Fridericia's correction) prolongation in the experimental arm | Cycle 1 Day 15 (2 hours post dose) | 
| Progression-free survival (PFS) | PFS per RECIST 1.1 | Approximately 36 months | 
| Clinical benefit rate (CBR) | CBR per RECIST 1.1 | Approximately 36 months | 
| Time to response (TTR) | TTR per RECIST 1.1 | Approximately 36 months | 
| Duration of response (DOR) | DOR per RECIST 1.1 | Approximately 36 months | 
| Pharmacokinetics (PK) of ribociclib: Cmax | when given in combination with NSAI | Cycle 1 Day 15 | 
| Pharmacokinetics (PK) of ribociclib: Tmax | when given in combination with NSAI | Cycle 1 Day 15 | 
| Pharmacokinetics (PK) of ribociclib: AUC0 - 24h | when given in combination with NSAI | Cycle 1 Day 15 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Breast Cancer, HR-positive, HER2-negative, ER-positive, advanced breast cancer, ribociclib, LEE011, premenopausal, postmenopausal