Clinical trial NCT00876395: Everolimus in Combination With Trastuzumab and Paclitaxel in the Treatment of HER2 Positive Locally Advanced or Metastatic Breast Cancer
Official title: A Randomized Phase III, Double-Blind, Placebo-Controlled Multicenter Trial of Everolimus in Combination With Trastuzumab and Paclitaxel, as First Line Therapy in Women With HER2 Positive Locally Advanced or Metastatic Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Cancer
Keywords: Breast Cancer
HER2+
mTOR
everolimus
RAD001
first line
metastatic
locally advanced
Trastuzumab
Paclitaxel
First Line Therapy
HER2 Positive
Metastatic Breast Cancer
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2009-04-06
Enrollment: 719
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: The purpose of this Phase III study was to confirm the value of adding everolimus to weekly paclitaxel and trastuzumab as treatment of HER2-overexpressing metastatic breast cancer.


Eligibility criteria: Inclusion Criteria:

* Adult Women (≥ 18 years old).
* Histologically or cytologically confirmed invasive breast carcinoma with local recurrence or radiological evidence of metastatic disease.
* Must have at least one lesion that can be accurately measured or bone lesions in the absence of measurable disease.
* HER2+ patients by local laboratory testing (IHC 3+ staining or in situ hybridization positive).
* Prior trastuzumab and/or chemotherapy (taxanes included) as neo-adjuvant or adjuvant treatment is allowed but should be discontinued \> 12 months prior to randomization.
* Prior treatment for breast cancer with endocrine therapy (adjuvant or metastatic settings) is allowed but should be discontinued at randomization. Patients treated with bisphosphonates at entry or who start bisphosphonates during study may continue this therapy during protocol treatment.
* Documentation of negative pregnancy test.
* Organ functions at time of inclusion.

Exclusion Criteria:

* Prior mTOR inhibitors for the treatment of cancer.
* Other anticancer therapy for locally advanced or metastatic breast cancer except for prior hormonal therapy.
* Patients with only non-measurable lesions other than bone metastasis (e.g. pleural effusion, ascites, etc).
* Radiotherapy to ≥ 25% of the bone marrow within 4 weeks prior to randomization
* History of central nervous system metastasis.
* Impairment of gastrointestinal (GI) function or GI disease or active ulceration of the upper gastrointestinal tract.
* Serious peripheral neuropathy.
* Cardiac disease or dysfunction.
* Uncontrolled hypertension.
* HIV.
* Pregnant,

Primary outcomes:
measure: Progression-free Survival (PFS) Per Investigators' Assessment Based on Local Radiology Review - Full Population
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 about 56 months
measure: Progression-free Survival (PFS) Per Investigators' Assessment Based on Local Radiology Review - (Hormone Receptor (HR)-Negative Population
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 about 56 months
Secondary outcomes:
measure: Overall Survival (OS) - Full Population
timeFrame: up to about 76 months
measure: Overall Survival (OS) - HR-negative Population
timeFrame: up to about 76 months
measure: Overall Response Rate (ORR) - Full Population
timeFrame: up to about 23 months
measure: Overall Response Rate (ORR) - HR-negative Population
timeFrame: up to about 23 months
measure: Clinical Benefit Rate (CBR) Equal to or Greater Than 24 Weeks - Full Population
timeFrame: up to about 23 months
measure: Clinical Benefit Rate (CBR) Equal to or Greater Than 24 Weeks - HR-negative Population
timeFrame: up to about 23 months
measure: Time to Overall Response Based on Investigator - Full Population
timeFrame: up to about 23 months
measure: Time to Overall Response Based on Investigator - HR-negative Population
timeFrame: up to about 23 months
measure: Overall Response (OR) - Full Population
timeFrame: up to about 23 months
measure: Overall Response (OR) - HR-negative Population
timeFrame: up to about 23 months
measure: Everolimus Blood Level Concentrations at Steady States for Everolimus
timeFrame: predose, 2 hours post-dose at Cycle 2/Day 1, Cycle 2/Day 15, Cycle 2/ Day 22
measure: Paclitaxel Plasma Concentrations
timeFrame: Cycle 2/Day 15 (Pre-infusion and end of infusion)
measure: Trastuzumab Serum Concentrations
timeFrame: Cycle 4/Day 1 (Pre-infusion and end of infusion)
measure: Time to Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Score - Full Population
timeFrame: up to about 56 months
measure: Time to Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Score - HR-negative Population
timeFrame: up to about 56 months
Other outcomes:
Locations:
city: Mobile
country: United States
facility: University of South Alabama / Mitchell Cancer Institute Dept. of Mitchell Cancer Inst.
state: Alabama
city: Chandler
country: United States
facility: Ironwood Cancer and Research Centers
state: Arizona
city: Fayetteville
country: United States
facility: Highlands Oncology Group
state: Arkansas
city: Bakersfield
country: United States
facility: Comprehensive Blood and Cancer Center Dept. of CBCC (2)
state: California
city: Fullerton
country: United States
facility: St. Jude Heritage Medical Group Virginia Crosson Cancer Center
state: California
city: Los Angeles
country: United States
facility: University of California at Los Angeles Dept. of UCLA
state: California
city: Oxnard
country: United States
facility: Ventura County Hematology and Oncology
state: California
city: Redondo Beach
country: United States
facility: Cancer Care Associates Medical Group Dept. of CCA
state: California
city: Santa Barbara
country: United States
facility: Santa Barbara Hematolgy Oncology Medical Group Dept.ofSantaBarbaraHem/Onc
state: California
city: Santa Maria
country: United States
facility: Central Coast Medical Oncology Corporation Onc Dept
state: California
city: Greenwood Village
country: United States
facility: Rocky Mountain Cancer Centers RMCC - Denver-Midtown (3)
state: Colorado
city: Fort Myers
country: United States
facility: Florida Cancer Specialists Dept.of FloridaCancerSpec. (2)
state: Florida
city: West Palm Beach
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Indianapolis
country: United States
facility: Central Indiana Cancer Centers CICC - East (3)
state: Indiana
city: Overland Park
country: United States
facility: Kansas City Cancer Center Dept. of KCCC
state: Kansas
city: Omaha
country: United States
facility: University of Nebraska Medical Center Unv Nebraska Med Ctr (2)
state: Nebraska
city: Albany
country: United States
facility: New York Oncology Hematology NYOH Amsterdam
state: New York
city: New York
country: United States
facility: Beth Israel Medical Center Dept.ofBeth Israel Med. Ctr(2)
state: New York
city: Portland
country: United States
facility: Northwest Cancer Specialists Vancouver Cancer Center (3)
state: Oregon
city: Nashville
country: United States
facility: Sarah Cannon Research Institute Dept.ofSarahCannonCancerCtr(5)
state: Tennessee
city: Dallas
country: United States
facility: Texas Oncology Charles A. Sammons Cancer Ctr
state: Texas
city: Dallas
country: United States
facility: Texas Oncology P A SC-Austin
state: Texas
city: Tyler
country: United States
facility: Tyler Cancer Center Dept.ofTylerCancerCtr. (2)
state: Texas
city: Norfolk
country: United States
facility: Virginia Oncology Associates SC
state: Virginia
city: Richmond
country: United States
facility: Virginia Cancer Institute VCI (3)
state: Virginia
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Mar del Plata
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: Sante Fe
city: Rio Negro
country: Argentina
facility: Novartis Investigative Site
state: Viedma
city: Capital Federal
country: Argentina
facility: Novartis Investigative Site
city: Cordoba
country: Argentina
facility: Novartis Investigative Site
city: Southport
country: Australia
facility: Novartis Investigative Site
state: Queensland
city: East Bentleigh
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Charleroi
country: Belgium
facility: Novartis Investigative Site
city: Hasselt
country: Belgium
facility: Novartis Investigative Site
city: Verviers
country: Belgium
facility: Novartis Investigative Site
city: Wilrijk
country: Belgium
facility: Novartis Investigative Site
city: Yvoir
country: Belgium
facility: Novartis Investigative Site
city: Belo Horizonte
country: Brazil
facility: Novartis Investigative Site
state: MG
city: Belo Horizonte
country: Brazil
facility: Novartis Investigative Site
state: MG
city: Rio de Janeiro
country: Brazil
facility: Novartis Investigative Site
state: RJ
city: Sao Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: São Paulo
country: Brazil
facility: Novartis Investigative Site
state: SP
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: St-Jerome
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Guangzhou
country: China
facility: Novartis Investigative Site
state: Guangdong
city: Harbin
country: China
facility: Novartis Investigative Site
state: Heilongjiang
city: Nanjing
country: China
facility: Novartis Investigative Site
state: Jiangsu
city: Nanjing
country: China
facility: Novartis Investigative Site
state: Jiangsu
city: Shanghai
country: China
facility: Novartis Investigative Site
state: Shanghai
city: Hangzhou
country: China
facility: Novartis Investigative Site
state: Zhejiang
city: Beijing
country: China
facility: Novartis Investigative Site
city: Beijing
country: China
facility: Novartis Investigative Site
city: Guangzhou
country: China
facility: Novartis Investigative Site
city: Shanghai
country: China
facility: Novartis Investigative Site
city: Bogota
country: Colombia
facility: Novartis Investigative Site
state: Cundinamarca
city: Bogota
country: Colombia
facility: Novartis Investigative Site
city: Florida Blanca
country: Colombia
facility: Novartis Investigative Site
city: Monteria
country: Colombia
facility: Novartis Investigative Site
city: Alexandria
country: Egypt
facility: Novartis Investigative Site
city: Cairo
country: Egypt
facility: Novartis Investigative Site
city: Limoges
country: France
facility: Novartis Investigative Site
city: Rouen
country: France
facility: Novartis Investigative Site
city: Saint-Herblain Cédex
country: France
facility: Novartis Investigative Site
city: Strasbourg Cedex
country: France
facility: Novartis Investigative Site
city: Thonon-les-Bains Cedex
country: France
facility: Novartis Investigative Site
city: Toulouse Cedex 9
country: France
facility: Novartis Investigative Site
city: Villejuif Cedex
country: France
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Chemnitz
country: Germany
facility: Novartis Investigative Site
city: Esslingen
country: Germany
facility: Novartis Investigative Site
city: Kiel
country: Germany
facility: Novartis Investigative Site
city: Muenster
country: Germany
facility: Novartis Investigative Site
city: Athens
country: Greece
facility: Novartis Investigative Site
state: GR
city: Thessaloniki
country: Greece
facility: Novartis Investigative Site
state: GR
city: Athens
country: Greece
facility: Novartis Investigative Site
city: Athens
country: Greece
facility: Novartis Investigative Site
city: Heraklion Crete
country: Greece
facility: Novartis Investigative Site
city: Hong Kong SAR
country: Hong Kong
facility: Novartis Investigative Site
city: Shatin, New Territories
country: Hong Kong
facility: Novartis Investigative Site
city: Tuen Mun
country: Hong Kong
facility: Novartis Investigative Site
city: Wilton
country: Ireland
facility: Novartis Investigative Site
state: Cork
city: Dublin 4
country: Ireland
facility: Novartis Investigative Site
city: Dublin 8
country: Ireland
facility: Novartis Investigative Site
city: Dublin 9
country: Ireland
facility: Novartis Investigative Site
city: Monza
country: Italy
facility: Novartis Investigative Site
state: MB
city: Modena
country: Italy
facility: Novartis Investigative Site
state: MO
city: Camposampiero
country: Italy
facility: Novartis Investigative Site
state: PD
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Nagoya
country: Japan
facility: Novartis Investigative Site
state: Aichi
city: Kashiwa
country: Japan
facility: Novartis Investigative Site
state: Chiba
city: Fukuoka-city
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Kitakyushu
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Maebashi city
country: Japan
facility: Novartis Investigative Site
state: Gunma
city: Sapporo city
country: Japan
facility: Novartis Investigative Site
state: Hokkaido
city: Isehara-city
country: Japan
facility: Novartis Investigative Site
state: Kanagawa
city: Kumamoto City
country: Japan
facility: Novartis Investigative Site
state: Kumamoto
city: Sakyo-ku
country: Japan
facility: Novartis Investigative Site
state: Kyoto
city: Osaka-city
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Suita-city
country: Japan
facility: Novartis Investigative Site
state: Osaka
city: Kitaadachi-gun
country: Japan
facility: Novartis Investigative Site
state: Saitama
city: Bunkyo-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Chuo-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Osaka
country: Japan
facility: Novartis Investigative Site
city: Gyeonggi-do
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Ashrafieh
country: Lebanon
facility: Novartis Investigative Site
city: Beirut
country: Lebanon
facility: Novartis Investigative Site
city: Ciudad De Mexico
country: Mexico
facility: Novartis Investigative Site
state: Distrito Federal
city: Zaragoza
country: Mexico
facility: Novartis Investigative Site
state: Veracruz
city: San Borja
country: Peru
facility: Novartis Investigative Site
state: Lima
city: Surquillo
country: Peru
facility: Novartis Investigative Site
state: Lima
city: San Juan
country: Puerto Rico
facility: San Juan VA Hospital San Juan Hospital
city: Kazan
country: Russian Federation
facility: Novartis Investigative Site
state: Tatarstan Republic
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Moscow
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: St. Petersburg
country: Russian Federation
facility: Novartis Investigative Site
city: Bloemfontein
country: South Africa
facility: Novartis Investigative Site
city: Durban
country: South Africa
facility: Novartis Investigative Site
city: Pretoria
country: South Africa
facility: Novartis Investigative Site
city: Genève
country: Switzerland
facility: Novartis Investigative Site
city: Zuerich
country: Switzerland
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
state: Taiwan, ROC
city: Kaohsiung
country: Taiwan
facility: Novartis Investigative Site
city: Taichung
country: Taiwan
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Taoyuan
country: Taiwan
facility: Novartis Investigative Site
city: Altunizade
country: Turkey
facility: Novartis Investigative Site
city: Ankara
country: Turkey
facility: Novartis Investigative Site
city: Izmir
country: Turkey
facility: Novartis Investigative Site
city: Izmir
country: Turkey
facility: Novartis Investigative Site
city: Truro
country: United Kingdom
facility: Novartis Investigative Site
state: Cornwall
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Sutton
country: United Kingdom
facility: Novartis Investigative Site
city: Valencia
country: Venezuela
facility: Novartis Investigative Site
state: Estado Carabobo
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Toi M, Shao Z, Hurvitz S, Tseng LM, Zhang Q, Shen K, Liu D, Feng J, Xu B, Wang X, Lee KS, Ng TY, Ridolfi A, Noel-Baron F, Ringeisen F, Jiang Z. Efficacy and safety of everolimus in combination with trastuzumab and paclitaxel in Asian patients with HER2+ advanced breast cancer in BOLERO-1. Breast Cancer Res. 2017 Apr 11;19(1):47. doi: 10.1186/s13058-017-0839-0.
citation: Buyse M, Hurvitz SA, Andre F, Jiang Z, Burris HA, Toi M, Eiermann W, Lindsay MA, Slamon D. Statistical controversies in clinical research: statistical significance-too much of a good thing .... Ann Oncol. 2016 May;27(5):760-2. doi: 10.1093/annonc/mdw047. Epub 2016 Feb 9.
citation: Hurvitz SA, Andre F, Jiang Z, Shao Z, Mano MS, Neciosup SP, Tseng LM, Zhang Q, Shen K, Liu D, Dreosti LM, Burris HA, Toi M, Buyse ME, Cabaribere D, Lindsay MA, Rao S, Pacaud LB, Taran T, Slamon D. Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): a phase 3, randomised, double-blind, multicentre trial. Lancet Oncol. 2015 Jul;16(7):816-29. doi: 10.1016/S1470-2045(15)00051-0. Epub 2015 Jun 16.