Clinical trial NCT01783444: A Phase II Study of Everolimus in Combination With Exemestane Versus Everolimus Alone Versus Capecitabine in Advance Breast Cancer.
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
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
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2013-02-05
Enrollment: 309
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Progression Free Survival (PFS) - Everolimus Plus Exemestane Versus Everolimus Alone
timeFrame: 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:
measure: Progression Free Survival (PFS) - Everolimus Plus Exemestane Versus Capecitabine Alone
timeFrame: 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
measure: Overall Survival (OS)
timeFrame: Every 3 months following end of treatment visit, assessed for approximately 54 months
measure: Overall Response Rate (ORR)
timeFrame: 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
measure: Clinical Benefit Rate (CBR)
timeFrame: 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
measure: Time to Eastern Cooperative Oncology Group (ECOG) Performance Deterioration
timeFrame: Baseline, every 6 weeks up to about 43 months
measure: Time to 10% Definitive Deterioration in the Global Health Status / Quality of Life
timeFrame: Baseline, every 6 weeks up to about 43 months
measure: Mean Change in Treatment Satisfaction Questionnaire for Medication (TSQM) Between Week 3 and 12
timeFrame: Week 3, Week 12
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California at Los Angeles Mattel Children's Hospital
state: California
city: San Diego
country: United States
facility: Sharp Memorial Hospital SharpClinicalOncologyResearch
state: California
city: Fort Myers
country: United States
facility: Florida Cancer Specialists Dept of Oncology (2)
state: Florida
city: Fort Myers
country: United States
facility: Florida Cancer Specialists FL Cancer Specialists
state: Florida
city: Burlington
country: United States
facility: Lahey Clinic Dept of Lahey Clinic (2)
state: Massachusetts
city: Newton
country: United States
facility: New England Hematology/ Oncology Associates, P.C. SC
state: Massachusetts
city: Kalispell
country: United States
facility: Glacier View Research Institute - Cancer SC
state: Montana
city: Elizabeth
country: United States
facility: Trinitas Comprehensive Cancer Center SC
state: New Jersey
city: Hackensack
country: United States
facility: Hackensack University Medical Center Dept of Oncology
state: New Jersey
city: Newark
country: United States
facility: Rutgers-New Jersey Medical School SC
state: New Jersey
city: Cincinnati
country: United States
facility: Oncology Hematology Care Inc Oncology Hematology Care 2
state: Ohio
city: Tulsa
country: United States
facility: Oklahoma Cancer Specialists and Research Institute Oklahoma Cancer Specialists
state: Oklahoma
city: Chattanooga
country: United States
facility: Chattanooga Oncology and Hematology Assoicates, PC Chattanooga Oncology
state: Tennessee
city: Germantown
country: United States
facility: The Jones Clinic SC
state: Tennessee
city: Knoxville
country: United States
facility: University of Tennessee SC
state: Tennessee
city: Nashville
country: United States
facility: Sarah Cannon Research Institute SC (2)
state: Tennessee
city: Fort Worth
country: United States
facility: The Center for Cancer and Blood Disorders Dept. of The Ctr for C & BD
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Health Systems SC-4
state: Virginia
city: Tacoma
country: United States
facility: Northwest Medical Specialties Dept of Onc
state: Washington
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Posadas
country: Argentina
facility: Novartis Investigative Site
state: Misiones
city: Rosario
country: Argentina
facility: Novartis Investigative Site
state: Santa Fe
city: Rio Negro
country: Argentina
facility: Novartis Investigative Site
state: Viedma
city: Cordoba
country: Argentina
facility: Novartis Investigative Site
city: Randwick
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Wahroonga
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Malvern
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Parkville
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Liege
country: Belgium
facility: Novartis Investigative Site
city: Salvador
country: Brazil
facility: Novartis Investigative Site
state: BA
city: Porto Alegre
country: Brazil
facility: Novartis Investigative Site
state: Rio Grande Do Sul
city: Natal
country: Brazil
facility: Novartis Investigative Site
state: RN
city: Passo Fundo
country: Brazil
facility: Novartis Investigative Site
state: RS
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Aarhus
country: Denmark
facility: Novartis Investigative Site
city: Copenhagen
country: Denmark
facility: Novartis Investigative Site
city: Næstved
country: Denmark
facility: Novartis Investigative Site
city: Odense C
country: Denmark
facility: Novartis Investigative Site
city: Roskilde
country: Denmark
facility: Novartis Investigative Site
city: Vejle
country: Denmark
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
state: HUN
city: Debrecen
country: Hungary
facility: Novartis Investigative Site
city: Tatabanya
country: Hungary
facility: Novartis Investigative Site
city: Hyderabad
country: India
facility: Novartis Investigative Site
state: Andhra Pradesh
city: Pune
country: India
facility: Novartis Investigative Site
state: Maharashtra
city: Kolkatta
country: India
facility: Novartis Investigative Site
state: West Bengal
city: Mumbai
country: India
facility: Novartis Investigative Site
city: Limerick
country: Ireland
facility: Novartis Investigative Site
state: Co Limerick
city: Dublin 4
country: Ireland
facility: Novartis Investigative Site
city: Galway
country: Ireland
facility: Novartis Investigative Site
city: Ashrafieh
country: Lebanon
facility: Novartis Investigative Site
city: Beirut
country: Lebanon
facility: Novartis Investigative Site
city: Beirut
country: Lebanon
facility: Novartis Investigative Site
city: Hazmieh
country: Lebanon
facility: Novartis Investigative Site
city: Saida
country: Lebanon
facility: Novartis Investigative Site
city: Kota Kinabalu
country: Malaysia
facility: Novartis Investigative Site
state: Sabah
city: Kuala Lumpur
country: Malaysia
facility: Novartis Investigative Site
city: Jesus Maria
country: Peru
facility: Novartis Investigative Site
state: Lima
city: San Borja
country: Peru
facility: Novartis Investigative Site
state: Lima
city: Surquillo
country: Peru
facility: Novartis Investigative Site
state: Lima
city: Arequipa
country: Peru
facility: Novartis Investigative Site
city: Arkhangelsk
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: St Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Eskilstuna
country: Sweden
facility: Novartis Investigative Site
city: Joenkoeping
country: Sweden
facility: Novartis Investigative Site
city: Stockholm
country: Sweden
facility: Novartis Investigative Site
city: Uppsala
country: Sweden
facility: Novartis Investigative Site
city: Vasteras
country: Sweden
facility: Novartis Investigative Site
city: Vaxjo
country: Sweden
facility: Novartis Investigative Site
city: Songkhla
country: Thailand
facility: Novartis Investigative Site
state: Hat Yai
city: Muang Lopburi
country: Thailand
facility: Novartis Investigative Site
state: Lopburi
city: Muang
country: Thailand
facility: Novartis Investigative Site
city: Adana
country: Turkey
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
city: Izmir
country: Turkey
facility: Novartis Investigative Site
city: East Kilbride
country: United Kingdom
facility: Novartis Investigative Site
city: Middlesborough
country: United Kingdom
facility: Novartis Investigative Site
city: Nottingham
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: 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.