A Study of Everolimus Plus Exemestane in Chinese Postmenopausal Women With Estrogen Receptor Positive, Locally Advanced, Recurrent, or Metastatic Breast Cancer After Recurrence or Progression on Non-steroidal Aromatase Inhibitor (BOLERO-5)

A Randomized, Double-blind, Placebo Controlled, Phase II Study of Everolimus in Combination With Exemestane in the Treatment of Chinese Postmenopausal Women With Estrogen Receptor Positive, HER-2 Negative, Locally Advanced, Recurrent, or Metastatic Breast Cancer After Recurrence or Progression on Prior Letrozole or Anastrozole

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.

Study Overview

• Status: Completed
• Conditions: Advanced Breast Cancer
• Intervention / Treatment: Drug: Everolimus; Drug: Exemestane; Drug: Everolimus Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 159
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Beijing, China, 100036
    • Novartis Investigative Site
  • Chongqing, China, 400016
    • Novartis Investigative Site
  • Guangzhou, China, 510060
    • Novartis Investigative Site
  • Qingdao, China, 266000
    • Novartis Investigative Site
  • Shanghai, China, 200025
    • Novartis Investigative Site
  • Wuhan, China, 430000
    • Novartis Investigative Site
  • Guangdong
    • Guangzhou, Guangdong, China, 510000
      • Novartis Investigative Site
  • Heilongjiang
    • Harbin, Heilongjiang, China, 150081
      • Novartis Investigative Site
  • Hubei
    • Wuhan, Hubei, China, 430022
      • Novartis Investigative Site
  • Jiangsu
    • Nanjing, Jiangsu, China, 210009
      • Novartis Investigative Site
  • Shanghai
    • Shanghai, Shanghai, China, 200032
      • Novartis Investigative Site
  • Sichuan
    • Chengdu, Sichuan, China, 610041
      • Novartis Investigative Site
    • Chengdu, Sichuan, China, 610072
      • Novartis Investigative Site
  • Tianjin
    • Tianjin, Tianjin, China, 300060
      • Novartis Investigative Site
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310022
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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:

  • Prior bilateral oophorectomy
  • Or age ≥60
  • Or age < 60 and amenorrhea for 12 or more months

• Recurrence or progression on prior NSAI was defined as:

  • Recurrence while on, or within one year (12 months) of end of adjuvant treatment with letrozole or anastrozole
  • Or Progression while on or within one month (30 days) of the end of prior treatment with letrozole or anastrozole
• 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

  • measurable disease or non-measurable lytic or mixed (lytic + blastic) bone lesions in the absence of measurable disease.
  • non-measurable lytic or mixed (lytic + blastic) bone lesions in the absence of measurable disease.
• 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:

• HER2-overexpressing patients by local laboratory testing (IHC 3+ staining or in situ hybridization positive), based on the most recent test.
• Patients who had received more than one chemotherapy line for ABC
• Patients with symptomatic visceral disease and candidates to chemotherapy
• Patients with only non-measurable lesions other than lytic or mixed (lytic and blastic) bone metastasis (e.g. pleural effusion, ascites etc.)
• Patients receiving concomitant immunosuppressive agents or chronic corticosteroids used at the time of study entry except topical applications, inhaled sprays, eye drops or local injections.
• Uncontrolled diabetes mellitus as defined by HbA1c >7% despite adequate therapy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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	Drug: Everolimus; 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.; Other Names: RAD001; Drug: Exemestane; Commercially available exemestane was supplied as 25 mg tablets. Exemestane was administered as continuous oral daily dose of 25 mg tablets.
Active Comparator: Placebo + Exemestane; Participants received placebo as a continuous oral daily dose and exemestane as a continuous oral daily dose of 25 mg	Drug: Exemestane; Commercially available exemestane was supplied as 25 mg tablets. Exemestane was administered as continuous oral daily dose of 25 mg tablets.; Drug: Everolimus Placebo; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Secondary Outcome Measures

Outcome Measure	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.	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)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics of everolimus (Cmin)	Characterize the pharmacokinetics of everolimus (Cmin, C2h) when administered	predose, two hours post dose

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): September 15, 2017
• Primary Completion (Actual): April 25, 2022
• Study Completion (Actual): April 25, 2022

Study Registration Dates

• First Submitted: September 15, 2017
• First Submitted That Met QC Criteria: October 12, 2017
• First Posted (Actual): October 18, 2017

Study Record Updates

• Last Update Posted (Estimated): January 23, 2024
• Last Update Submitted That Met QC Criteria: April 17, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: breast cancer; HER2 negative; everolimus; breast carcinoma; exemestane; breast lump; advanced Breast Cancer; non-steroidal aromatase inhibitors; breast cancer progression
• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; Neoplasms; Neoplasms by Site; Disease Attributes; Breast Diseases; Disease Progression; Breast Neoplasms; Recurrence; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Hormones, Hormone Substitutes, and Hormone Antagonists; Protein Kinase Inhibitors; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; MTOR Inhibitors; Everolimus; Exemestane
• Other Study ID Numbers: CRAD001Y2202

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No