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

Breast Cancer Clinical Trial

— BOLERO-6  

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01783444
• Other study ID #: CRAD001Y2201
• Secondary ID: 2012-003757-28
• Status: Completed
• Phase: Phase 2
• Start date: February 26, 2013
• Est. completion date: July 30, 2018

Study information

• Verified date: February 2021
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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 negative, advanced breast cancer after recurrence or progression on letrozole or anastrozole.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 309
• Est. completion date: July 30, 2018
• Est. primary completion date: July 2, 2018
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

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)
• Exemestane
Exemestane, tablets for oral use, 25 mg per day in (locally supplied)
• Everolimus
Everolimus, 5 mg tablets for oral use, 10 mg (2 x 5 mg) per day (centrally supplied)

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Caba	Buenos Aires
Argentina	Novartis Investigative Site	Cordoba
Argentina	Novartis Investigative Site	Posadas	Misiones
Argentina	Novartis Investigative Site	Rio Negro	Viedma
Argentina	Novartis Investigative Site	Rosario	Santa Fe
Australia	Novartis Investigative Site	Malvern	Victoria
Australia	Novartis Investigative Site	Parkville	Victoria
Australia	Novartis Investigative Site	Randwick	New South Wales
Australia	Novartis Investigative Site	Wahroonga	New South Wales
Belgium	Novartis Investigative Site	Liege
Brazil	Novartis Investigative Site	Natal	RN
Brazil	Novartis Investigative Site	Passo Fundo	RS
Brazil	Novartis Investigative Site	Porto Alegre	Rio Grande Do Sul
Brazil	Novartis Investigative Site	Salvador	BA
Brazil	Novartis Investigative Site	Sao Paulo	SP
Denmark	Novartis Investigative Site	Aarhus
Denmark	Novartis Investigative Site	Copenhagen
Denmark	Novartis Investigative Site	Næstved
Denmark	Novartis Investigative Site	Odense C
Denmark	Novartis Investigative Site	Roskilde
Denmark	Novartis Investigative Site	Vejle
Hungary	Novartis Investigative Site	Budapest	HUN
Hungary	Novartis Investigative Site	Debrecen
Hungary	Novartis Investigative Site	Tatabanya
India	Novartis Investigative Site	Hyderabad	Andhra Pradesh
India	Novartis Investigative Site	Kolkatta	West Bengal
India	Novartis Investigative Site	Mumbai
India	Novartis Investigative Site	Pune	Maharashtra
Ireland	Novartis Investigative Site	Dublin 4
Ireland	Novartis Investigative Site	Galway
Ireland	Novartis Investigative Site	Limerick	Co Limerick
Lebanon	Novartis Investigative Site	Ashrafieh
Lebanon	Novartis Investigative Site	Beirut
Lebanon	Novartis Investigative Site	Beirut
Lebanon	Novartis Investigative Site	Hazmieh
Lebanon	Novartis Investigative Site	Saida
Malaysia	Novartis Investigative Site	Kota Kinabalu	Sabah
Malaysia	Novartis Investigative Site	Kuala Lumpur
Peru	Novartis Investigative Site	Arequipa
Peru	Novartis Investigative Site	Jesus Maria	Lima
Peru	Novartis Investigative Site	San Borja	Lima
Peru	Novartis Investigative Site	Surquillo	Lima
Russian Federation	Novartis Investigative Site	Arkhangelsk
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	St Petersburg
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Sevilla	Andalucia
Sweden	Novartis Investigative Site	Eskilstuna
Sweden	Novartis Investigative Site	Joenkoeping
Sweden	Novartis Investigative Site	Stockholm
Sweden	Novartis Investigative Site	Uppsala
Sweden	Novartis Investigative Site	Vasteras
Sweden	Novartis Investigative Site	Vaxjo
Thailand	Novartis Investigative Site	Muang
Thailand	Novartis Investigative Site	Muang Lopburi	Lopburi
Thailand	Novartis Investigative Site	Songkhla	Hat Yai
Turkey	Novartis Investigative Site	Adana
Turkey	Novartis Investigative Site	Istanbul
Turkey	Novartis Investigative Site	Izmir
United Kingdom	Novartis Investigative Site	East Kilbride
United Kingdom	Novartis Investigative Site	Middlesborough
United Kingdom	Novartis Investigative Site	Nottingham
United States	Lahey Clinic Dept of Lahey Clinic (2)	Burlington	Massachusetts
United States	University of Virginia Health Systems SC-4	Charlottesville	Virginia
United States	Chattanooga Oncology and Hematology Assoicates, PC Chattanooga Oncology	Chattanooga	Tennessee
United States	Oncology Hematology Care Inc Oncology Hematology Care 2	Cincinnati	Ohio
United States	Trinitas Comprehensive Cancer Center SC	Elizabeth	New Jersey
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	The Center for Cancer and Blood Disorders Dept. of The Ctr for C & BD	Fort Worth	Texas
United States	The Jones Clinic SC	Germantown	Tennessee
United States	Hackensack University Medical Center Dept of Oncology	Hackensack	New Jersey
United States	Glacier View Research Institute - Cancer SC	Kalispell	Montana
United States	University of Tennessee SC	Knoxville	Tennessee
United States	University of California at Los Angeles Mattel Children's Hospital	Los Angeles	California
United States	Sarah Cannon Research Institute SC (2)	Nashville	Tennessee
United States	Rutgers-New Jersey Medical School SC	Newark	New Jersey
United States	New England Hematology/ Oncology Associates, P.C. SC	Newton	Massachusetts
United States	Sharp Memorial Hospital SharpClinicalOncologyResearch	San Diego	California
United States	Northwest Medical Specialties Dept of Onc	Tacoma	Washington
United States	Oklahoma Cancer Specialists and Research Institute Oklahoma Cancer Specialists	Tulsa	Oklahoma

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Belgium,  Brazil,  Denmark,  Hungary,  India,  Ireland,  Lebanon,  Malaysia,  Peru,  Russian Federation,  Spain,  Sweden,  Thailand,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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