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

NCT ID: NCT01783444

Last Updated: 2021-02-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 309 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-02-26
• Study Completion Date: 2018-07-30

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.

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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).

Group Type: EXPERIMENTAL

Capecitabine

Intervention Type: DRUG

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

Everolimus 10 mg

Everolimus (10 mg daily) (investigational arm).

Group Type: EXPERIMENTAL

Everolimus

Intervention Type: DRUG

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

Everolimus 10 mg + Exemestane 25 mg

Everolimus (10 mg daily) with Exemestane (25 mg daily) (control arm).

Group Type: ACTIVE_COMPARATOR

Exemestane

Intervention Type: DRUG

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

Everolimus

Intervention Type: DRUG

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

Interventions

Capecitabine

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

Intervention Type: DRUG

Exemestane

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

Intervention Type: DRUG

Everolimus

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

Intervention Type: DRUG

Other Intervention Names

Capecitabine monotherapy; Control arm; Everolimus monotherapy; RAD001

Eligibility Criteria

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.

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Locations

University of California at Los Angeles Mattel Children's Hospital

Los Angeles, California, United States

Sharp Memorial Hospital SharpClinicalOncologyResearch

San Diego, California, United States

Florida Cancer Specialists Dept of Oncology (2)

Fort Myers, Florida, United States

Florida Cancer Specialists FL Cancer Specialists

Fort Myers, Florida, United States

Lahey Clinic Dept of Lahey Clinic (2)

Burlington, Massachusetts, United States

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

Newton, Massachusetts, United States

Glacier View Research Institute - Cancer SC

Kalispell, Montana, United States

Trinitas Comprehensive Cancer Center SC

Elizabeth, New Jersey, United States

Hackensack University Medical Center Dept of Oncology

Hackensack, New Jersey, United States

Rutgers-New Jersey Medical School SC

Newark, New Jersey, United States

Oncology Hematology Care Inc Oncology Hematology Care 2

Cincinnati, Ohio, United States

Oklahoma Cancer Specialists and Research Institute Oklahoma Cancer Specialists

Tulsa, Oklahoma, United States

Chattanooga Oncology and Hematology Assoicates, PC Chattanooga Oncology

Chattanooga, Tennessee, United States

The Jones Clinic SC

Germantown, Tennessee, United States

University of Tennessee SC

Knoxville, Tennessee, United States

Sarah Cannon Research Institute SC (2)

Nashville, Tennessee, United States

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

Fort Worth, Texas, United States

University of Virginia Health Systems SC-4

Charlottesville, Virginia, United States

Northwest Medical Specialties Dept of Onc

Tacoma, Washington, United States

Novartis Investigative Site

CABA, Buenos Aires, Argentina

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Posadas, Misiones Province, Argentina

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Rosario, Santa Fe Province, Argentina

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Rio Negro, Viedma, Argentina

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Córdoba, , Argentina

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Randwick, New South Wales, Australia

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Wahroonga, New South Wales, Australia

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Malvern, Victoria, Australia

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Parkville, Victoria, Australia

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Liège, , Belgium

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Salvador, Estado de Bahia, Brazil

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Natal, Rio Grande do Norte, Brazil

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Passo Fundo, Rio Grande do Sul, Brazil

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Porto Alegre, Rio Grande do Sul, Brazil

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São Paulo, São Paulo, Brazil

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Aarhus, , Denmark

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Copenhagen, , Denmark

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Næstved, , Denmark

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Odense C, , Denmark

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Roskilde, , Denmark

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Vejle, , Denmark

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Budapest, HUN, Hungary

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Debrecen, , Hungary

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Tatabánya, , Hungary

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Hyderabad, Andhra Pradesh, India

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Pune, Maharashtra, India

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Kolkata, West Bengal, India

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Mumbai, , India

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Limerick, Co Limerick, Ireland

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Dublin, , Ireland

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Galway, , Ireland

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Beirut, , Lebanon

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Beirut, , Lebanon

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El Achrafiyé, , Lebanon

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Hazmiyeh, , Lebanon

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Saida, , Lebanon

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Kota Kinabalu, Sabah, Malaysia

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Kuala Lumpur, , Malaysia

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Jesus Maria, Lima region, Peru

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San Borja, Lima region, Peru

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Surquillo, Lima region, Peru

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Arequipa, , Peru

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Arkhangelsk, , Russia

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Moscow, , Russia

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Saint Petersburg, , Russia

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Seville, Andalusia, Spain

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Barcelona, Catalonia, Spain

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Madrid, , Spain

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Madrid, , Spain

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Eskilstuna, , Sweden

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Jönköping, , Sweden

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Stockholm, , Sweden

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Uppsala, , Sweden

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Vaxjo, , Sweden

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Västerås, , Sweden

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Lopburi, Changwat Lop Buri, Thailand

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Songkhla, Hat Yai, Thailand

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Muang, , Thailand

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Adana, , Turkey (Türkiye)

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Istanbul, , Turkey (Türkiye)

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Izmir, , Turkey (Türkiye)

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East Kilbride, , United Kingdom

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Middlesbrough, , United Kingdom

Novartis Investigative Site

Nottingham, , United Kingdom

Countries

United States; Argentina; Australia; Belgium; Brazil; Denmark; Hungary; India; Ireland; Lebanon; Malaysia; Peru; Russia; Spain; Sweden; Thailand; Turkey (Türkiye); United Kingdom

References

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.

Reference Type: DERIVED

PMID: 29862411 (View on PubMed)

Provided Documents

Document Type: Statistical Analysis Plan

View Document

Document Type: Study Protocol

View Document

Other Identifiers

2012-003757-28

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CRAD001Y2201

Identifier Type: -

Identifier Source: org_study_id