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Breast CancerPhase 2BOLERO-6NCT01783444

A Phase II Study of Everolimus in Combination With Exemestane Versus Everolimus Alone Versus Capecitabine in Advance Breast Cancer.

A Phase 2 study testing Capecitabine, Exemestane and Everolimus in people with Breast Cancer, run by Novartis Pharmaceuticals at 83 sites in 18 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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… Read more about this study

Who is it for?
Ages 18 years and older, women only
Conditions the study is for
Breast Cancer
What is being tested?
Capecitabine, Exemestane and Everolimus
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
309 participants
Where
83 sitesin 18 countries
Study dates
26 Feb 2013to 30 Jul 2018
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • Women only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.

Who cannot join

  • 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.

Trial locations and contacts

83 sites in 18 countries.

83 sites in 18 countries

United States19 sites

  • Lahey Clinic Dept of Lahey Clinic (2)

    Burlington, Massachusetts, 01805

  • University of Virginia Health Systems SC-4

    Charlottesville, Virginia, 22908-0334

  • Chattanooga Oncology and Hematology Assoicates, PC Chattanooga Oncology

    Chattanooga, Tennessee, 37404

  • Oncology Hematology Care Inc Oncology Hematology Care 2

    Cincinnati, Ohio, 45242

  • Trinitas Comprehensive Cancer Center SC

    Elizabeth, New Jersey, 07207

  • Florida Cancer Specialists Dept of Oncology (2)

    Fort Myers, Florida, 33901

  • Florida Cancer Specialists FL Cancer Specialists

    Fort Myers, Florida, 33901

  • The Center for Cancer and Blood Disorders Dept. of The Ctr for C & BD

    Fort Worth, Texas, 76104

  • The Jones Clinic SC

    Germantown, Tennessee, 38138

  • Hackensack University Medical Center Dept of Oncology

    Hackensack, New Jersey, 07601

  • Glacier View Research Institute - Cancer SC

    Kalispell, Montana, 59901

  • University of Tennessee SC

    Knoxville, Tennessee, 27920-6969

  • University of California at Los Angeles Mattel Children's Hospital

    Los Angeles, California, 90095

  • Sarah Cannon Research Institute SC (2)

    Nashville, Tennessee, 37203

  • Rutgers-New Jersey Medical School SC

    Newark, New Jersey, 07101

  • New England Hematology/ Oncology Associates, P.C. SC

    Newton, Massachusetts, 02462

  • Sharp Memorial Hospital SharpClinicalOncologyResearch

    San Diego, California, 92123

  • Northwest Medical Specialties Dept of Onc

    Tacoma, Washington, 98405

  • Oklahoma Cancer Specialists and Research Institute Oklahoma Cancer Specialists

    Tulsa, Oklahoma, 74136

Other trials in United States

Denmark6 sites

  • Novartis Investigative Site

    Aarhus, 8000 C

  • Novartis Investigative Site

    Copenhagen, DK-2100

  • Novartis Investigative Site

    Næstved, DK-4700

  • Novartis Investigative Site

    Odense C, DK 5000

  • Novartis Investigative Site

    Roskilde, 4000

  • Novartis Investigative Site

    Vejle, 7100

Other trials in Denmark

Sweden6 sites

  • Novartis Investigative Site

    Eskilstuna, SE-631 88

  • Novartis Investigative Site

    Jönköping, 551 85

  • Novartis Investigative Site

    Stockholm, SE-171 76

  • Novartis Investigative Site

    Uppsala, SE-751 85

  • Novartis Investigative Site

    Västerås, 721 89

  • Novartis Investigative Site

    Vaxjo, SE-351 85

Other trials in Sweden

Argentina5 sites

  • Novartis Investigative Site

    CABA, Buenos Aires, C1025ABI

  • Novartis Investigative Site

    Córdoba, X5016KEH

  • Novartis Investigative Site

    Posadas, Misiones Province

  • Novartis Investigative Site

    Rio Negro, Viedma, 8500

  • Novartis Investigative Site

    Rosario, Santa Fe Province, S2000KZE

Other trials in Argentina

Brazil5 sites

  • Novartis Investigative Site

    Natal, Rio Grande do Norte, 59075 740

  • Novartis Investigative Site

    Passo Fundo, Rio Grande do Sul, 99010-260

  • Novartis Investigative Site

    Porto Alegre, Rio Grande do Sul, 90610-000

  • Novartis Investigative Site

    Salvador, Estado de Bahia, 41253-190

  • Novartis Investigative Site

    São Paulo, São Paulo, 01317-002

Other trials in Brazil

Lebanon5 sites

  • Novartis Investigative Site

    Beirut, 1107 2020

  • Novartis Investigative Site

    Beirut

  • Novartis Investigative Site

    El Achrafiyé, 166830

  • Novartis Investigative Site

    Hazmiyeh, 470

  • Novartis Investigative Site

    Saida, 652

Other trials in Lebanon

Australia4 sites

  • Novartis Investigative Site

    Malvern, Victoria, 3144

  • Novartis Investigative Site

    Parkville, Victoria, 3050

  • Novartis Investigative Site

    Randwick, New South Wales, 2031

  • Novartis Investigative Site

    Wahroonga, New South Wales, 2076

Other trials in Australia

India4 sites

  • Novartis Investigative Site

    Hyderabad, Andhra Pradesh, 500 034

  • Novartis Investigative Site

    Kolkata, West Bengal, 700 053

  • Novartis Investigative Site

    Mumbai, 400 012

  • Novartis Investigative Site

    Pune, Maharashtra, 411013

Other trials in India

Peru4 sites

  • Novartis Investigative Site

    Arequipa

  • Novartis Investigative Site

    Jesus Maria, Lima region, 11

  • Novartis Investigative Site

    San Borja, Lima region, 41

  • Novartis Investigative Site

    Surquillo, Lima region, 34

Other trials in Peru

Spain4 sites

  • Novartis Investigative Site

    Barcelona, Catalonia, 08035

  • Novartis Investigative Site

    Madrid, 28033

  • Novartis Investigative Site

    Madrid, 28040

  • Novartis Investigative Site

    Seville, Andalusia, 41013

Other trials in Spain

Hungary3 sites

  • Novartis Investigative Site

    Budapest, HUN, 1145

  • Novartis Investigative Site

    Debrecen, 4032

  • Novartis Investigative Site

    Tatabánya, 2800

Other trials in Hungary

Ireland3 sites

  • Novartis Investigative Site

    Dublin, D04 T6F

  • Novartis Investigative Site

    Galway

  • Novartis Investigative Site

    Limerick, Co Limerick

Other trials in Ireland

Russia3 sites

  • Novartis Investigative Site

    Arkhangelsk, 163045

  • Novartis Investigative Site

    Moscow, 115478

  • Novartis Investigative Site

    Saint Petersburg, 197758

Other trials in Russia

Thailand3 sites

  • Novartis Investigative Site

    Lopburi, Changwat Lop Buri, 15000

  • Novartis Investigative Site

    Muang, 40002

  • Novartis Investigative Site

    Songkhla, Hat Yai, 90110

Other trials in Thailand

Turkey (Türkiye)3 sites

  • Novartis Investigative Site

    Adana, 01330

  • Novartis Investigative Site

    Istanbul, 34303

  • Novartis Investigative Site

    Izmir, 35340

Other trials in Turkey (Türkiye)

United Kingdom3 sites

  • Novartis Investigative Site

    East Kilbride, G75 8RG

  • Novartis Investigative Site

    Middlesbrough, TS4 3BW

  • Novartis Investigative Site

    Nottingham, NG5 1PB

Other trials in United Kingdom

Malaysia2 sites

  • Novartis Investigative Site

    Kota Kinabalu, Sabah, 88586

  • Novartis Investigative Site

    Kuala Lumpur, 59100

Other trials in Malaysia

Belgium1 site

  • Novartis Investigative Site

    Liège, 4000

Other trials in Belgium

About this study

Official title: 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.

Read the 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.

Conditions
Breast Cancer
Being tested
Capecitabine, Exemestane, Everolimus
Keywords
Everolimus, Exemestane, Capecitabine, locally advanced, metastatic, breast cancer, breast cancer positive for human epidermal growth factor receptor 2, HER2, HER2 positive, breast cancer progression, estrogen-receptor positive breast cancer, ER
Medical subject headings
Breast Neoplasms, Neoplasm Metastasis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • CapecitabineDrug

    Also called Capecitabine monotherapy

    Capecitabine, tablets for oral use, 1250 mg/m² twice daily for 2 weeks followed by one week rest (3-week-cycle) (locally supplied)

  • ExemestaneDrug

    Also called Control arm

    Exemestane, tablets for oral use, 25 mg per day in (locally supplied)

  • EverolimusDrug

    Also called Everolimus monotherapy, RAD001

    Everolimus, 5 mg tablets for oral use, 10 mg (2 x 5 mg) per day (centrally supplied)

Study groups in NCT01783444
Study groupRoleWhat they receive
Capecitabine 1250 mg/m2ExperimentalCapecitabine (1250 mg/m2 twice daily) for two weeks, followed by one week rest period in 3-weeks cycles (investigational arm).
Receives: Drug: Capecitabine
Everolimus 10 mgExperimentalEverolimus (10 mg daily) (investigational arm).
Receives: Drug: Everolimus
Everolimus 10 mg + Exemestane 25 mgActive comparatorEverolimus (10 mg daily) with Exemestane (25 mg daily) (control arm).
Receives: Drug: Exemestane; Drug: Everolimus

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 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 outcomes (7)

  1. 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.

    Measured: 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

  2. 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.

    Measured: Every 3 months following end of treatment visit, assessed for approximately 54 months

  3. 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.

    Measured: 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

  4. 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.

    Measured: 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

  5. 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.

    Measured: Baseline, every 6 weeks up to about 43 months

  6. 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.

    Measured: Baseline, every 6 weeks up to about 43 months

  7. 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.

    Measured: Week 3, Week 12

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted5 Feb 2013 (estimated)
  2. Study start26 Feb 2013
  3. Primary completion2 Jul 2018
  4. Study completion30 Jul 2018

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
309 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01783444
Sponsor's protocol ID
CRAD001Y2201
Other IDs
2012-003757-28
Acronym
BOLERO-6
Status last verified
Feb 2021
First submitted
11 Jan 2013
Last updated
26 Feb 2021
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: 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

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.

    PubMed 29862411

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Capecitabine, Exemestane and Everolimus in people with Breast Cancer, run by Novartis Pharmaceuticals at 83 sites in 18 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 1 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 26 Feb 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 83 sites in United States, Denmark, Sweden, Argentina, Brazil and 13 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 26 Feb 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Progression Free Survival (PFS) - Everolimus Plus Exemestane Versus Everolimus Alone (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 39 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01783444, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Feb 2021.

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