The purpose of the study was to evaluate the safety and efficacy of a reduced ribociclib starting dose of 400 mg in combination with a non-steroidal aromatase inhibitor (NSAI) (letrozole or anastrozole) for the treatment of pre- and postmenopausal women with hormone receptor-positive (HR-positive), HER2-negative advanced breast cancer (aBC) who have received no prior therapy for advanced disease. Premenopausal women were required to receive goserelin in both treatment arms.
Patients were assigned at visit Cycle 1 Day 1 to one of the following two treatment arms in a ratio of 1:1: * Experimental arm: Ribociclib 400 mg (2 × 200 mg tablets by mouth) QD on Days 1 to 21 of a 28-day cycle, followed by 7 days off ribociclib (Days 22 to 28) in combination with ET consisting of: • For postmenopausal women: * Letrozole 2.5 mg by mouth QD continuously or anastrozole 1 mg by mouth QD continuously • For premenopausal women: * Letrozole 2.5 mg by mouth QD continuously or anastrozole 1 mg by mouth QD continuously, combined with goserelin 3.6 mg subcutaneously once every 4 weeks. * Control arm: Ribociclib 600 mg (3 × 200 mg tablets by mouth) QD on Days 1 to 21 of a 28-day cycle, followed by 7 days off ribociclib (Days 22 to 28) in combination with ET consisting of: * For postmenopausal women: \~ Letrozole 2.5 mg by mouth QD continuously or anastrozole 1 mg by mouth QD continuously. * For premenopausal women: * Letrozole 2.5 mg by mouth QD continuously or anastrozole 1 mg by mouth QD continuously, combined with goserelin 3.6 mg subcutaneously once every 4 weeks. Participants received 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. For participants who discontinued treatment for reasons other than documented disease progression, death, lost to follow-up, or withdrawal of consent, tumor assessments continued to be performed until disease progression, death, lost to follow-up, or withdrawal of consent (post-treatment efficacy follow-up).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
Ribociclib (at a dosage of 400 mg or 600 mg) QD orally taken on days 1 to 21 of a 28-day cycle, followed by 7 days off ribociclib (days 22 to 28). Ribociclib was supplied as 200 mg tablets as individual patient supply packaged bottles.
Anastrozole 1 mg tablets for oral use QD continuously
Letrozole 2.5 mg tablets for oral use QD continuously
Overall Response Rate (ORR)
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.
Time frame: Up to 23.8 months
Change From Baseline in QTc (With Fridericia's Correction) at Cycle 1 Day 15 (at 2 Hours Post-dose)
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).
Time frame: Baseline and Cycle 1 Day 15 at 2 hours post-dose. Cycle = 28 days
Progression-free Survival (PFS)
Progression free survival (PFS) was defined as the time from the date of randomization to the date of the first documented disease progression or death due to any cause. PFS was censored if no PFS event was observed. The censoring date was the date of the last adequate tumor assessment. Clinical deterioration without objective radiological evidence was not considered as documented disease progression. PFS was assessed via a local radiology assessment as well as Blinded Independent Review Committee (BIRC) according to RECIST 1.1.
Time frame: Up to approximately 60 months
Clinical Benefit Rate (CBR)
Clinical benefit rate (CBR) was defined as the proportion of patients 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 were defined as per local review as well as Blinded Independent Review Committee (BIRC) according to RECIST 1.1. A patient was considered to have SD for 24 weeks or longer if a SD response was recorded at 24-1=23 weeks or later from randomization, allowing for the ±1 week visit window for tumor assessments. 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.
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NONE
Enrollment
376
Goserelin 3.6 mg subcutaneously once every 4 weeks (pre-menopausal women only)
Southern Cancer Center PC
Mobile, Alabama, United States
Marin Cancer Care
Greenbrae, California, United States
Rocky Mountain Cancer Centers
Longmont, Colorado, 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
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
...and 79 more locations
Time frame: Up to approximately 60 months
Time to Response (TTR)
Time to response (TTR) was defined as the time from the date of randomization to the first documented response of either complete response (CR) or partial response (PR), which had to be subsequently confirmed (although the date of initial response was used, not the date of confirmation). CR and PR were 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.
Time frame: Up to approximately 60 months
Duration of Response (DOR)
Duration of response (DOR) only applied to patients whose best overall response was complete response (CR) or partial response (PR) according to RECIST 1.1 based on tumor response data per local review. The start date was the date of first documented response of CR or PR (i.e. the start date of response, not the date when response was confirmed), and the end date was defined as the date of the first documented progression or death due to underlying cancer. Patients continuing without progression or death due to underlying cancer were censored at the date of their last adequate tumor assessment. 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.
Time frame: Up to approximately 60 months
Pharmacokinetics (PK) of Ribociclib: Maximum Observed Plasma Concentration (Cmax)
PK parameters were calculated by non-compartmental analysis. Cmax is the maximum observed plasma drug concentration after single dose administration.
Time frame: Cycle 1 Day 15 at pre-dose, and 2, 4, 6 and 24 hours post-dose. Cycle = 28 days
PK of Ribociclib: Time to Reach Observed Maximum Concentration (Tmax)
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.
Time frame: Cycle 1 Day 15 at pre-dose, and 2, 4, 6 and 24 hours post-dose. Cycle = 28 days
PK of Ribociclib: Area Under the Plasma Concentration-time Curve From 0 to 24 Hours (AUC0-24)
PK parameters were calculated by non-compartmental analysis. AUC0-24 is the area under the plasma concentration-time curve from 0 to 24 hours
Time frame: Cycle 1 Day 15 at pre-dose, and 2, 4, 6 and 24 hours post-dose. Cycle = 28 days