Everolimus in Combination With Trastuzumab and Paclitaxel in the Treatment of HER2 Positive Locally Advanced or Metastatic Breast Cancer

Breast Cancer Clinical Trial

— BOLERO-1  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00876395
• Other study ID #: CRAD001J2301
• Secondary ID: 2008-006556-21
• Status: Completed
• Phase: Phase 3
• Start date: September 10, 2009
• Est. completion date: October 23, 2017

Study information

• Verified date: December 2018
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 719
• Est. completion date: October 23, 2017
• Est. primary completion date: May 30, 2014
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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,

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• Everolimus
Everolimus was administered in a continuous oral daily dosing of 10 mg (two 5-mg tablets).
• Placebo
Everolimus placebo was administered in a continuous oral daily dosing of 10 mg (two 5-mg tablets).
• Trastuzumab
Trastuzumab, 2 mg/kg weekly was used intravenously.
• Paclitaxel
Paclitaxel, 80 mg/m2 weekly was used intravenously.

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Caba	Buenos Aires
Argentina	Novartis Investigative Site	Capital Federal
Argentina	Novartis Investigative Site	Cordoba
Argentina	Novartis Investigative Site	Mar del Plata	Buenos Aires
Argentina	Novartis Investigative Site	Posadas	Misiones
Argentina	Novartis Investigative Site	Rio Negro	Viedma
Argentina	Novartis Investigative Site	Rosario	Sante Fe
Australia	Novartis Investigative Site	East Bentleigh	Victoria
Australia	Novartis Investigative Site	Southport	Queensland
Belgium	Novartis Investigative Site	Charleroi
Belgium	Novartis Investigative Site	Hasselt
Belgium	Novartis Investigative Site	Verviers
Belgium	Novartis Investigative Site	Wilrijk
Belgium	Novartis Investigative Site	Yvoir
Brazil	Novartis Investigative Site	Belo Horizonte	MG
Brazil	Novartis Investigative Site	Belo Horizonte	MG
Brazil	Novartis Investigative Site	Rio de Janeiro	RJ
Brazil	Novartis Investigative Site	Sao Paulo	SP
Brazil	Novartis Investigative Site	São Paulo	SP
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	St-Jerome	Quebec
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Guangzhou
China	Novartis Investigative Site	Guangzhou	Guangdong
China	Novartis Investigative Site	Hangzhou	Zhejiang
China	Novartis Investigative Site	Harbin	Heilongjiang
China	Novartis Investigative Site	Nanjing	Jiangsu
China	Novartis Investigative Site	Nanjing	Jiangsu
China	Novartis Investigative Site	Shanghai	Shanghai
China	Novartis Investigative Site	Shanghai
Colombia	Novartis Investigative Site	Bogota	Cundinamarca
Colombia	Novartis Investigative Site	Bogota
Colombia	Novartis Investigative Site	Florida Blanca
Colombia	Novartis Investigative Site	Monteria
Egypt	Novartis Investigative Site	Alexandria
Egypt	Novartis Investigative Site	Cairo
France	Novartis Investigative Site	Limoges
France	Novartis Investigative Site	Rouen
France	Novartis Investigative Site	Saint-Herblain Cédex
France	Novartis Investigative Site	Strasbourg Cedex
France	Novartis Investigative Site	Thonon-les-Bains Cedex
France	Novartis Investigative Site	Toulouse Cedex 9
France	Novartis Investigative Site	Villejuif Cedex
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Chemnitz
Germany	Novartis Investigative Site	Esslingen
Germany	Novartis Investigative Site	Kiel
Germany	Novartis Investigative Site	Muenster
Greece	Novartis Investigative Site	Athens	GR
Greece	Novartis Investigative Site	Athens
Greece	Novartis Investigative Site	Athens
Greece	Novartis Investigative Site	Heraklion Crete
Greece	Novartis Investigative Site	Thessaloniki	GR
Hong Kong	Novartis Investigative Site	Hong Kong SAR
Hong Kong	Novartis Investigative Site	Shatin, New Territories
Hong Kong	Novartis Investigative Site	Tuen Mun
Ireland	Novartis Investigative Site	Dublin 4
Ireland	Novartis Investigative Site	Dublin 8
Ireland	Novartis Investigative Site	Dublin 9
Ireland	Novartis Investigative Site	Wilton	Cork
Italy	Novartis Investigative Site	Camposampiero	PD
Italy	Novartis Investigative Site	Modena	MO
Italy	Novartis Investigative Site	Monza	MB
Italy	Novartis Investigative Site	Napoli
Italy	Novartis Investigative Site	Roma	RM
Japan	Novartis Investigative Site	Bunkyo-ku	Tokyo
Japan	Novartis Investigative Site	Chuo-ku	Tokyo
Japan	Novartis Investigative Site	Fukuoka-city	Fukuoka
Japan	Novartis Investigative Site	Isehara-city	Kanagawa
Japan	Novartis Investigative Site	Kashiwa	Chiba
Japan	Novartis Investigative Site	Kitaadachi-gun	Saitama
Japan	Novartis Investigative Site	Kitakyushu	Fukuoka
Japan	Novartis Investigative Site	Kumamoto City	Kumamoto
Japan	Novartis Investigative Site	Maebashi city	Gunma
Japan	Novartis Investigative Site	Nagoya	Aichi
Japan	Novartis Investigative Site	Osaka
Japan	Novartis Investigative Site	Osaka-city	Osaka
Japan	Novartis Investigative Site	Sakyo-ku	Kyoto
Japan	Novartis Investigative Site	Sapporo city	Hokkaido
Japan	Novartis Investigative Site	Suita-city	Osaka
Korea, Republic of	Novartis Investigative Site	Gyeonggi-do	Korea
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Korea, Republic of	Novartis Investigative Site	Seoul
Korea, Republic of	Novartis Investigative Site	Seoul
Lebanon	Novartis Investigative Site	Ashrafieh
Lebanon	Novartis Investigative Site	Beirut
Mexico	Novartis Investigative Site	Ciudad De Mexico	Distrito Federal
Mexico	Novartis Investigative Site	Zaragoza	Veracruz
Peru	Novartis Investigative Site	San Borja	Lima
Peru	Novartis Investigative Site	Surquillo	Lima
Puerto Rico	San Juan VA Hospital San Juan Hospital	San Juan
Russian Federation	Novartis Investigative Site	Kazan	Tatarstan Republic
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	Moscow
Russian Federation	Novartis Investigative Site	St Petersburg
Russian Federation	Novartis Investigative Site	St. Petersburg
South Africa	Novartis Investigative Site	Bloemfontein
South Africa	Novartis Investigative Site	Durban
South Africa	Novartis Investigative Site	Pretoria
Switzerland	Novartis Investigative Site	Genève
Switzerland	Novartis Investigative Site	Zuerich
Taiwan	Novartis Investigative Site	Kaohsiung
Taiwan	Novartis Investigative Site	Taichung
Taiwan	Novartis Investigative Site	Taipei
Taiwan	Novartis Investigative Site	Taipei	Taiwan, ROC
Taiwan	Novartis Investigative Site	Taoyuan
Turkey	Novartis Investigative Site	Altunizade
Turkey	Novartis Investigative Site	Ankara
Turkey	Novartis Investigative Site	Izmir
Turkey	Novartis Investigative Site	Izmir
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	Sutton
United Kingdom	Novartis Investigative Site	Truro	Cornwall
United States	New York Oncology Hematology NYOH Amsterdam	Albany	New York
United States	Comprehensive Blood and Cancer Center Dept. of CBCC (2)	Bakersfield	California
United States	Ironwood Cancer and Research Centers	Chandler	Arizona
United States	Texas Oncology Charles A. Sammons Cancer Ctr	Dallas	Texas
United States	Texas Oncology P A SC-Austin	Dallas	Texas
United States	Highlands Oncology Group	Fayetteville	Arkansas
United States	Florida Cancer Specialists Dept.of FloridaCancerSpec. (2)	Fort Myers	Florida
United States	St. Jude Heritage Medical Group Virginia Crosson Cancer Center	Fullerton	California
United States	Rocky Mountain Cancer Centers RMCC - Denver-Midtown (3)	Greenwood Village	Colorado
United States	Central Indiana Cancer Centers CICC - East (3)	Indianapolis	Indiana
United States	University of California at Los Angeles Dept. of UCLA	Los Angeles	California
United States	University of South Alabama / Mitchell Cancer Institute Dept. of Mitchell Cancer Inst.	Mobile	Alabama
United States	Sarah Cannon Research Institute Dept.ofSarahCannonCancerCtr(5)	Nashville	Tennessee
United States	Beth Israel Medical Center Dept.ofBeth Israel Med. Ctr(2)	New York	New York
United States	Virginia Oncology Associates SC	Norfolk	Virginia
United States	University of Nebraska Medical Center Unv Nebraska Med Ctr (2)	Omaha	Nebraska
United States	Kansas City Cancer Center Dept. of KCCC	Overland Park	Kansas
United States	Ventura County Hematology and Oncology	Oxnard	California
United States	Northwest Cancer Specialists Vancouver Cancer Center (3)	Portland	Oregon
United States	Cancer Care Associates Medical Group Dept. of CCA	Redondo Beach	California
United States	Virginia Cancer Institute VCI (3)	Richmond	Virginia
United States	Santa Barbara Hematolgy Oncology Medical Group Dept.ofSantaBarbaraHem/Onc	Santa Barbara	California
United States	Central Coast Medical Oncology Corporation Onc Dept	Santa Maria	California
United States	Tyler Cancer Center Dept.ofTylerCancerCtr. (2)	Tyler	Texas
United States	Florida Cancer Specialists	West Palm Beach	Florida
Venezuela	Novartis Investigative Site	Valencia	Estado Carabobo

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Venezuela,  Argentina,  Australia,  Belgium,  Brazil,  Canada,  China,  Colombia,  Egypt,  France,  Germany,  Greece,  Hong Kong,  Ireland,  Italy,  Japan,  Korea, Republic of,  Lebanon,  Mexico,  Peru,  Puerto Rico,  Russian Federation,  South Africa,  Switzerland,  Taiwan,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free Survival (PFS) Per Investigators' Assessment Based on Local Radiology Review - Full Population	PFS is defined as the time from the date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first. This was assessed in the full patient population.	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
Primary	Progression-free Survival (PFS) Per Investigators' Assessment Based on Local Radiology Review - (Hormone Receptor (HR)-Negative Population	PFS is defined as the time from the date of randomization to the date of first documented tumor progression or death from any cause, whichever occurs first. This was assessed in the HR-negative patient population.	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	Overall Survival (OS) - Full Population	OS is defined as the time from date of randomization to the date of death due to any cause. For patients with documented progression, survival follow up was performed either by telephone or clinic visit at least every 3 months. Additional survival updates were requested prior to interim or final analysis or prior to providing data to the health authorities. This was assessed in the full patient population.	up to about 76 months
Secondary	Overall Survival (OS) - HR-negative Population	OS is defined as the time from date of randomization to the date of death due to any cause. For patients with documented progression, survival follow up was performed either by telephone or clinic visit at least every 3 months. Additional survival updates were requested prior to interim or final analysis or prior to providing data to the health authorities. This was assessed in the HR-negative patient population.	up to about 76 months
Secondary	Overall Response Rate (ORR) - Full Population	ORR is defined as the percentage of participants whose best overall response is either complete response (CR) or partial response (PR) according to RECIST. This was assessed in the full patient population. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.	up to about 23 months
Secondary	Overall Response Rate (ORR) - HR-negative Population	ORR is defined as the percentage of participants whose best overall response is either complete response (CR) or partial response (PR) according to RECIST. This was assessed in a subset of patients with Hormone Receptor Negative disease. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.	up to about 23 months
Secondary	Clinical Benefit Rate (CBR) Equal to or Greater Than 24 Weeks - Full Population	CBR is defined as the percentage of participants whose best overall response is either complete response (CR), a partial response (PR) or stable disease (SD) lasting for at least 24 weeks, according to RECIST. This was assessed in the full patient population. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.	up to about 23 months
Secondary	Clinical Benefit Rate (CBR) Equal to or Greater Than 24 Weeks - HR-negative Population	CBR is defined as the percentage of participants whose best overall response is either complete response (CR), a partial response (PR) or stable disease (SD) lasting for at least 24 weeks, according to RECIST. This was assessed in a subset of patients with Hormone Receptor Negative disease. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.	up to about 23 months
Secondary	Time to Overall Response Based on Investigator - Full Population	Time to overall response defined as the time between date of randomization until first documented response Complete reseponse (CR) or partial response (PR) ), according to RECIST. This was assessed in the full patient population and in a subset of patients with Hormone Receptor Negative disease. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.	up to about 23 months
Secondary	Time to Overall Response Based on Investigator - HR-negative Population	Time to overall response defined as the time between date of randomization until first documented response Complete reseponse (CR) or partial response (PR) ), according to RECIST. This was assessed in the full patient population and in a subset of patients with Hormone Receptor Negative disease. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.	up to about 23 months
Secondary	Overall Response (OR) - Full Population	OR applies only to patients whose best OR was CR or PR. Start date = date of first documented response (CR or PR) and end date = date of documented response (CR or PR) and end date = date of event defined as the first documented progression or death due to underlying cause. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.	up to about 23 months
Secondary	Overall Response (OR) - HR-negative Population	OR applies only to patients whose best OR was CR or PR. Start date = date of first documented response (CR or PR) and end date = date of documented response (CR or PR) and end date = date of event defined as the first documented progression or death due to underlying cause. This was assessed in the HR-negative patient population. Complete response is achieved when all lesions evaluated at Baseline are absent at subsequent visit.	up to about 23 months
Secondary	Everolimus Blood Level Concentrations at Steady States for Everolimus	Blood levels at steady states for everolimus 10 mg/day and 5 mg/day. Only valid samples are included. Some patients had dose reduction to 5 mg daily dose therefore the everolimus blood concentration for them have been summarized separately. Cycle = 28 days	predose, 2 hours post-dose at Cycle 2/Day 1, Cycle 2/Day 15, Cycle 2/ Day 22
Secondary	Paclitaxel Plasma Concentrations	Blood levels at steady states for everolimus/placebo	Cycle 2/Day 15 (Pre-infusion and end of infusion)
Secondary	Trastuzumab Serum Concentrations	Blood levels at steady states for everolimus/placebo	Cycle 4/Day 1 (Pre-infusion and end of infusion)
Secondary	Time to Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Score - Full Population	Time to definitive deterioration of the ECOG PS by one category of the score from baseline will be performed. Baseline is the last available assessment on or before randomization date. A deterioration is considered definitive if no improvements in the ECOG PS status is observed at a subsequent time of measurement during the treatment period following the time point where the deterioration is observed.	up to about 56 months
Secondary	Time to Deterioration of Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Score - HR-negative Population	Time to definitive deterioration of the ECOG PS by one category of the score from baseline will be performed. Baseline is the last available assessment on or before randomization date. A deterioration is considered definitive if no improvements in the ECOG PS status is observed at a subsequent time of measurement during the treatment period following the time point where the deterioration is observed.	up to about 56 months

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