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

A Three-arm, Randomized, Open Label, Phase II Study of Everolimus in Combination With Exemestane Versus Everolimus Alone Versus Capecitabine in the Treatment of Postmenopausal Women With Estrogen Receptor Positive, Locally Advanced, Recurrent, or Metastatic Breast Cancer After Recurrence or Progression on Prior Letrozole or Anastrozole.

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.

Study Overview

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

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.

Randomization and Treatment Phase:

At Visit 3 all eligible patients were randomized in 1:1:1 ratio to receive everolimus (10mg daily oral tablets) in combination with exemestane (25 mg daily oral tablets), everolimus (10mg daily oral tablets) or capecitabine monotherapy (1250mg/m2 twice daily orally for two weeks followed by a one week rest period in 3-weeks cycles). 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. After randomization, study treatment started and continued until progression, intolerable toxicity or consent withdrawal. Further treatment after progression and study treatment discontinuation was at the investigator's discretion. Dose adjustment (reduction, interruption) according to safety findings was allowed. Regular safety and efficacy reviews by Data Monitoring Committee (DMC) were performed. Tumor assessments were performed every 6 weeks until disease progression. Additional evaluation were performed to confirm response at 4 weeks after it was first observed. After at least 150 PFS events had been documented per RECIST 1.1 by local assessment in each of the two following groups: (i) everolimus + exemestane arm plus everolimus monotherapy arm, and (ii) everolimus + exemestane arm plus capecitabine monotherapy arm, the frequency of tumor assessments was changed to every 12 weeks or as clinically indicated.

Follow-up phase:

Patients were followed for safety for 30 days after study treatment discontinuation. If a patient did not discontinue study treatment due to disease progression, lost to follow-up or consent withdrawal, then tumor assessments continued to be performed every 6 weeks until disease progression, death, lost to follow-up or investigator decision in patient best interest.

Survival Data Collection:

All patients were followed for survival status at least every 3 months regardless of treatment discontinuation reason and up to two years after randomization of last patient. Survival information could be obtained via phone and information were documented in the source documents and eCRF. Additional survival follow-up might be performed more frequently if a survival update was required for reporting the results or to meet safety or regulatory needs.

• Study Type: Interventional
• Enrollment (Actual): 309
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Cordoba, Argentina, X5016KEH
    • Novartis Investigative Site
  • Buenos Aires
    • Caba, Buenos Aires, Argentina, C1025ABI
      • Novartis Investigative Site
  • Misiones
    • Posadas, Misiones, Argentina
      • Novartis Investigative Site
  • Santa Fe
    • Rosario, Santa Fe, Argentina, S2000KZE
      • Novartis Investigative Site
  • Viedma
    • Rio Negro, Viedma, Argentina, 8500
      • Novartis Investigative Site
• Australia
  • New South Wales
    • Randwick, New South Wales, Australia, 2031
      • Novartis Investigative Site
    • Wahroonga, New South Wales, Australia, 2076
      • Novartis Investigative Site
  • Victoria
    • Malvern, Victoria, Australia, 3144
      • Novartis Investigative Site
    • Parkville, Victoria, Australia, 3050
      • Novartis Investigative Site
• Belgium
  • Liege, Belgium, 4000
    • Novartis Investigative Site
• Brazil
  • BA
    • Salvador, BA, Brazil, 41253-190
      • Novartis Investigative Site
  • RN
    • Natal, RN, Brazil, 59075 740
      • Novartis Investigative Site
  • RS
    • Passo Fundo, RS, Brazil, 99010-260
      • Novartis Investigative Site
  • Rio Grande Do Sul
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90610-000
      • Novartis Investigative Site
  • SP
    • Sao Paulo, SP, Brazil, 01317-002
      • Novartis Investigative Site
• Denmark
  • Aarhus, Denmark, 8000 C
    • Novartis Investigative Site
  • Copenhagen, Denmark, DK-2100
    • Novartis Investigative Site
  • Næstved, Denmark, DK-4700
    • Novartis Investigative Site
  • Odense C, Denmark, DK 5000
    • Novartis Investigative Site
  • Roskilde, Denmark, 4000
    • Novartis Investigative Site
  • Vejle, Denmark, 7100
    • Novartis Investigative Site
• Hungary
  • Debrecen, Hungary, 4032
    • Novartis Investigative Site
  • Tatabanya, Hungary, 2800
    • Novartis Investigative Site
  • HUN
    • Budapest, HUN, Hungary, 1145
      • Novartis Investigative Site
• India
  • Mumbai, India, 400 012
    • Novartis Investigative Site
  • Andhra Pradesh
    • Hyderabad, Andhra Pradesh, India, 500 034
      • Novartis Investigative Site
  • Maharashtra
    • Pune, Maharashtra, India, 411013
      • Novartis Investigative Site
  • West Bengal
    • Kolkatta, West Bengal, India, 700 053
      • Novartis Investigative Site
• Ireland
  • Dublin 4, Ireland, D04 T6F
    • Novartis Investigative Site
  • Galway, Ireland
    • Novartis Investigative Site
  • Co Limerick
    • Limerick, Co Limerick, Ireland
      • Novartis Investigative Site
• Lebanon
  • Ashrafieh, Lebanon, 166830
    • Novartis Investigative Site
  • Beirut, Lebanon, 1107 2020
    • Novartis Investigative Site
  • Beirut, Lebanon
    • Novartis Investigative Site
  • Hazmieh, Lebanon, 470
    • Novartis Investigative Site
  • Saida, Lebanon, 652
    • Novartis Investigative Site
• Malaysia
  • Kuala Lumpur, Malaysia, 59100
    • Novartis Investigative Site
  • Sabah
    • Kota Kinabalu, Sabah, Malaysia, 88586
      • Novartis Investigative Site
• Peru
  • Arequipa, Peru
    • Novartis Investigative Site
  • Lima
    • Jesus Maria, Lima, Peru, 11
      • Novartis Investigative Site
    • San Borja, Lima, Peru, 41
      • Novartis Investigative Site
    • Surquillo, Lima, Peru, 34
      • Novartis Investigative Site
• Russian Federation
  • Arkhangelsk, Russian Federation, 163045
    • Novartis Investigative Site
  • Moscow, Russian Federation, 115478
    • Novartis Investigative Site
  • St Petersburg, Russian Federation, 197758
    • Novartis Investigative Site
• Spain
  • Madrid, Spain, 28033
    • Novartis Investigative Site
  • Madrid, Spain, 28040
    • Novartis Investigative Site
  • Andalucia
    • Sevilla, Andalucia, Spain, 41013
      • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
• Sweden
  • Eskilstuna, Sweden, SE-631 88
    • Novartis Investigative Site
  • Joenkoeping, Sweden, 551 85
    • Novartis Investigative Site
  • Stockholm, Sweden, SE-171 76
    • Novartis Investigative Site
  • Uppsala, Sweden, SE-751 85
    • Novartis Investigative Site
  • Vasteras, Sweden, 721 89
    • Novartis Investigative Site
  • Vaxjo, Sweden, SE-351 85
    • Novartis Investigative Site
• Thailand
  • Muang, Thailand, 40002
    • Novartis Investigative Site
  • Hat Yai
    • Songkhla, Hat Yai, Thailand, 90110
      • Novartis Investigative Site
  • Lopburi
    • Muang Lopburi, Lopburi, Thailand, 15000
      • Novartis Investigative Site
• Turkey
  • Adana, Turkey, 01330
    • Novartis Investigative Site
  • Istanbul, Turkey, 34303
    • Novartis Investigative Site
  • Izmir, Turkey, 35340
    • Novartis Investigative Site
• United Kingdom
  • East Kilbride, United Kingdom, G75 8RG
    • Novartis Investigative Site
  • Middlesborough, United Kingdom, TS4 3BW
    • Novartis Investigative Site
  • Nottingham, United Kingdom, NG5 1PB
    • Novartis Investigative Site
• United States
  • California
    • Los Angeles, California, United States, 90095
      • University of California at Los Angeles Mattel Children's Hospital
    • San Diego, California, United States, 92123
      • Sharp Memorial Hospital SharpClinicalOncologyResearch
  • Florida
    • Fort Myers, Florida, United States, 33901
      • Florida Cancer Specialists FL Cancer Specialists
    • Fort Myers, Florida, United States, 33901
      • Florida Cancer Specialists Dept of Oncology (2)
  • Massachusetts
    • Burlington, Massachusetts, United States, 01805
      • Lahey Clinic Dept of Lahey Clinic (2)
    • Newton, Massachusetts, United States, 02462
      • New England Hematology/ Oncology Associates, P.C. SC
  • Montana
    • Kalispell, Montana, United States, 59901
      • Glacier View Research Institute - Cancer SC
  • New Jersey
    • Elizabeth, New Jersey, United States, 07207
      • Trinitas Comprehensive Cancer Center SC
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center Dept of Oncology
    • Newark, New Jersey, United States, 07101
      • Rutgers-New Jersey Medical School SC
  • Ohio
    • Cincinnati, Ohio, United States, 45242
      • Oncology Hematology Care Inc Oncology Hematology Care 2
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74136
      • Oklahoma Cancer Specialists and Research Institute Oklahoma Cancer Specialists
  • Tennessee
    • Chattanooga, Tennessee, United States, 37404
      • Chattanooga Oncology and Hematology Assoicates, PC Chattanooga Oncology
    • Germantown, Tennessee, United States, 38138
      • The Jones Clinic SC
    • Knoxville, Tennessee, United States, 27920-6969
      • University of Tennessee SC
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute SC (2)
  • Texas
    • Fort Worth, Texas, United States, 76104
      • The Center for Cancer and Blood Disorders Dept. of The Ctr for C & BD
  • Virginia
    • Charlottesville, Virginia, United States, 22908-0334
      • University of Virginia Health Systems SC-4
  • Washington
    • Tacoma, Washington, United States, 98405
      • Northwest Medical Specialties Dept of Onc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Capecitabine 1250 mg/m2; Capecitabine (1250 mg/m2 twice daily) for two weeks, followed by one week rest period in 3-weeks cycles (investigational arm).	Drug: Capecitabine; Capecitabine, tablets for oral use, 1250 mg/m² twice daily for 2 weeks followed by one week rest (3-week-cycle) (locally supplied); Other Names: Capecitabine monotherapy
EXPERIMENTAL: Everolimus 10 mg; Everolimus (10 mg daily) (investigational arm).	Drug: Everolimus; Everolimus, 5 mg tablets for oral use, 10 mg (2 x 5 mg) per day (centrally supplied); Other Names: RAD001; Everolimus monotherapy
ACTIVE_COMPARATOR: Everolimus 10 mg + Exemestane 25 mg; Everolimus (10 mg daily) with Exemestane (25 mg daily) (control arm).	Drug: Everolimus; Everolimus, 5 mg tablets for oral use, 10 mg (2 x 5 mg) per day (centrally supplied); Other Names: RAD001; Everolimus monotherapy; Drug: Exemestane; Exemestane, tablets for oral use, 25 mg per day in (locally supplied); Other Names: Control arm

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS) - Everolimus Plus Exemestane Versus Everolimus Alone	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 have an event, PFS was censored at the date of the last adequate tumor assessment. PFS was compared between the everolimus + exemestane combination therapy with the everolimus monotherapy.	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 39 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS) - Everolimus Plus Exemestane Versus Capecitabine Alone	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 have an event, PFS was censored at the date of the last adequate tumor assessment. PFS was compared between the everolimus + exemestane combination therapy with the everolimus monotherapy.	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 39 months
Overall Survival (OS)	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.	Every 3 months following end of treatment visit, assessed for approximately 54 months
Overall Response Rate (ORR)	Overall Response Rate (ORR) as the proportion of patients whose best overall response is either complete response (CR) or partial response (PR) according to RECIST 1.1 This was assessed in the full patient population. Complete response is achieved when all lesions evaluated at baseline are absent at subsequent visit. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Only descriptive statistics.	From the date of randomization until the date of the first documented disease progression or date of death from any cause whichever came first, assessed for approximately 43 months
Clinical Benefit Rate (CBR)	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. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR, Stable disease (SD), neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD; CBR = CR+PR+SD. Only descriptive statistics.	From the date of randomization until the date of the first documented disease progression or date of death from any cause whichever came first, assessed for approximately 43 months
Time to Eastern Cooperative Oncology Group (ECOG) Performance Deterioration	The Eastern Cooperative Oncology Group (ECOG) Performance Status is a scale used to assess physical health of subjects,ranging from 0 (most active) to 5 (least active). Definitive deterioration is defined as no improvement in the ECOG status following observation of the deterioration.	Baseline, every 6 weeks up to about 43 months
Time to 10% Definitive Deterioration in the Global Health Status / Quality of Life	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 the number of days between the date of randomization and the date of the assessment at which definitive deterioration is seen. Definitive 10% (5-point) deterioration is defined as a decrease in score by at least 10% (5-points) compared to baseline, with no later increase above this threshold observed during the course of the study.	Baseline, every 6 weeks up to about 43 months
Mean Change in Treatment Satisfaction Questionnaire for Medication (TSQM) Between Week 3 and 12	TSQM was used to measure the Patients' self-reported satisfaction or dissatisfaction with the study treatment. The differences in mean scale scores between weeks 3 and 12 comparing treatment satisfaction in the different treatment arms: everolimus + exemestane combination therapy versus everolimus monotherapy, and everolimus + exemestane combination therapy versus capecitabine monotherapy. The TSQM version 1.4 domain scores range from 0 to 100 with higher scores representing a higher satisfaction on that domain.	Week 3, Week 12

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Jerusalem G, de Boer RH, Hurvitz S, Yardley DA, Kovalenko E, Ejlertsen B, Blau S, Ozguroglu 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 26, 2013
• Primary Completion (ACTUAL): July 2, 2018
• Study Completion (ACTUAL): July 30, 2018

Study Registration Dates

• First Submitted: January 11, 2013
• First Submitted That Met QC Criteria: February 4, 2013
• First Posted (ESTIMATE): February 5, 2013

Study Record Updates

• Last Update Posted (ACTUAL): February 26, 2021
• Last Update Submitted That Met QC Criteria: February 19, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: Capecitabine; breast cancer; HER2; Everolimus; metastatic; HER2 positive; Exemestane; locally advanced; ER; breast cancer progression; breast cancer positive for human epidermal growth factor receptor 2; estrogen-receptor positive breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Capecitabine; Everolimus; Exemestane
• Other Study ID Numbers: CRAD001Y2201; 2012-003757-28 (EUDRACT_NUMBER)

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