Study of Efficacy and Safety in Premenopausal Women With Hormone Receptor Positive, HER2-negative Advanced Breast Cancer
- Conditions
- Advanced Metastatic Breast Cancer
- Interventions
- Registration Number
- NCT02278120
- Lead Sponsor
- Novartis Pharmaceuticals
- Brief Summary
The purpose of this study was to determine whether treatment with tamoxifen or a non-steroidal aromatase inhibitors (NSAI) + goserelin + LEE011 prolonged progression-free survival (PFS) compared to treatment with tamoxifen or a NSAI + goserelin + placebo in premenopausal women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer.
- Detailed Description
This was a randomized, Phase III, double-blind, global study comparing the treatment efficacy and safety of ribociclib + goserelin + tamoxifen or a NSAI (letrozole or anastrozole) versus placebo + goserelin + tamoxifen or a NSAI in premenopausal women with HR+, HER2- advanced breast cancer.
Eligible participants were randomized in a 1:1 ratio to either the ribociclib arm or the placebo arm. Study treatment continued until disease progression, unacceptable toxicity, death, or discontinuation for any other reason.
Participants who discontinued treatment due to reasons other than disease progression or withdrawal of consent for efficacy follow-up continued to be monitored until disease progression, death, withdrawal of consent, loss to follow-up, or subject/guardian decision (post-treatment efficacy follow-up).
All participants who discontinued treatment were followed for survival until the predetermined number of overall survival (OS) events was reached.
Following the final OS analysis (performed when approximately 189 deaths were recorded) and with protocol amendment 6 (dated 18-Jul-2019), participants and investigators were unblinded and those participants in the placebo arm had the opportunity to cross-over to the ribociclib arm to receive ribociclib + goserelin + NSAI. Cross-over was optional and was conducted at the investigator's discretion and upon participant consent.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- Female
- Target Recruitment
- 672
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Ribociclib + NSAI/tamoxifen + goserelin Anastrozole Ribociclib 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) Ribociclib + NSAI/tamoxifen + goserelin Goserelin Ribociclib 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) Placebo + NSAI/tamoxifen + goserelin Placebo Placebo 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). Participants were unblinded once the final OS analysis was conducted and after the implementation of protocol amendment 6 (16-Jul-2019) and were given the option to crossover to treatment with ribociclib +NSAI/tamoxifen + goserelin. Placebo + NSAI/tamoxifen + goserelin Tamoxifen Placebo 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). Participants were unblinded once the final OS analysis was conducted and after the implementation of protocol amendment 6 (16-Jul-2019) and were given the option to crossover to treatment with ribociclib +NSAI/tamoxifen + goserelin. Ribociclib + NSAI/tamoxifen + goserelin Tamoxifen Ribociclib 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) Ribociclib + NSAI/tamoxifen + goserelin Ribociclib Ribociclib 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) Ribociclib + NSAI/tamoxifen + goserelin Letrozole Ribociclib 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) Placebo + NSAI/tamoxifen + goserelin Letrozole Placebo 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). Participants were unblinded once the final OS analysis was conducted and after the implementation of protocol amendment 6 (16-Jul-2019) and were given the option to crossover to treatment with ribociclib +NSAI/tamoxifen + goserelin. Placebo + NSAI/tamoxifen + goserelin Anastrozole Placebo 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). Participants were unblinded once the final OS analysis was conducted and after the implementation of protocol amendment 6 (16-Jul-2019) and were given the option to crossover to treatment with ribociclib +NSAI/tamoxifen + goserelin. Placebo + NSAI/tamoxifen + goserelin Goserelin Placebo 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). Participants were unblinded once the final OS analysis was conducted and after the implementation of protocol amendment 6 (16-Jul-2019) and were given the option to crossover to treatment with ribociclib +NSAI/tamoxifen + goserelin.
- Primary Outcome Measures
Name Time Method Progression Free Survival (PFS) by Investigator Assessment From randomization to first documented progression or death, assessed up to approximately 29 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. In cases where patients did not experience an event, the PFS was censored at 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 local radiology assessment according to RECIST 1.1. As per protocol, the final PFS analysis was conducted after approximately 392 PFS events were documented. The Kaplan-Meier method was used to estimate PFS, and the median PFS, along with 95% confidence intervals, was reported for each treatment group. A stratified Cox regression model was used to estimate the hazard ratio of PFS, along with 95% confidence interval
- Secondary Outcome Measures
Name Time Method Duration of Response (DOR) by Investigator Assessment Up to approximately 29 months DOR was defined as the time from the first documented response (CR or PR) to the first documented progression or death due to underlying cancer as defined in RECIST 1.1 per investigator assessment. The Kaplan-Meier method was used to estimate DOR, and the median DOR, along with 95% confidence intervals, was reported for each treatment group. If a participant had not had an event, duration was censored at the date of last adequate tumor assessment.
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.Time to Definitive 10% Deterioration in the Global Health Status/Quality of Life (GHS/QoL) Scale Score of the European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC QLQ-C30) Up to approximately 29 months The EORTC QLQ-C30 is a questionnaire that includes 5 functional scales, 3 symptom scales, 1 GHS/QoL scale, and 6 single items. GHS/QoL scale score ranges between 0 and 100. A high score for GHS/QoL represents better functioning or QoL.The time to definitive 10% deterioration is defined as the time from the date of randomization to the date of event, which is defined as at least 10% relative to baseline worsening of the QoL score (without further improvement above the threshold) or death due to any cause. The Kaplan-Meier method was used to estimate the distribution, and the median time to definitive 10% deterioration, along with 95% confidence intervals, was reported for each treatment group. If a patient had not had an event, time to deterioration was censored at the date of the last adequate QoL evaluation.
Overall Survival (OS) From randomization to death, assessed up to approximately 45 months OS was defined as the time from the date of randomization to the date of death from any cause. In cases where the patient's death was not recorded, the OS value was censored at the date of the last known patient's survival status. OS was estimated using the Kaplan-Meier method. As per protocol, the final OS analysis was conducted after approximately 189 deaths were documented.
The median OS, along with 95% confidence intervals, was reported for each treatment group.The distribution of OS between the two treatment arms was compared using a log-rank test at one-sided cumulative 2.5% level of significance. A stratified Cox regression was used to estimate the OS hazard ratio and the associated 95% CI.Overall Response Rate (ORR) by Investigator Assessment Up to approximately 29 months ORR is the percentage of participants with the best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1 as per local assessment. 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.
Clinical Benefit Rate (CBR) by Investigator Assessment Up to approximately 29 months 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 and local assessment. 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.
Time to Definitive Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) by at Least One Category of the Score Baseline, up to approximately 29 months ECOG PS categorized patients based on their ability to perform daily activities and self-care, with scores ranging from 0 to 5. A score of 0 indicated no restrictions in activity, while higher scores indicated increasing limitations. Time to definitive deterioration was defined as the time from the date of randomization to the date of the event, defined as experiencing an increase in ECOG PS by at least one category from the baseline or death. A deterioration was considered definitive if no improvements in the ECOG PS were observed at a subsequent time. The Kaplan-Meier method was used to estimate the distribution, and the median time to definitive deterioration, along with 95% confidence intervals, was reported for each treatment group. Patients receiving any further therapy prior to definitive worsening were censored at their date of last assessment prior to start of therapy. Patients that had not worsened at the data cutoff point were censored at the date of last assessment.
Change From Baseline in the GHS/QoL Scale Score of the EORTC QLQ-C30 Baseline, every 2 cycles after randomization during 18 months, then every 3 cycles up to end of treatment (EOT); EOT; and every 8 or 12 weeks post-treatment until progression, assessed up to approximately 29 months. Cycle=28 days The EORTC QLQ-C30 is a questionnaire that includes 5 functional scales, 3 symptom scales, 1 GHS/QoL scale, and 6 single items. GHS/QoL scale score ranges between 0 and 100. A high score for GHS/QoL represents better functioning or QoL.The change from baseline in the GHS/QoL score was assessed. A positive change from baseline indicated improvement. For subjects who discontinued treatment without disease progression, post-treatment efficacy visits occurred every 8 weeks during the initial 18 months since start of treatment, followed by visits every 12 weeks until disease progression.
Time to Response (TTR) by Investigator Assessment Up to approximately 29 months 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 as per local assessment. The Kaplan-Meier method was used to estimate TTR, and the median TTR, along with 95% confidence intervals, was reported for each treatment group. Participants who did not achieve a confirmed response were censored at the maximum follow-up time 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.
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.
Trial Locations
- Locations (36)
Penn State University Milton S Hershey Medical Center
🇺🇸Hershey, Pennsylvania, United States
Danbury Hospital SC
🇺🇸Danbury, Connecticut, United States
University Of California Los Angeles Dept of Onc
🇺🇸Los Angeles, California, United States
Meridian Health Systems SC
🇺🇸Neptune, New Jersey, United States
Clinical Research Alliance .
🇺🇸Lake Success, New York, United States
Comprehensive Blood and Cancer SC-2
🇺🇸Bakersfield, California, United States
Memorial Cancer Institute SC
🇺🇸Hollywood, Florida, United States
University of New Mexico Hospital SC-2
🇺🇸Albuquerque, New Mexico, United States
Florida Cancer Specialists Onc Dept
🇺🇸Fort Myers, Florida, United States
Bon Secours Cancer Center SC
🇺🇸Greenville, South Carolina, United States
Sidney Kimmel CCC At JH Dept of Onc.
🇺🇸Baltimore, Maryland, United States
University of Chicago SC-3
🇺🇸Chicago, Illinois, United States
Uni of TX MD Anderson Cancer Cntr SC-5
🇺🇸Houston, Texas, United States
University Of Miami Univ Miami 2
🇺🇸Miami, Florida, United States
Duke Univ Medical Center Duke (SC)
🇺🇸Durham, North Carolina, United States
SCRI Oncology Partners Tennessee Oncology (3)
🇺🇸Nashville, Tennessee, United States
Mays Cancer Ctr Uthsa Mdacc SC-4
🇺🇸San Antonio, Texas, United States
Methodist Hospita Methodist Can Cen Dept of Oncology
🇺🇸Houston, Texas, United States
Novartis Investigative Site
🇦🇪Al Ain Abu Dhabi, United Arab Emirates
Brooke Army Medical Center SC
🇺🇸San Antonio, Texas, United States
Florida Cancer Specialists SC-2
🇺🇸Fort Myers, Florida, United States
Massachusetts General Hospital Onc Dept
🇺🇸Boston, Massachusetts, United States
Erlanger Medical Center SC
🇺🇸Chattanooga, Tennessee, United States
Northern Utah Cancer Associates
🇺🇸Ogden, Utah, United States
The Center for Cancer and Blood Disorders SC
🇺🇸Fort Worth, Texas, United States
Providence Regional Cancer Partnership
🇺🇸Everett, Washington, United States
NorthWest Georgia Oncology Centers IRB
🇺🇸Marietta, Georgia, United States
Washington Uni School of Med SC
🇺🇸Saint Louis, Missouri, United States
Bon Secours Virginia Health System
🇺🇸Midlothian, Virginia, United States
Northwest Medical Specialties Dept of Onc
🇺🇸Tacoma, Washington, United States
Kadlec Clinic Hematology and Onco Kadlec Clinic Hematology & Onc
🇺🇸Kennewick, Washington, United States
Comprehensive Cancer Center at Saint Joseph Hospital SC
🇺🇸Denver, Colorado, United States
Norton Cancer Institute SC
🇺🇸Louisville, Kentucky, United States
University of Michigan Comprehensive Cancer Center Onc Dept
🇺🇸Ann Arbor, Michigan, United States
Moanalua Medical Center. Attn: Oncology Dept SC
🇺🇸Honolulu, Hawaii, United States
University of Wisconsin / Paul P. Carbone Comp Cancer Center Univ Wisc 3
🇺🇸Madison, Wisconsin, United States