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A Phase II Study of Everolimus in Combination With Exemestane Versus Everolimus Alone Versus Capecitabine in Advance Breast Cancer. (BOLERO-6)

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ClinicalTrials.gov Identifier: NCT01783444
Recruitment Status : Completed
First Posted : February 5, 2013
Last Update Posted : March 1, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE January 11, 2013
First Posted Date  ICMJE February 5, 2013
Last Update Posted Date March 1, 2019
Actual Study Start Date  ICMJE February 26, 2013
Actual Primary Completion Date July 2, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 6, 2019)
Progression Free Survival (PFS) - Everolimus plus exemestane versus everolimus alone [ Time Frame: 28 months after first patient randomized or once approximatly 150 PFS have occurred ]
Progression Free Survival (PFS) is defined as the time from date of randomization to the date of first radiologically documented progression or death due to any cause. If a patient did not progress or die at the time of the analysis data cut-off or start of new antineoplastic therapy, PFS was censored at the date of the last adequate tumor assessment before the earliest of the cut-off date or the start date of additional anti-neoplastic therapy. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria RECIST v1.1, as 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 and/or unequivocal progression of the non-target lesions and/or appearance of a new lesion. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm.
Original Primary Outcome Measures  ICMJE
 (submitted: February 4, 2013)
Progression Free Survival (PFS) [ Time Frame: 28 months after first patient randomized or once 150 PFS have occurred ]
Once 150 PFS events have occured (determined by local assessment). To estimate the hazard ratio of PFS for everolimus plus exemestane versus everolimus alone in postmenopausal women with ER positive, HER2 negative, advanced breast cancer after recurrence or progression on letrozole or anastrozole.
Change History Complete list of historical versions of study NCT01783444 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 27, 2019)
  • Progression Free Survival (PFS) - Everolimus plus exemestane versus Capecitabine alone [ Time Frame: 28 months after first patient randomized or once approximatly 150 PFS events have occured ]
    Progression Free Survival (PFS) is defined as the time from date of randomization to the date of first radiologically documented progression or death due to any cause. If a patient did not progress or die at the time of the analysis data cut-off or start of new antineoplastic therapy, PFS was censored at the date of the last adequate tumor assessment before the earliest of the cut-off date or the start date of additional anti-neoplastic therapy. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria RECIST v1.1, as 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 and/or unequivocal progression of the non-target lesions and/or appearance of a new lesion. In addition to the relative increase of 20%, the sum must demonstrate an absolute increase of at least 5 mm.
  • Overall Survival (OS) [ Time Frame: Every 3 months following the end of study visit until 2015 (up to 3 years) ]
    Overall Survival (OS) is defined as the time from date of randomization to date of death due to any cause. If a patient was not known to have died by the date of analysis cut-off, OS was censored at the date of last known date patient alive.
  • Overall Response Rate (ORR) [ Time Frame: From the date of first dose of study medication until the date of the first documented disease progression or date of death from any cause whichever came first, assessed for approximately for 28 months ]
    Overall Response Rate (ORR) is defined as the proportion of participants with best overall response of complete response (CR) or partial response (PR) based on local investigator's assessment according to RECIST 1.1. ORR was analyzed in the full population. Response Evaluation Criteria in Solid Tumors (RECIST v1.1) for target/non target lesions: Complete Response (CR), disappearance of all target/non target lesions (all lymph nodes assigned as non-target lesions must be non-pathological in size (< 10 mm short axis)); Partial response (PR), >=30% decrease in the sum of the longest diameter of target lesions ; Overall Response (OR)= CR+PR. Only descriptive analysis.
  • Clinical Benefit Rate (CBR) [ Time Frame: From the date of first dose of study medication until the date of the first documented disease progression or date of death from any cause whichever came first, assessed for approximately 28 months ]
    Clinical Benefit Rate (CBR) is defined as the proportion of participants with a best overall response of complete response (CR) or partial response (PR) or stable disease (SD) or Non-CR/non-PD lasting more than 24 weeks based on local investigator's assessment according to RECIST 1.1. Only descriptive analysis.
  • Time to definitive deterioration in Eastern Cooperative Oncology Group (ECOG) performance status [ Time Frame: Baseline, Day 1, every 6 weeks for approximately 8 months ]
    The Eastern Cooperative Oncology Group (ECOG) Performance Status is a scale used to assess how a patient's disease is progressing, assess how the disease affects the daily living abilities of the patient, and determine appropriate treatment and prognosis. The ECOG Performance Scores has 5 grades: 0 = fully active, able to carry on all pre-disease performance without restriction, 1 = restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light housework, office work, 2 = ambulatory and capable of all self-care but unable to carry out any work activities, up and 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 and 5 = dead. Definitive deterioration is defined as no improvement in the ECOG status following observation of the deterioration.
  • Time to 10% definitive deterioration in the global health status/Quality of life per EORTC-QLQ-C30 [ Time Frame: Baseline, every 6 weeks for approximately 8 months ]
    The global health status/QoL scale score of the QLQ-C30 is identified as the primary PRO variable of interest. Physical Functioning (PF), Emotional Functioning (EF) and Social Functioning (SF) scale scores of the QLQ-C30. The time to definitive 10% deterioration is defined as the time from the randomization date to the date of an event, which is defined as a worsening (decrease) in score by at least 10% compared to baseline, with no later increase above this threshold observed during the course of the study or death due to any cause. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high /healthy level of functioning, a high score for the global health status / QoL represents a high QoL.
  • Mean change from Baseline in the global health status/Quality of life per EORTC module (BR23) at Weeks 12 and 24 [ Time Frame: Baseline, Week 12, Week 24 ]
    EORTC Quality of Life Questionnaire - Breast Cancer Module (EORTC QLQ-BR23) is to be used in conjunction with the EORTC QLQ-C30 for assessing the quality of life of breast cancer patients. Functional scales (Body image, Sexual functioning, Sexual enjoyment and Future perspective) and Symptoms scales/Items (Sytemic therapy side effects, Breast symptoms, Arm symptoms and Upset by hair loss) are scored as part of the BR-23. The scores are linearly converted to a 0-100 scale, where higher function scores reflect improved function and higher symptom scores present a higher level of symptoms.
  • Mean change in Treatment Satisfaction Questionnaire for Medication (TSQM) between Week 3 and Week 12 [ Time Frame: Week 3, Week 12 ]
    The TSQM was developed and validated as a general measure for treatment satisfaction. It contains 14 items assessing the following 4 domains: effectiveness (sum of scores for questions 1 - 3), side effects (sum of scores for questions 4 - 8), convenience (sum of scores for questions 9 - 11) and Global Satisfaction (sum of scores for questions 12 - 14). The scores of the domain were added together and an algorithm was used to create a score of 0 to 100. Higher scores indicated greater satisfaction. A positive change from baseline indicates improvement.
Original Secondary Outcome Measures  ICMJE
 (submitted: February 4, 2013)
  • Overall Survival [ Time Frame: Every 3 months following the end of study visit until 2015 (up to 3 years) ]
    To evaluate the treatment groups with respect to Overall Survival. End of study visit is defined as time when progression of disease recorded or death whichever comes first.
  • Overall response rate [ Time Frame: From the date of first dose of study medication until the date of the first documented disease progression or date of death from any cause whichever came first, assessed for approximately for 28 months ]
    Overall response rate (ORR) based on the local radiologist/investigator's tumor assessment (RECIST 1.1)
  • Clinical Benefit Rate (CBR) [ Time Frame: From the date of first dose of study medication until the date of the first documented disease progression or date of death from any cause whichever came first, assessed for approximately 28 months ]
    Clinical Benefit Rate is defined as the proportion of patients with best overall response of complete response (CR), partial response (PR), or stable disease (SD) with duration of 24 weeks or longer.
  • Changes in ECOG (Eastern Cooperative Oncology Group) performance status [ Time Frame: Baseline, Day 1, every 6 weeks for approximately 8 months ]
    The ECOG performance status scale (1-5) allows patients to be classified as to their functional impairment, ECOG performance status will be compared to baseline ECOG performance classification.
  • Change in quality of life scores over time: EORTC (QLQ-C30)/EORTC module (BR23) [ Time Frame: Baseline, every 6 weeks for approximately 8 months ]
  • Time to quality of life (QoL)deterioration : TSQM score [ Time Frame: Baseline, week 3,6, 12 and for approximately 8 months ]
  • Safety: Incidence of Adverse Event(s) [ Time Frame: every study visit for approximately 8 months ]
  • Safety: Incidence of Serious Adverse Events [ Time Frame: every study visit for approximately 8 months ]
  • Safety: changes in vital signs when compared to baseline vital signs [ Time Frame: baseline, every study visit for approximately 8 months ]
  • Safety: changes in laboratory values compared to laboratory values obtained at the baseline visit [ Time Frame: baseline, every study visit for approximately 8 months ]
Current Other Outcome Measures  ICMJE Not Provided
Original Other Outcome Measures  ICMJE Not Provided
 
Descriptive Information
Brief Title  ICMJE A Phase II Study of Everolimus in Combination With Exemestane Versus Everolimus Alone Versus Capecitabine in Advance Breast Cancer.
Official Title  ICMJE Phase II Study of Everolimus in Combination With Exemestane Versus Everolimus Alone Versus Capecitabine in the Treatment of Postmenopausal Women With ER+Locally Advanced, Recurrent, or Metastatic Breast Cancer After Recurrence or Progression on Prior Letrozole or Anastrozole.
Brief Summary This was a three-arm, randomized, open label, multi-center phase II study investigating the combination of everolimus (10mg daily) with exemestane (25mg daily) versus everolimus (10mg daily) versus capecitabine (1250mg/m2 twice daily for 14 days, 3-week cycle) in patients with estrogen-receptor positive, HER2 negative, advanced breast cancer after recurrence or progression on letrozole or anastrozole.
Detailed Description

The reference therapy (control arm) used in the course of this trial was the combination arm of everolimus plus exemestane. The investigational therapies in the context of this study were everolimus monotherapy and capecitabine monotherapy. All treatments were taken orally until disease progression, intolerable toxicity or withdrawal of patient's informed consent. Patients were randomly assigned with equal allocation to one of the treatment arms:

  1. Exemestane (25mg daily) in combination with everolimus (10mg daily)
  2. Everolimus (10mg daily)
  3. Capecitabine (1250mg/m2 twice daily) orally for two weeks, followed by a one week rest period in 3-weeks cycles.

Treatment assignment was stratified by the presence of visceral disease (yes vs. no). Visceral refered to lung, liver, heart, ovary, spleen, kidney, adrenal gland, malignant pleural or pericardial effusion or malignant ascites.

Study Type  ICMJE Interventional
Study Phase Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Breast Cancer
Intervention  ICMJE
  • Drug: Capecitabine
    Capecitabine, for oral use 1250 mg/m2 twice daily for 2 weeks followed by one week rest (3-week cycle). Capecitabine was locally supplied by the Investigator.
    Other Name: Capecitabine monotherapy
  • Drug: Exemestane
    Exemestane tablets of 25 mg was taken orally once per day. Dose modifications in the management of adverse events were allowed.
    Other Name: Control Arm
  • Drug: Everolimus
    Everolimus was centrally dispensed via IWRS. Everolimus was taken as oral tablets for oral use 10 mg (2 × 5 mg) daily.
    Other Name: RAD001
Study Arms
  • Experimental: Capecitabine Monotherapy
    Capecitabine monotherapy arm (1250mg/m2 twice daily) orally for two weeks, followed by a one week rest period in 3-weeks cycles.
    Intervention: Drug: Capecitabine
  • Experimental: Everolimus Monotherapy
    Everolimus (10mg daily).
    Intervention: Drug: Everolimus
  • Active Comparator: Everolimus with Exemestane
    Everolimus (10mg daily) with exemestane (25mg daily).
    Intervention: Drug: Exemestane
Publications * Jerusalem G, de Boer RH, Hurvitz S, Yardley DA, Kovalenko E, Ejlertsen B, Blau S, Özgüroglu M, Landherr L, Ewertz M, Taran T, Fan J, Noel-Baron F, Louveau AL, Burris H. Everolimus Plus Exemestane vs Everolimus or Capecitabine Monotherapy for Estrogen Receptor-Positive, HER2-Negative Advanced Breast Cancer: The BOLERO-6 Randomized Clinical Trial. JAMA Oncol. 2018 Oct 1;4(10):1367-1374. doi: 10.1001/jamaoncol.2018.2262.

*   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 27, 2017)
317
Original Estimated Enrollment  ICMJE
 (submitted: February 4, 2013)
300
Actual Study Completion Date July 30, 2018
Actual Primary Completion Date July 2, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Key Inclusion Criteria:

-Women with locally advanced, recurrent, or metastatic breast cancer along with confirmation of estrogen-receptor positive (ER+). Measurable disease defined as at least one lesion ≥ 10 mm by CT or MRI that can be accurately measured in at least one dimension (CT scan slice thickness ≤ 5 mm) OR • Bone lesions: lytic or mixed (lytic + blastic) in the absence of measurable disease as defined above

Key Exclusion Criteria:

-Patients who received more than one chemotherapy line. Patients with only non-measurable lesions other than lytic or mixed (lytic and blastic) bone metastasis.Previous treatment with exemestane, mTOR inhibitors, PI3K inhibitors or AKT inhibitors

Sex/Gender
Sexes Eligible for Study: Female
Ages 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Australia,   Belgium,   Brazil,   Denmark,   Hungary,   India,   Ireland,   Lebanon,   Malaysia,   Peru,   Russian Federation,   Spain,   Sweden,   Thailand,   Turkey,   United Kingdom,   United States
Removed Location Countries Saudi Arabia
 
Administrative Information
NCT Number  ICMJE NCT01783444
Other Study ID Numbers  ICMJE CRAD001Y2201
2012-003757-28 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement
Plan to Share IPD: Undecided
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

Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date February 2019

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