Study of 2 Ribociclib Doses in Combination With Aromatase Inhibitors in Women With HR+, HER2- Advanced Breast Cancer
- Conditions
- Breast Cancer
- Interventions
- Registration Number
- NCT03822468
- Lead Sponsor
- Novartis Pharmaceuticals
- Brief Summary
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 a non-steroidal aromatase inhibitor (NSAI) in pre- and postmenopausal women with hormone receptor-positive (HR-positive), HER2-negative advanced breast cancer (aBC) who have not received prior therapy for advanced disease.
- Detailed Description
This is a phase II, multicenter, randomized, open-label study to evaluate the safety and efficacy of a reduced ribociclib dose of 400 mg in combination with an NSAI (letrozole or anastrozole) for the treatment of pre- and postmenopausal women with HR-positive, HER2-negative aBC who have received no prior therapy for advanced disease.
Patients will be randomly assigned to one of the below treatment arms in a 1:1 ratio:
* Experimental arm - Ribociclib 400 mg QD 3 weeks on/1 week off + NSAI (+ goserelin in premenopausal women)
* Control arm - Ribociclib 600 mg QD 3 weeks on/1 week off + NSAI (+ goserelin in premenopausal women).
Participants will receive study treatment until disease progression (radiologically documented according to RECIST 1.1 criteria), unacceptable toxicity, death, or discontinuation from the study treatment for any other reason. Continuation of study treatment beyond initial disease progression (RECIST 1.1) will not be allowed.
For participants who discontinue treatment for reasons other than documented disease progression, death, lost to follow-up, or withdrawal of consent, tumor assessments must continue to be performed until disease progression, death, lost to follow-up, or withdrawal of consent (post-treatment efficacy follow-up).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Female
- Target Recruitment
- 376
Not provided
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Ribociclib 400 mg Ribociclib Ribociclib 400 mg QD 3 weeks on/1 week off + letrozole or anastrozole (+goserelin in premenopausal women) Ribociclib 400 mg Anastrozole Ribociclib 400 mg QD 3 weeks on/1 week off + letrozole or anastrozole (+goserelin in premenopausal women) Ribociclib 400 mg Goserelin Ribociclib 400 mg QD 3 weeks on/1 week off + letrozole or anastrozole (+goserelin in premenopausal women) Ribociclib 600 mg Letrozole Ribociclib 600 mg QD 3 weeks on/1 week off + letrozole or anastrozole (+ goserelin in premenopausal women) Ribociclib 600 mg Goserelin Ribociclib 600 mg QD 3 weeks on/1 week off + letrozole or anastrozole (+ goserelin in premenopausal women) Ribociclib 400 mg Letrozole Ribociclib 400 mg QD 3 weeks on/1 week off + letrozole or anastrozole (+goserelin in premenopausal women) Ribociclib 600 mg Anastrozole Ribociclib 600 mg QD 3 weeks on/1 week off + letrozole or anastrozole (+ goserelin in premenopausal women) Ribociclib 600 mg Ribociclib Ribociclib 600 mg QD 3 weeks on/1 week off + letrozole or anastrozole (+ goserelin in premenopausal women)
- Primary Outcome Measures
Name Time Method Overall Response Rate (ORR) Up to 23.8 months ORR defined as the percentage of participants with best overall response (BOR) of confirmed complete response (CR) or partial response (PR) assessed by local investigators according to RECIST 1.1.
CR: Disappearance of all lesions with lymph nodes measuring \< 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.
- Secondary Outcome Measures
Name Time Method Change From Baseline in QTc (With Fridericia's Correction) at Cycle 1 Day 15 (at 2 Hours Post-dose) Baseline and Cycle 1 Day 15 at 2 hours post-dose. Cycle = 28 days Electrocardiogram (ECG) data was collected via 12-lead digital ECG machines. Change from baseline in the QT interval (a segment of the ECG that reflects the time it takes for the heart to repolarize after each heartbeat) was corrected for heart rate using Fridericia's formula (ΔQTcF).
Progression-free Survival (PFS) Up to approximately 60 months PFS was defined as the period starting from the date of randomization to the date of the first documented progression or death caused by any reason. PFS will be assessed via a local radiology assessment as well as BIRC according to RECIST 1.1.
Clinical Benefit Rate (CBR) Up to approximately 60 months CBR is defined as the percentage of participants with a best overall response of complete response (CR), or partial response (PR), or an overall response of stable disease (SD), lasting for at least 24 weeks. CR, PR, and SD are defined as per local review as well as BIRC according to RECIST 1.1.
CR: Disappearance of all lesions with lymph nodes measuring \< 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.Time to Response (TTR) Up to approximately 60 months TTR defined as defined as the time from the date of randomization to the first documented response of either CR or PR. CR and PR are based on tumor response data as per local review and according to RECIST 1.1.
CR: Disappearance of all lesions with lymph nodes measuring \< 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.Duration of Response (DOR) Up to approximately 60 months DOR defined as the time from the first documented response (CR or PR) to the first documented progression or death due to underlying cancer.
CR: Disappearance of all lesions with lymph nodes measuring \< 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.Pharmacokinetics (PK) of Ribociclib: Maximum Observed Plasma Concentration (Cmax) Cycle 1 Day 15 at pre-dose, and 2, 4, 6 and 24 hours post-dose. Cycle = 28 days PK parameters were calculated by non-compartmental analysis. Cmax is the maximum observed plasma drug concentration after single dose administration.
PK of Ribociclib: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24) Cycle 1 Day 15 at pre-dose, and 2, 4, 6 and 24 hours post-dose. Cycle = 28 days PK parameters were calculated by non-compartmental analysis. AUC0-24 is the area under the plasma concentration-time curve from 0 to 24 hours
PK of Ribociclib: Time to Reach Observed Maximum Concentration (Tmax) Cycle 1 Day 15 at pre-dose, and 2, 4, 6 and 24 hours post-dose. Cycle = 28 days PK parameters were calculated by non-compartmental analysis. Tmax is the time to reach maximum observed plasma concentration. Actual recorded sampling times were considered for the calculations.
Trial Locations
- Locations (15)
Southern Cancer Center PC
🇺🇸Mobile, Alabama, United States
Rocky Mountain Cancer Centers
🇺🇸Longmont, Colorado, United States
Nebraska Cancer Specialists
🇺🇸Omaha, Nebraska, United States
Comprehensive Cancer Cntr Of Nevada
🇺🇸Henderson, Nevada, United States
New York Oncology Hematology
🇺🇸Albany, New York, United States
Mount Sinai School Of Medicine
🇺🇸New York, New York, United States
Millennium Research Clin Develop
🇺🇸Houston, Texas, United States
Northwest Medical Specialties
🇺🇸Tacoma, Washington, United States
Marin Cancer Care
🇺🇸Greenbrae, California, United States
Florida Retina Institute
🇺🇸Orlando, Florida, United States
Weinberg Cancer Institute at FSH
🇺🇸Baltimore, Maryland, United States
Nebraska Hematology Oncology P C
🇺🇸Lincoln, Nebraska, United States
Montefiore Medical Center
🇺🇸Bronx, New York, United States
Texas Oncology
🇺🇸McAllen, Texas, United States
Novartis Investigative Site
🇹🇭Chiang Mai, Thailand