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This study aimed at evaluating the safety and efficacy of everolimus plus exemestane in Chinese postmenopausal women with ER+ HER2- locally advanced, recurrent, or metastatic breast cancer after recurrence or progression on letrozole or anastrozole.
This was a multicenter, double-blind, randomized, placebo-controlled, phase II study evaluating treatment with everolimus (10 mg daily) in combination with exemestane (25 mg daily) vs placebo in combination with exemestane (25 mg daily) in Chinese postmenopausal women with locally advanced, recurrent or metastatic ER+ HER2- breast cancer refractory to non-steroidal aromatase inhibitors.
Randomized participants started the study treatment at Cycle 1 Day 1, and were treated continuously until disease progression (assessed by RECIST 1.1), unacceptable toxicity, death or discontinuation from treatment for any other reason.
After end of treatment, all participants were followed up for safety up to 30 days after last dose of study treatment (exemestane and/or everolimus/placebo). All participants were followed for survival status at least every 3 months after treatment discontinuation unless they discontinued due to death, consent withdrawal or lost to follow-up
If a participants permanently discontinued study treatment for reasons other than disease progression, death, lost to follow-up, or withdrawal of consent to efficacy follow-up then they entered the post-treatment efficacy follow-up period until disease progression, death, lost to follow-up or withdrawal of consent for efficacy follow-up.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Everolimus + Exemestane | Experimental | Participants received everolimus as a continuous oral daily dose of 10 mg and exemestane as a continuous oral daily dose of 25 mg |
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| Placebo + Exemestane | Active Comparator | Participants received placebo as a continuous oral daily dose and exemestane as a continuous oral daily dose of 25 mg |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Everolimus | Drug | Everolimus was formulated as tablets of 5 mg strength and was packaged into blister packs . Everolimus (two 5 mg tablets daily) was administered in a blinded manner by continuous oral daily dosing. |
| Measure | Description | Time Frame |
|---|---|---|
| Progression-free Survival (PFS) Based on Local Radiology Review of Tumor Assessment | PFS was defined as time from the date of randomization to the date of first documented progression or death due to any cause. A patient who had not progressed or died at the date of the analysis cut-off or received another anticancer therapy had their PFS censored at the time of the last adequate tumor evaluation before the earlier of the cut-off date or the anticancer therapy date. Disease progression was assessed using the local investigator's tumor assessment per Response Evaluation Criteria in Solid Tumours (RECIST) 1.1. The distribution of PFS was estimated using the Kaplan-Meier method. Cox regression model stratified by randomization stratification factors was used to estimate the hazard ratio (HR) of PFS, along with 90% CI. As this was an estimation based approach, no p-value was provided. | From randomization up to date of first documented progression or death, assessed up to approximately 3.5 years |
| Measure | Description | Time Frame |
|---|---|---|
| Progression-free Survival (PFS) Based on Blinded Independent Review Committee (BIRC) Assessment | PFS was defined as time from the date of randomization to the date of first documented progression or death due to any cause. A patient who had not progressed or died at the date of the analysis cut-off or received another anticancer therapy had their PFS censored at the time of the last adequate tumor evaluation before the earlier of the cut-off date or the anticancer therapy date. Disease progression was assessed using the BIRC tumor assessment per RECIST 1.1. The distribution of PFS was estimated using the Kaplan-Meier method. Cox regression model stratified by randomization stratification factors was used to estimate the hazard ratio (HR) of PFS, along with 90% CI. As this was an estimation based approach, no p-value was provided. |
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Key Inclusion Criteria:
Chinese Postmenopausal women with ER+ HER2- locally advanced, recurrent, or metastatic breast cancer. Locally advanced breast cancer must not be amenable to curative treatment by surgery or radiotherapy.
Histological or cytological confirmation of estrogen-receptor positive (ER+) breast cancer
Postmenopausal women. Postmenopausal status was defined either by:
Recurrence or progression on prior NSAI was defined as:
Radiological or objective evidence of recurrence or progression on or after the last systemic therapy prior to enrollment
Patient had as per RECIST 1.1
Patient was able to swallow and retain oral medication
Patient met the hematologic and biochemistery laboratory values at the screening visit
Patient had a WHO performance status ≤2
Written informed consent obtained prior to any screening procedures
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Novartis Pharmaceuticals | Novartis Pharmaceuticals | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Novartis Investigative Site | Guangzhou | Guangdong | 510000 | China | ||
| Novartis Investigative Site |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38904918 | Derived | Shao ZM, Cai L, Wang S, Hu X, Shen K, Wang H, Li H, Feng J, Liu Q, Cheng J, Wu X, Wang X, Li H, Luo T, Liu J, Amin K, Slimane K, Qiao Y, Liu Y, Tong Z. BOLERO-5: a phase II study of everolimus and exemestane combination in Chinese post-menopausal women with ER + /HER2- advanced breast cancer. Discov Oncol. 2024 Jun 21;15(1):237. doi: 10.1007/s12672-024-01027-8. |
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Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.
This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
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The screening period began once patients had signed the study informed consent. All screening/baseline evaluations were performed within maximum 21 days prior to the first dose of study treatment
Participants took part in 15 investigative sites in China
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| ID | Title | Description |
|---|---|---|
| FG000 | Everolimus + Exemestane | Participants received everolimus as a continuous oral daily dose of 10 mg and exemestane as a continuous oral daily dose of 25 mg |
| FG001 | Placebo + Exemestane |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | May 23, 2017 | Apr 17, 2023 |
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| Exemestane | Drug | Commercially available exemestane was supplied as 25 mg tablets. Exemestane was administered as continuous oral daily dose of 25 mg tablets. |
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| Everolimus Placebo | Drug | Placebo was formulated to be indistinguishable from the everolimus tablets. Matching placebo (two tablets daily) was administered in a blinded manner by continuous oral daily dosing. |
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| From randomization up to date of first documented progression or death, assessed up to approximately 1.8 years |
| Overall Survival (OS) | OS was defined as the time from date of randomization to date of death due to any cause. If the participant was alive at the date of the analysis cut-off or lost to follow-up, then OS was censored at the last contact date prior to data cutoff date. The distribution of OS was estimated using the Kaplan-Meier method. Cox regression model stratified by randomization stratification factors was used to estimate the hazard ratio (HR) of OS, along with 90% CI. As this was an estimation based approach, no p-value was provided. | From randomization to date of death, up to approximately 3.8 years |
| Overall Response Rate (ORR) Based on Local Radiology Review of Tumor Assessment | ORR was defined as the percentage of participants with a best overall response defined as complete response (CR) or partial response (PR) according to RECIST using local radiologist's/investigator's tumor assessment. ORR was estimated and the exact binomial 90% CI was reported by treatment arm. 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 3.5 years |
| Overall Response Rate (ORR) Based on BIRC Assessment | ORR was defined as the percentage of participants with a best overall response defined as complete response (CR) or partial response (PR) according to RECIST using BIRC assessment. ORR was estimated and the exact binomial 90% CI was reported by treatment arm. 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 1.8 years |
| Clinical Benefit Rate (CBR) Based on Local Radiology Review of Tumor Assessment | CBR was defined as the percentage of patients with best overall response of CR, PR or an overall lesion response of stable disease (SD) or Non-CR/Non-progressive disease with duration of 24 weeks or longer according to RECIST 1.1 using local radiologist's/investigator's tumor assessment. CBR was estimated and the exact binomial 90% CI was reported by treatment arm. 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. | Up to approximately 3.5 years |
| Clinical Benefit Rate (CBR) Based on BIRC Assessment | CBR was defined as the percentage of patients with best overall response of CR, PR or an overall lesion response of stable disease (SD) or Non-CR/Non-progressive disease with duration of 24 weeks or longer according to RECIST 1.1 using BIRC assessment. CBR was estimated and the exact binomial 90% CI was reported by treatment arm. 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. | Up to approximately 1.8 years |
| Time to Response (TTR) Based on Local Radiology Review of Tumor Assessment | TTR was defined as the time between date of randomization until first documented response (CR or PR) according to RECIST 1.1 using local radiologist's/investigator's 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. | Up to approximately 3.5 years |
| Time to Response (TTR) Based on BIRC Assessment | TTR was defined as the time between date of randomization until first documented response (CR or PR) according to RECIST 1.1 using BIRC 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. | Up to approximately 1.8 years |
| Duration of Response (DOR) Based on Local Radiology Review of Tumor Assessment | DOR was defined as the time from date of first documented CR or PR to date of first documented disease progression or death due to any cause, according to RECIST 1.1 using local radiologist's/investigator's 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. | From date of first documented response to date of first documented disease progression or death, assessed up to approximately 3.5 years |
| Duration of Response (DOR) Based on BIRC Assessment | DOR was defined as the time from date of first documented CR or PR to date of first documented disease progression or death due to any cause, according to RECIST 1.1 using BIRC 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. | From date of first documented response to date of first documented disease progression or death, assessed up to approximately 1.8 years |
| Time to Definitive Deterioration of the Eastern Cooperative Oncology Group Performance Status (ECOG PS) by at Least One Category of the Score From Baseline | ECOG PS is a measure of functional status with scores ranging from 0 (fully active) to 5 (dead). Deterioration was considered definitive if no improvements in the ECOG PS status were observed after an instance of deterioration. Death was considered as worsening of the ECOG PS if it occurred close to the last assessment, where "close" is defined as twice the planned period between two assessments. Participants who died after more than twice the planned period between two assessments were censored at the date of their last assessment before the cut-off. Participants receiving any further anticancer therapy prior to definitive worsening were censored at their date of last assessment prior to start of therapy. Participants that had not worsened were censored at the date of last assessment prior to cut off. Time to definitive deterioration was estimated using the Kaplan-Meier method. | From randomization up to definitive deterioration of the ECOG PS by one categotu of the score, assessed up to approximately 3.5 years |
| Everolimus Predose Concentration (Cmin) | Blood samples were collected to assess everolimus predose concentration (Cmin) at steady state at Cycle 1 Week 4 (any day during week 4). Steady-state was defined as having no dose adjustment/interruption of everolimus and exemestane in the previous 4 days prior to the day of the pre-dose PK sample collection. Everolimus concentrations were determined in the whole blood by a liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. The method has a lower limit of quantitation (LLOQ) of 0.3 ng/mL for everolimus. Values below the LLOQ were set to 0. | Predose on Cycle 1 Week 4 ( each cycle is defined as 4 weeks) |
| Everolimus Concentration at 2 Hours Post Dose (C2h) | Blood samples were collected to assess everolimus concentration at 2 hours post dose (C2h) at steady state at Cycle 1 Week 4 (any day during week 4) Steady-state was defined as having no dose adjustment/interruption of everolimus and exemestane in the previous 4 days prior to the day of the pre-dose PK sample collection. Everolimus concentrations were determined in the whole blood by a liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. The method has a LLOQ of 0.3 ng/mL for everolimus. Values below the LLOQ were set to 0. | Two hours post everolimus administration on Cycle 1 Week 4 ( each cycle is defined as 4 weeks) |
| Exemestane Predose Concentration (Cmin) | Blood samples were collected to assess exemestane predose concentration (Cmin) at steady state at Cycle 1 Week 4 (any day during week 4). Steady-state was defined as having no dose adjustment/interruption of everolimus and exemestane in the previous 4 days prior to the day of the pre-dose PK sample collection. Exemestane concentrations were determined in the whole blood by a liquid chromatography with LC-MS/MS method. The method has a LLOQ of 20 pg/mL for exemestane. Values below the LLOQ were set to 0. | Predose of exemestane on Cycle 1 Week 4 ( each cycle is defined as 4 weeks) |
| Exemestane Concentration at 2 Hours Post Dose (C2h) | Blood samples were collected to assess exemestane concentration at 2 hours post dose (C2h) at steady state at Cycle 1 Week 4 (any day during week 4) Steady-state was defined as having no dose adjustment/interruption of everolimus and exemestane in the previous 4 days prior to the day of the pre-dose PK sample collection. Exemestane concentrations were determined in the whole blood by a liquid chromatography with LC-MS/MS method. The method has a LLOQ of 20 pg/mL for exemestane. Values below the LLOQ were set to 0. | Two hours post exemestane administration on Cycle 1 Week 4 ( each cycle is defined as 4 weeks) |
| Estradiol Levels After 4 Weeks of Study Treatment | Blood samples were collected to assess estradiol levels after 4 weeks of study treatment. Estradiol was determined in plasma using competitive immunoassay. The method has a LLOQ of 1.952 pg/mL for estradiol. Values below the LLOQ were set to 0. | Baseline, and at Cycle 1 Week 4 prior to any study drug (each cycle is defined as 4 weeks) |
| Harbin |
| Heilongjiang |
| 150081 |
| China |
| Novartis Investigative Site | Wuhan | Hubei | 430022 | China |
| Novartis Investigative Site | Nanjing | Jiangsu | 210009 | China |
| Novartis Investigative Site | Shanghai | Shanghai Municipality | 200032 | China |
| Novartis Investigative Site | Chengdu | Sichuan | 610041 | China |
| Novartis Investigative Site | Chengdu | Sichuan | 610072 | China |
| Novartis Investigative Site | Tianjin | Tianjin Municipality | 300060 | China |
| Novartis Investigative Site | Hangzhou | Zhejiang | 310022 | China |
| Novartis Investigative Site | Beijing | 100036 | China |
| Novartis Investigative Site | Chongqing | 400016 | China |
| Novartis Investigative Site | Guangzhou | 510060 | China |
| Novartis Investigative Site | Qingdao | 266000 | China |
| Novartis Investigative Site | Shanghai | 200025 | China |
| Novartis Investigative Site | Wuhan | 430000 | China |
Participants received placebo as a continuous oral daily dose and exemestane as a continuous oral daily dose of 25 mg
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Everolimus + Exemestane | Participants received everolimus as a continuous oral daily dose of 10 mg and exemestane as a continuous oral daily dose of 25 mg |
| BG001 | Placebo + Exemestane | Participants received placebo as a continuous oral daily dose and exemestane as a continuous oral daily dose of 25 mg |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
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| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
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| Age, Continuous | Mean | Standard Deviation | Years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Primary | Progression-free Survival (PFS) Based on Local Radiology Review of Tumor Assessment | PFS was defined as time from the date of randomization to the date of first documented progression or death due to any cause. A patient who had not progressed or died at the date of the analysis cut-off or received another anticancer therapy had their PFS censored at the time of the last adequate tumor evaluation before the earlier of the cut-off date or the anticancer therapy date. Disease progression was assessed using the local investigator's tumor assessment per Response Evaluation Criteria in Solid Tumours (RECIST) 1.1. The distribution of PFS was estimated using the Kaplan-Meier method. Cox regression model stratified by randomization stratification factors was used to estimate the hazard ratio (HR) of PFS, along with 90% CI. As this was an estimation based approach, no p-value was provided. | Full Analysis Set (FAS) including all subjects to whom study treatment was assigned by randomization. | Posted | Median | 90% Confidence Interval | Months | From randomization up to date of first documented progression or death, assessed up to approximately 3.5 years |
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| Secondary | Progression-free Survival (PFS) Based on Blinded Independent Review Committee (BIRC) Assessment | PFS was defined as time from the date of randomization to the date of first documented progression or death due to any cause. A patient who had not progressed or died at the date of the analysis cut-off or received another anticancer therapy had their PFS censored at the time of the last adequate tumor evaluation before the earlier of the cut-off date or the anticancer therapy date. Disease progression was assessed using the BIRC tumor assessment per RECIST 1.1. The distribution of PFS was estimated using the Kaplan-Meier method. Cox regression model stratified by randomization stratification factors was used to estimate the hazard ratio (HR) of PFS, along with 90% CI. As this was an estimation based approach, no p-value was provided. | FAS including all subjects to whom study treatment was assigned by randomization. | Posted | Median | 90% Confidence Interval | Months | From randomization up to date of first documented progression or death, assessed up to approximately 1.8 years |
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| Secondary | Overall Survival (OS) | OS was defined as the time from date of randomization to date of death due to any cause. If the participant was alive at the date of the analysis cut-off or lost to follow-up, then OS was censored at the last contact date prior to data cutoff date. The distribution of OS was estimated using the Kaplan-Meier method. Cox regression model stratified by randomization stratification factors was used to estimate the hazard ratio (HR) of OS, along with 90% CI. As this was an estimation based approach, no p-value was provided. | FAS including all subjects to whom study treatment was assigned by randomization. | Posted | Median | 90% Confidence Interval | Months | From randomization to date of death, up to approximately 3.8 years |
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| Secondary | Overall Response Rate (ORR) Based on Local Radiology Review of Tumor Assessment | ORR was defined as the percentage of participants with a best overall response defined as complete response (CR) or partial response (PR) according to RECIST using local radiologist's/investigator's tumor assessment. ORR was estimated and the exact binomial 90% CI was reported by treatment arm. 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. | FAS including all subjects to whom study treatment was assigned by randomization. | Posted | Number | 90% Confidence Interval | Percentage of participants | Up to approximately 3.5 years |
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| Secondary | Overall Response Rate (ORR) Based on BIRC Assessment | ORR was defined as the percentage of participants with a best overall response defined as complete response (CR) or partial response (PR) according to RECIST using BIRC assessment. ORR was estimated and the exact binomial 90% CI was reported by treatment arm. 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. | FAS including all subjects to whom study treatment was assigned by randomization. | Posted | Number | 90% Confidence Interval | Percentage of participants | Up to approximately 1.8 years |
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| Secondary | Clinical Benefit Rate (CBR) Based on Local Radiology Review of Tumor Assessment | CBR was defined as the percentage of patients with best overall response of CR, PR or an overall lesion response of stable disease (SD) or Non-CR/Non-progressive disease with duration of 24 weeks or longer according to RECIST 1.1 using local radiologist's/investigator's tumor assessment. CBR was estimated and the exact binomial 90% CI was reported by treatment arm. 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. | FAS including all subjects to whom study treatment was assigned by randomization. | Posted | Number | 90% Confidence Interval | Percentage of participants | Up to approximately 3.5 years |
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| Secondary | Clinical Benefit Rate (CBR) Based on BIRC Assessment | CBR was defined as the percentage of patients with best overall response of CR, PR or an overall lesion response of stable disease (SD) or Non-CR/Non-progressive disease with duration of 24 weeks or longer according to RECIST 1.1 using BIRC assessment. CBR was estimated and the exact binomial 90% CI was reported by treatment arm. 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. | FAS including all subjects to whom study treatment was assigned by randomization. | Posted | Number | 90% Confidence Interval | Percentage of participants | Up to approximately 1.8 years |
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| Secondary | Time to Response (TTR) Based on Local Radiology Review of Tumor Assessment | TTR was defined as the time between date of randomization until first documented response (CR or PR) according to RECIST 1.1 using local radiologist's/investigator's 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. | Participants in the FAS with a confirmed CR or PR as per local radiologist's/investigator's tumor assessment. | Posted | Median | Full Range | Days | Up to approximately 3.5 years |
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| Secondary | Time to Response (TTR) Based on BIRC Assessment | TTR was defined as the time between date of randomization until first documented response (CR or PR) according to RECIST 1.1 using BIRC 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. | Participants in the FAS with a confirmed CR or PR as per BIRC assessment | Posted | Median | Full Range | Days | Up to approximately 1.8 years |
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| Secondary | Duration of Response (DOR) Based on Local Radiology Review of Tumor Assessment | DOR was defined as the time from date of first documented CR or PR to date of first documented disease progression or death due to any cause, according to RECIST 1.1 using local radiologist's/investigator's 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. | Participants in the FAS with a confirmed CR or PR as per local radiologist's/investigator's tumor assessment | Posted | Median | Full Range | Days | From date of first documented response to date of first documented disease progression or death, assessed up to approximately 3.5 years |
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| Secondary | Duration of Response (DOR) Based on BIRC Assessment | DOR was defined as the time from date of first documented CR or PR to date of first documented disease progression or death due to any cause, according to RECIST 1.1 using BIRC 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. | Participants in the FAS with a confirmed CR or PR as per BIRC assessment | Posted | Median | Full Range | Days | From date of first documented response to date of first documented disease progression or death, assessed up to approximately 1.8 years |
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| Secondary | Time to Definitive Deterioration of the Eastern Cooperative Oncology Group Performance Status (ECOG PS) by at Least One Category of the Score From Baseline | ECOG PS is a measure of functional status with scores ranging from 0 (fully active) to 5 (dead). Deterioration was considered definitive if no improvements in the ECOG PS status were observed after an instance of deterioration. Death was considered as worsening of the ECOG PS if it occurred close to the last assessment, where "close" is defined as twice the planned period between two assessments. Participants who died after more than twice the planned period between two assessments were censored at the date of their last assessment before the cut-off. Participants receiving any further anticancer therapy prior to definitive worsening were censored at their date of last assessment prior to start of therapy. Participants that had not worsened were censored at the date of last assessment prior to cut off. Time to definitive deterioration was estimated using the Kaplan-Meier method. | FAS including all subjects to whom study treatment was assigned by randomization | Posted | Median | 90% Confidence Interval | Months | From randomization up to definitive deterioration of the ECOG PS by one categotu of the score, assessed up to approximately 3.5 years |
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| Secondary | Everolimus Predose Concentration (Cmin) | Blood samples were collected to assess everolimus predose concentration (Cmin) at steady state at Cycle 1 Week 4 (any day during week 4). Steady-state was defined as having no dose adjustment/interruption of everolimus and exemestane in the previous 4 days prior to the day of the pre-dose PK sample collection. Everolimus concentrations were determined in the whole blood by a liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. The method has a lower limit of quantitation (LLOQ) of 0.3 ng/mL for everolimus. Values below the LLOQ were set to 0. | All subjects with an evaluable everolimus concentration at the specified time point | Posted | Geometric Mean | Geometric Coefficient of Variation | nanogram/mililiter (ng/mL) | Predose on Cycle 1 Week 4 ( each cycle is defined as 4 weeks) |
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| Secondary | Everolimus Concentration at 2 Hours Post Dose (C2h) | Blood samples were collected to assess everolimus concentration at 2 hours post dose (C2h) at steady state at Cycle 1 Week 4 (any day during week 4) Steady-state was defined as having no dose adjustment/interruption of everolimus and exemestane in the previous 4 days prior to the day of the pre-dose PK sample collection. Everolimus concentrations were determined in the whole blood by a liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. The method has a LLOQ of 0.3 ng/mL for everolimus. Values below the LLOQ were set to 0. | All subjects with an evaluable everolimus concentration at the specified time point | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Two hours post everolimus administration on Cycle 1 Week 4 ( each cycle is defined as 4 weeks) |
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| Secondary | Exemestane Predose Concentration (Cmin) | Blood samples were collected to assess exemestane predose concentration (Cmin) at steady state at Cycle 1 Week 4 (any day during week 4). Steady-state was defined as having no dose adjustment/interruption of everolimus and exemestane in the previous 4 days prior to the day of the pre-dose PK sample collection. Exemestane concentrations were determined in the whole blood by a liquid chromatography with LC-MS/MS method. The method has a LLOQ of 20 pg/mL for exemestane. Values below the LLOQ were set to 0. | All subjects with an evaluable exemestane concentration at the specified time point | Posted | Geometric Mean | Geometric Coefficient of Variation | picogram/mililiter (pg/mL) | Predose of exemestane on Cycle 1 Week 4 ( each cycle is defined as 4 weeks) |
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| Secondary | Exemestane Concentration at 2 Hours Post Dose (C2h) | Blood samples were collected to assess exemestane concentration at 2 hours post dose (C2h) at steady state at Cycle 1 Week 4 (any day during week 4) Steady-state was defined as having no dose adjustment/interruption of everolimus and exemestane in the previous 4 days prior to the day of the pre-dose PK sample collection. Exemestane concentrations were determined in the whole blood by a liquid chromatography with LC-MS/MS method. The method has a LLOQ of 20 pg/mL for exemestane. Values below the LLOQ were set to 0. | All subjects with an evaluable exemestane concentration at the specified time point | Posted | Geometric Mean | Geometric Coefficient of Variation | pg/mL | Two hours post exemestane administration on Cycle 1 Week 4 ( each cycle is defined as 4 weeks) |
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| Secondary | Estradiol Levels After 4 Weeks of Study Treatment | Blood samples were collected to assess estradiol levels after 4 weeks of study treatment. Estradiol was determined in plasma using competitive immunoassay. The method has a LLOQ of 1.952 pg/mL for estradiol. Values below the LLOQ were set to 0. | All subjects with evaluable estradiol concentrations at the specified time points | Posted | Geometric Mean | Geometric Coefficient of Variation | pg/mL | Baseline, and at Cycle 1 Week 4 prior to any study drug (each cycle is defined as 4 weeks) |
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| Post-Hoc | All Collected Deaths | On-treatment deaths were collected from first dose of study medication to 30 days after the last dose of study medication for a maximum duration of approximately 3.5 years Post-treatment survival follow-up deaths were collected after 30 days post-treatment, for a maximum duration of approximately 3.8 years All deaths refer to the sum of on-treatment and post-treatment deaths | Safety set including all subjects who received at least one dose of study treatment. | Posted | Count of Participants | Participants | On-treatment deaths: Up to 3.5 years. Post-treatment survival follow-up deaths: Up to 3.8 years |
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Adverse events were collected from first dose of study treatment to 30 days after last dose of study medication (on-treatment), up to approx. 3.5 years. Deaths were collected in the post treatment survival follow up from 31 days after last dose of study medication until the end of the study, up to approx. 3.8 years. These are not considered AEs
Any sign or symptom that occurs during the conduct of the trial and safety follow-up. Deaths in the post treatment survival follow-up are not considered Adverse Events. The total number at risk in the post treatment survival includes patients that entered the post treatment survival follow-up period.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Everolimus + Exemestane (On-treatment) | AEs collected during on-treatment period (up to 30 days post-treatment) | 3 | 80 | 18 | 80 | 79 | 80 |
| EG001 | Placebo + Exemestane (On-treatment) | AEs collected during on-treatment period (up to 30 days post- treatment) | 2 | 79 | 10 | 79 | 62 | 79 |
| EG002 | Everolimus + Exemestane (Post-treatment Survival Follow-up) | Deaths collected in the post- treatment survival follow-up period (starting from day 31 post- treatment). No AEs were collected during this period | 41 | 73 | 0 | 0 | 0 | 0 |
| EG003 | Placebo + Exemestane (Post-treatment Survival Follow-up) | Deaths collected in the post- treatment survival follow-up period (starting from day 31 post- treatment). No AEs were collected during this period | 43 | 75 | 0 | 0 | 0 | 0 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Cardiac failure | Cardiac disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Vomiting | Gastrointestinal disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Multiple organ dysfunction syndrome | General disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Pyrexia | General disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Cholecystitis | Hepatobiliary disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Hepatic function abnormal | Hepatobiliary disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Herpes virus infection | Infections and infestations | MedDRA (25.0) | Systematic Assessment |
| |
| Pneumonia | Infections and infestations | MedDRA (25.0) | Systematic Assessment |
| |
| Subcutaneous abscess | Infections and infestations | MedDRA (25.0) | Systematic Assessment |
| |
| Spinal compression fracture | Injury, poisoning and procedural complications | MedDRA (25.0) | Systematic Assessment |
| |
| Neutrophil count decreased | Investigations | MedDRA (25.0) | Systematic Assessment |
| |
| Diabetic ketosis | Metabolism and nutrition disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Electrolyte imbalance | Metabolism and nutrition disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Hypercalcaemia | Metabolism and nutrition disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Hyperglycaemia | Metabolism and nutrition disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Bone pain | Musculoskeletal and connective tissue disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Pathological fracture | Musculoskeletal and connective tissue disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Renal failure | Renal and urinary disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Interstitial lung disease | Respiratory, thoracic and mediastinal disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Pleural effusion | Respiratory, thoracic and mediastinal disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Respiratory failure | Respiratory, thoracic and mediastinal disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Hypotension | Vascular disorders | MedDRA (25.0) | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Leukopenia | Blood and lymphatic system disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Neutropenia | Blood and lymphatic system disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Abdominal pain upper | Gastrointestinal disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Aphthous ulcer | Gastrointestinal disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Diarrhoea | Gastrointestinal disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Mouth ulceration | Gastrointestinal disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Nausea | Gastrointestinal disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Stomatitis | Gastrointestinal disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Toothache | Gastrointestinal disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Vomiting | Gastrointestinal disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Asthenia | General disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Chest discomfort | General disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Malaise | General disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Oedema peripheral | General disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Pyrexia | General disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Pneumonia | Infections and infestations | MedDRA (25.0) | Systematic Assessment |
| |
| Upper respiratory tract infection | Infections and infestations | MedDRA (25.0) | Systematic Assessment |
| |
| Urinary tract infection | Infections and infestations | MedDRA (25.0) | Systematic Assessment |
| |
| Alanine aminotransferase increased | Investigations | MedDRA (25.0) | Systematic Assessment |
| |
| Aspartate aminotransferase increased | Investigations | MedDRA (25.0) | Systematic Assessment |
| |
| Bilirubin conjugated increased | Investigations | MedDRA (25.0) | Systematic Assessment |
| |
| Blood albumin decreased | Investigations | MedDRA (25.0) | Systematic Assessment |
| |
| Blood alkaline phosphatase increased | Investigations | MedDRA (25.0) | Systematic Assessment |
| |
| Blood bilirubin increased | Investigations | MedDRA (25.0) | Systematic Assessment |
| |
| Blood cholesterol increased | Investigations | MedDRA (25.0) | Systematic Assessment |
| |
| Blood creatine phosphokinase increased | Investigations | MedDRA (25.0) | Systematic Assessment |
| |
| Blood creatinine increased | Investigations | MedDRA (25.0) | Systematic Assessment |
| |
| Blood glucose increased | Investigations | MedDRA (25.0) | Systematic Assessment |
| |
| Blood lactate dehydrogenase increased | Investigations | MedDRA (25.0) | Systematic Assessment |
| |
| Blood triglycerides increased | Investigations | MedDRA (25.0) | Systematic Assessment |
| |
| Gamma-glutamyltransferase increased | Investigations | MedDRA (25.0) | Systematic Assessment |
| |
| Low density lipoprotein increased | Investigations | MedDRA (25.0) | Systematic Assessment |
| |
| Neutrophil count decreased | Investigations | MedDRA (25.0) | Systematic Assessment |
| |
| Platelet count decreased | Investigations | MedDRA (25.0) | Systematic Assessment |
| |
| Weight decreased | Investigations | MedDRA (25.0) | Systematic Assessment |
| |
| Weight increased | Investigations | MedDRA (25.0) | Systematic Assessment |
| |
| White blood cell count decreased | Investigations | MedDRA (25.0) | Systematic Assessment |
| |
| Decreased appetite | Metabolism and nutrition disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Hypercholesterolaemia | Metabolism and nutrition disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Hyperglycaemia | Metabolism and nutrition disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Hyperlipidaemia | Metabolism and nutrition disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Hypertriglyceridaemia | Metabolism and nutrition disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Hyperuricaemia | Metabolism and nutrition disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Hypokalaemia | Metabolism and nutrition disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Hyponatraemia | Metabolism and nutrition disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Hypophosphataemia | Metabolism and nutrition disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Headache | Nervous system disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Insomnia | Psychiatric disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Epistaxis | Respiratory, thoracic and mediastinal disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Interstitial lung disease | Respiratory, thoracic and mediastinal disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Pneumonitis | Respiratory, thoracic and mediastinal disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Dermatitis acneiform | Skin and subcutaneous tissue disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Pruritus | Skin and subcutaneous tissue disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Rash | Skin and subcutaneous tissue disorders | MedDRA (25.0) | Systematic Assessment |
| |
| Hypertension | Vascular disorders | MedDRA (25.0) | Systematic Assessment |
|
The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Study director | Novartis Pharmaceuticals | 862-778-8300 | Novartis.email@novartis.com |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jul 11, 2022 | Apr 17, 2023 | SAP_001.pdf |
| ID | Term |
|---|---|
| D001943 | Breast Neoplasms |
| ID | Term |
|---|---|
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D001941 | Breast Diseases |
| D012871 | Skin Diseases |
| D017437 | Skin and Connective Tissue Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| D000068338 | Everolimus |
| C056516 | exemestane |
| ID | Term |
|---|---|
| D020123 | Sirolimus |
| D018942 | Macrolides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
Not provided
Not provided
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Participants received placebo as a continuous oral daily dose and exemestane as a continuous oral daily dose of 25 mg |
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| Participants |
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