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Everolimus in Combination With Exemestane in the Treatment of Postmenopausal Women With Estrogen Receptor Positive Locally Advanced or Metastatic Breast Cancer Who Are Refractory to Letrozole or Anastrozole (BOLERO-2)

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ClinicalTrials.gov Identifier: NCT00863655
Recruitment Status : Completed
First Posted : March 18, 2009
Results First Posted : August 31, 2012
Last Update Posted : May 2, 2017
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE March 16, 2009
First Posted Date  ICMJE March 18, 2009
Results First Submitted Date  ICMJE July 31, 2012
Results First Posted Date  ICMJE August 31, 2012
Last Update Posted Date May 2, 2017
Actual Study Start Date  ICMJE June 3, 2009
Actual Primary Completion Date December 4, 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 21, 2017)		 Progression-free Survival (PFS) Based on Local Radiology Review of Tumor Assessments. [ Time Frame: date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first, reported between day of first patient randomized up to about 19 months ]
Progression-free survival, the primary endpoint in this study, is defined as the time from the date of randomization to the date of first documented radiological progression or death due to any cause. Disease progression was based on the tumor assessment by the local radiologist or investigator using RECIST 1.0 criteria. If a patient did not progress or known to have died at the date of the analysis cut-off or start of another antineoplastic therapy, the PFS date was censored to the date of last adequate tumor assessment prior to cut-off date or start of antineoplastic therapy. For patients with lytic or mixed (lytic+sclerotic) bone lesions, the following is considered progression: appearance of ≥1 new lytic lesions in bone; the appearance of ≥ new lesions outside of bone and unequivocal progression of existing bone lesions.
Original Primary Outcome Measures  ICMJE
 (submitted: March 17, 2009)		 progression-free survival (PFS), defined as the time from the date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first. [ Time Frame: 6 weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 21, 2017)
  • Overall Survival (OS) by Number of Deaths [ Time Frame: up to 53 months ]
    Overall survival, the key secondary endpoint in this study, is defined as the time from date of randomization to the date of death due to any cause. If a patient is not known to have died, survival was censored at the date of last contact.
  • Overall Survival (OS) by Median [ Time Frame: up to 53 months ]
    Overall survival, the key secondary endpoint in this study, is defined as the time from date of randomization to the date of death due to any cause.
  • Overall Response Rate (ORR) [ Time Frame: up to 21 months ]
    Overall response rate (ORR) is the percentage of patients with a best overall response of complete response (CR) or partial response (PR) according to RECIST 1.0. Per RECIST criteria 1.0, CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters.
  • Clinical Benefit Rate (CBR) [ Time Frame: up to 21 months ]
    CBR is defined as the percentage of patients with best overall response of either complete response (CR), a partial response (PR) or stable disease (SD) >= 24 weeks, according to RECIST 1.0. Per RECIST criteria 1.0, CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters; SD = Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD; PD = At least a 20% increase in the sum of the longest diameter of all measured target lesions, taking as reference the smallest sum of longest diameter of all target lesions recorded at or after baseline.
  • Proportion of Patients With no Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG PS) Using Kaplan-Meier [ Time Frame: 2, 4, 6, 9 months ]
    The ECOG PS (Eastern Cooperative Oncology Group Performance Scale) is a standard criteria for measuring how treatment of cancer impacts level of functioning in terms of the ability to care for oneself, daily activity, & physical ability (walking, working, etc.). Scale score ranges:0 to 5, 5 being the worst. Scale index: 0: Fully active, able to carry on all pre-disease performance without restriction. 1: Restricted in physically strenuous activity but ambulatory & able to carry out work of a light or sedentary nature. 2: Ambulatory & capable of all self-care but unable to carry out any work activities. Up & about more than 50% of waking hours. 3: Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 4 - Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 5 - Dead. A deterioration of ECOG is an increase of 1 of the ECOG PS without improvement back to initial level at a subsequent time of measurement.
  • Patient-reported Outcomes (PROs): Time to Deterioration of PRO Scores Using Kaplan Meier - EORTC QLQ-C30 [ Time Frame: Up to 21 months ]
    The QLQ-C30 is composed of both multi-item scales and single-item measures. These include 5 functional scales, 3 symptom scales, a global health status - QoL scale, and 6 single items. Each of the multi-item scales includes a different set of items - no item occurs in more than 1 scale. All of the scales measures range in score from 0 to 100. A high scale score = higher response level. Thus a high score for a functional scale represents a healthy level of function, a high score for the global health status / QoL represents a high quality of life but a high score for a symptom scale / item represents a high level of symptomatology / problems. The principle for scoring these scales: 1.) Estimate the average of the items that contribute to the scale = raw score. 2.) Linear transformation to standardize the raw score, so that scores range from 0 to 100; a higher score represents a higher ("better") level of functioning, or a higher ("worse") level of symptoms.
  • Proportion of Patients With Having no Overall Response Based on Investigator Assessment [ Time Frame: 2, 4, 6, 9 months ]
    overall response = complete response (CR) + partial response (PR) per RECIST 1.0 Time to overall response (CR or PR) based on investigator is the time between date of randomization/start of treatment until first documented response (CR or PR). This analysis included all patients/responders. Patients who did not achieve a confirmed PR or CR were censored at last adequate tumor assessment date when they did not progress. Per RECIST criteria 1.0, CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters.
  • Duration of Response (Among Participants With Best Overall Response of CR or PR) Estimated Per Kaplan-Meier [ Time Frame: 21 months ]
    Duration of response of CR or PR based on investigator applies only to patients whose best overall response was CR or PR (RECIST 1.0). The start date was the date of first documented response (CR or PR) and the end date and censoring is defined the same as that for time to progression. Per RECIST criteria 1.0, CR: Disappearance of all target lesions; PR: At least a 30% decrease in the sum of the longest diameter of all target lesions, taking as reference the baseline sum of the longest diameters.
  • Everolimus Concentrations at Week 4 [ Time Frame: pre-dose, 2 hours post-dose ]
    Characterize the pharmacokinetics (PK) of everolimus in combination with exemestane using Cmin (pre-dose) and C2h (post-dose) at week 4 in a small group of patients.
  • Exemestane Concentrations at Week 4 [ Time Frame: predose, 2 hours post-dose ]
    Characterize the PK of exemestane in combination with or without everolimus using Cmin and C2h at week 4 in a small group of patients.
  • Estradiol Plasma Concentrations [ Time Frame: Baseline, Week 4 ]
    Compare estradiol concentrations from baseline to week 4 in both treatment arms.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 17, 2009)
  • Overall survival (OS), the key secondary endpoint in this study, is defined as the time from date of randomization to the date of death due to any cause. [ Time Frame: Every 3 months after End of Treatment + 28 days (every 6 weeks before) ]
  • Overall response rate (ORR) defined as the proportion of patients whose best overall response is either complete response (CR) or partial response (PR) according to RECIST [ Time Frame: Every 6 weeks ]
  • Incidence of adverse events, serious adverse events, shift from baseline in vital signs and laboratory results (hematology, blood chemistry) will be reported. [ Time Frame: Continuous and every 6 weeks ]
  • Patient reported outcome (PRO). [ Time Frame: Every 6 weeks ]
  • Clinical benefit rate (CBR) defined as the proportion of patients whose best overall response is either complete response (CR), a partial response (PR) or stable disease (SD) lasting for at least 24 weeks, according to RECIST. [ Time Frame: Every 6 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Everolimus in Combination With Exemestane in the Treatment of Postmenopausal Women With Estrogen Receptor Positive Locally Advanced or Metastatic Breast Cancer Who Are Refractory to Letrozole or Anastrozole
Official Title  ICMJE A Randomized Double-Blind, Placebo-Controlled Study of Everolimus in Combination With Exemestane in the Treatment of Postmenopausal Women With Estrogen Receptor Positive Locally Advanced or Metastatic Breast Cancer Who Are Refractory to Letrozole or Anastrozole
Brief Summary There are no treatments specifically approved after recurrence or progression on a non steroidal aromatase inhibitors (NSAI). In light of the need for new treatment options for postmenopausal women after failure of prior NSAI therapy, the purpose of this Phase III study is to compare efficacy and safety of a treatment with exemestane + everolimus to exemestane + placebo in postmenopausal women with estrogen receptor positive locally advanced or metastatic breast cancer refractory to NSAI.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Breast Cancer
Intervention  ICMJE
  • Drug: Everolimus
    Everolimus was formulated as tablets of 5-mg strength and was packaged into blister packs . Everolimus (two 5 mg tablets daily) were administered in a blinded manner on their respective treatment arms by continuous oral daily dosing.
    Other Name: RAD001
  • Drug: Exemestane
    Exemestane 25 mg orally daily.
  • Drug: Everolimus Placebo
    Placebo was formulated to be indistinguishable from the everolimus tablets. Matching placebo (two tablets daily) were administered in a blinded manner on their respective treatment arms by continuous oral daily dosing.
Study Arms  ICMJE
  • Experimental: Everolimus + Exemestane
    Everolimus 10 mg daily in combination with exemestane 25 mg daily
    Interventions:
    • Drug: Everolimus
    • Drug: Exemestane
  • Active Comparator: Placebo + Exemestane
    Placebo of everolimus in combination with exemestane 25 mg daily
    Interventions:
    • Drug: Exemestane
    • Drug: Everolimus Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 19, 2014)		 724
Original Estimated Enrollment  ICMJE
 (submitted: March 17, 2009)		 705
Actual Study Completion Date  ICMJE December 4, 2014
Actual Primary Completion Date December 4, 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Adult women (≥ 18 years of age) with metastatic or locally advanced breast cancer not amenable to curative treatment by surgery or radiotherapy.
  • Histological or cytological confirmation of estrogen-receptor positive (ER+) breast cancer
  • Postmenopausal women.
  • Disease refractory to non steroidal aromatase inhibitors (NSAI),
  • Radiological or clinical evidence of recurrence or progression on or after the last systemic therapy prior to randomization.
  • Patients must have at least one lesion that can be accurately measured or bone lesions in the absence of measurable disease as defined above.

Exclusion Criteria:

  • HER2-overexpressing patients
  • Patients with only non-measurable lesions other than bone metastasis (e.g. pleural effusion, ascites etc.).
  • Patients who received more than one chemotherapy line for Advanced Breast Cancer.
  • Previous treatment with exemestane or mTOR inhibitors.
  • Known hypersensitivity to mTOR inhibitors, e.g. sirolimus (rapamycin).
  • Radiotherapy within four weeks prior to randomization
  • Currently receiving hormone replacement therapy,

Other protocol-defined inclusion/exclusion criteria may apply
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Austria,   Belgium,   Brazil,   Canada,   Czech Republic,   Egypt,   France,   Germany,   Hong Kong,   Hungary,   Italy,   Japan,   Korea, Republic of,   Netherlands,   New Zealand,   Norway,   Poland,   Spain,   Sweden,   Thailand,   Turkey,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00863655
Other Study ID Numbers  ICMJE CRAD001Y2301
2008-008698-69 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Novartis ( Novartis Pharmaceuticals )
Original Responsible Party External Affairs, Novartis Pharmaceuticals
Current Study Sponsor  ICMJE Novartis Pharmaceuticals
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date March 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP