Study To Evaluate the Efficacy and Safety Of Bevacizumab, and Associated Biomarkers, In Combination With Paclitaxel Compared With Paclitaxel Plus Placebo as First-line Treatment Of Patients With Her2-Negative Metastatic Breast Cancer

Metastatic Breast Cancer Clinical Trial

Official title:

A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study To Evaluate the Efficacy and Safety Of Bevacizumab, and Associated Biomarkers, In Combination With Paclitaxel Compared With Paclitaxel Plus Placebo as First-line Treatment Of Patients With Her2-Negative Metastatic Breast Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01663727
• Other study ID #: GO25632
• Secondary ID: 2011-005335-97
• Status: Completed
• Phase: Phase 3
• Start date: August 27, 2012
• Est. completion date: November 21, 2017

Study information

• Verified date: January 2019
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a Phase III, randomized, double-blind, placebo-controlled multicenter study to evaluate the efficacy and safety of bevacizumab administered in combination with paclitaxel in patients with previously untreated, locally recurrent, or metastatic HER2-negative breast cancer. Patients will be randomized to one of two treatment arms: bevacizumab or placebo. All patients will be given an intravenous (IV) infusion of of paclitaxel (90 mg/m2) for 3 weeks during each 28-day cycle. bevacizumab or placebo (10 mg/kg) will be administered by IV infusion on Days 1 and 15 of each 28-day cycle. Patients will be treated until disease progression, unacceptable toxicity or death from any cause occurs.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 481
• Est. completion date: November 21, 2017
• Est. primary completion date: November 30, 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically or cytologically confirmed, HER2-negative adenocarcinoma of the breast, with measurable or non-measurable locally recurrent or metastatic disease. Locally recurrent disease must not be amenable to resection with curative intent.

• ECOG performance status of 0 or 1

• For women of childbearing potential, use of an acceptable and effective method of non-hormonal contraception

• For patients who have received recent radiotherapy, recovery prior to randomization from any significant acute toxicity, and radiation treatments have to be completed more than 3 weeks from randomization

Exclusion Criteria:

Disease-Specific Exclusions:

• HER2-positive status

• Prior chemotherapy for locally recurrent or metastatic disease

• Prior hormonal therapy < 2 weeks prior to randomization

• Prior adjuvant or neo-adjuvant chemotherapy is allowed, provided its conclusion has been for at least 12 months prior to randomization

• Investigational therapy within 28 days of randomization

General Medical Exclusions:

• Life expectancy of < 12 weeks

• Inadequate organ function

• Uncontrolled serious medical or psychiatric illness

• Active infection requiring intravenous (IV) antibiotics at screening

• Pregnancy or lactation

• History of other malignancies within 5 years prior to screening, except for tumors with a negligible risk for metastasis or death

Related Conditions & MeSH terms

• Breast Neoplasms
• Metastatic Breast Cancer

Intervention

Drug:
• Bevacizumab [Avastin]
Intravenous repeating dose
• Paclitaxel
Intravenous repeating dose
• Placebo
Intravenous repeating dose

Locations

Country	Name	City	State
Argentina	Hospital Britanico de Buenos Aires	Ciudad Autonoma Buenos Aires
Argentina	Centro Oncologico Riojano Integral (CORI)	La Rioja
Argentina	Centro de Investigacion Pergamino SA	Pergamino
Argentina	Instituto de Investigaciones Clínicas Quilmes	Quilmes
Argentina	Hospital Provincial del Centenario	Rosario
Argentina	Instituto CAICI	Rosario
Argentina	Instituto de Oncología de Rosario	Rosario
Argentina	Sanatorio Parque S.A.	Rosario, Santa FE
Argentina	ISIS Clinica Especializada	Santa Fe
Belgium	AZ KLINA	Brasschaat
Belgium	UZ Brussel	Brussel
Belgium	UZ Antwerpen	Edegem
Belgium	GHdC Site Saint-Joseph	Gilly (Charleroi)
Belgium	CHU Ambroise Paré; Hematology and Oncology Department	Mons
Brazil	Clinica de Tratamento e Pesquisa Oncologica - Oncotek	Brasilia	DF
Brazil	Centro de Pesquisas Oncologicas - CEPON	Florianopolis	SC
Brazil	Clinica de Neoplasias Litoral	Itajai	SC
Brazil	Hospital da Cidade de Passo Fundo; Centro de Pesquisa em Oncologia	Passo Fundo	RS
Brazil	Clinica de Oncologia de Porto Alegre - CliniOnco	Porto Alegre	RS
Brazil	Hospital Nossa Senhora da Conceicao	Porto Alegre	RS
Brazil	Hospital Sao Lucas - PUCRS; Pesquisa Clinica	Porto Alegre	RS
Brazil	Hospital das Clinicas - FMUSP Ribeirao Preto	Ribeirao Preto	SP
Brazil	Universidade Federal de Sao Paulo - UNIFESP	Sao Paulo	SP
Bulgaria	MHAT Dr. Tota Venkova AD	Gabrovo
Bulgaria	SHATOD Haskovo EOOD	Haskovo
Bulgaria	Complex Oncological Center - Plovdiv, EOOD	Plovdiv
Bulgaria	Complex Oncological Center - Shumen, EOOD; Department of Chemotherapy	Shumen
Bulgaria	MHAT Serdika, EOOD	Sofia
Bulgaria	SHATOD - Sofia City, EOOD	Sofia
Bulgaria	SHATOD - Sofia District, EOOD	Sofia
Bulgaria	UMHAT Tsaritsa Yoanna - ISUL, EAD	Sofia
Bulgaria	SHATOD Dr. Marko Antonov Markov-Varna, EOOD	Varna
Bulgaria	COC - Veliko Tarnovo	Veliko Tarnovo
Chile	Centro de Estudios Oncologicos de Santiago (CEOS) Oncologia	Santiago
Chile	Fundacion Arturo Lopez Perez	Santiago
Chile	Instituto Nacional del Cancer	Santiago
Chile	Instituto Oncologico Ltda.	Viña del Mar
Germany	Studienzentrum Aschaffenburg	Aschaffenburg
Germany	St. Johannes Hospital; Klinik fuer innere Medizin II, Onkologie, Haematologie	Dortmund
Germany	Wilhelm-Anton-Hospital gGmbH	Goch
Germany	Universitätsklinikum Heidelberg	Heidelberg
Germany	St. Elisabeth-Krankenhaus	Köln
Germany	Universitaetsklinikum Ulm	Ulm
Italy	Ospedale Mater Salutis	Legnago (VR)	Lombardia
Italy	Ospedale Versilia	Lido Di Camaiore	Toscana
Italy	Ospedale San Raffaele	Milano	Lombardia
Italy	Azienda Ospedaliera A. Cardarelli	Napoli	Campania
Italy	Fondazione Salvatore Maugeri IRCCS	Pavia	Lombardia
Italy	Ospedale degli Infermi	Rimini	Emilia-Romagna
Italy	Ospedale Casa Sollievo Della Sofferenza IRCCS	San Giovanni Rotondo	Puglia
Japan	NHO Shikoku Cancer Center; Dept of Respiratory Medicine	Ehime
Japan	NHO Kyushu Cancer Center	Fukuoka
Japan	Gifu University Hospital	Gifu
Japan	Hiroshima University Hospital	Hiroshima
Japan	Hyogo College of Medicine Hospital	Hyogo
Japan	Iwate Medical University Hospital	Iwate
Japan	Hakuaikai Sagara Hospital	Kagoshima
Japan	Tokai University Hospital	Kanagawa
Japan	Kumamoto City Hospital	Kumamoto
Japan	Kumamoto University Hospital	Kumamoto
Japan	Tohoku University Hospital	Miyagi
Japan	Niigata Cancer Center Hospital	Niigata
Japan	Kindai University Hospital	Osaka
Japan	NHO Osaka National Hospital	Osaka
Japan	Osaka International Cancer Institute	Osaka
Japan	NHO Hokkaido Cancer Center	Sapporo-shi
Japan	Shizuoka General Hospital	Shizuoka-shi
Japan	Juntendo University Hospital	Tokyo
Japan	Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital	Tokyo
Japan	Toranomon Hospital	Tokyo
Korea, Republic of	National Cancer Centre	Gyeonggi-do
Korea, Republic of	Seoul National University Bundang Hospital	Gyeonggi-do
Korea, Republic of	Asan Medical Center.	Seoul
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital, Yonsei University Health System; Pharmacy	Seoul
Panama	Centro Hemato Oncologico Panama	Panama
Panama	Medical Research Centre	Panama
Romania	Institutul Oncologic "Prof. Dr. Al. Trestioreanu"	Bucuresti
Romania	Institutul Oncologic Prof. Dr. Ion Chiricuta Cluj-Napoca; Radioterapie I - Oncologie	Cluj-Napoca
Romania	Medisprof SRL	Cluj-Napoca
Romania	Oncomed SRL	Timisoara
Russian Federation	CTPI Chernihiv Regional Oncological Dispensary	Chernihiv
Russian Federation	SHI Republican Clinical Oncological Dispensary of HM RT	Kazan
Russian Federation	Regional Clinical Oncology Dispensary	Krasnodar
Russian Federation	FSBSI "Russian Oncological Scientific Center n.a. N.N. Blokhin"	Moscow
Russian Federation	City Clinical Oncology Dispensary	Saint-Petersburg
Russian Federation	FBI "Scientific Research Institute of Oncology n. a. N. N. Petrov"	Saint-Petersburg
Russian Federation	SBEIHPE SSMU n.a. I.P.Pavlov of MOH and SD of RF	Saint-Petersburg
Russian Federation	Samara Regional Oncology Dispensary	Samara
Russian Federation	Non-state Healthcare Institution "Road Clinical Hospital of JSC Russian Railways"	St. Petersburg
South Africa	National Hospital; Oncotherapy Dept	Bloemfontein
South Africa	Cape Town Oncology Trials	Cape Town
South Africa	Hopelands Cancer Centre Durban	Durban
South Africa	Mary Potter Oncology Centre	Groenkloof
South Africa	Hopelands Cancer Centre	Hilton
South Africa	Cancercare	Port Elizabeth
South Africa	University of Pretoria; Department of Medical Oncology	Pretoria
Ukraine	CI Cherkasy Regional Oncological Dispensary of Cherkasy RC RC of Clinical Oncology	Cherkassy
Ukraine	CI Dnipropetrovsk CMCH 4 of Dnipropetrovsk RC Dept of Chemotherapy SI Dnipropetrovsk MA of MOHU	Dnipropetrovsk
Ukraine	CCTPI Donetsk Regional Antitumor Center	Donetsk
Ukraine	Kyiv ?ity Clinical Oncological Center	Kyiv
Ukraine	Medical and Prophylactic Institution Volyn Regional Oncological Dispensary	Lutsk
Ukraine	Lviv State Oncological Regional Treatment and Diagnostic Center	Lviv
Ukraine	RCI Sumy Regional Clinical Oncological Dispensary	Sumy
Ukraine	CCCH City Oncological Center SHEI Uzhgorod NU	Uzhgorod
United Kingdom	Velindre Cancer Centre	Cardiff
United Kingdom	Western General Hospital	Edinburgh
United Kingdom	Royal Devon and Exeter Hospital (Wonford)	Exeter
United Kingdom	Mount Vernon Hospital	Middlesex
United Kingdom	Peterborough City Hospital	Peterborough
United Kingdom	Derriford Hospital; Clinical Neurology Research Group	Plymouth
United States	Virginia Cancer Specialists - Alexandria	Alexandria	Virginia
United States	Fairfax Northern Virginia Hematology-Oncology PC	Arlington	Virginia
United States	Northeast Georgia Cancer Care LLC	Athens	Georgia
United States	Peachtree Hematology & Oncology Consultants, Pc	Atlanta	Georgia
United States	Greater Baltimore Medical Center	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Wellmonth Physician Services	Bristol	Virginia
United States	Lahey Clinic Inc. - PARENT ACCOUNT	Burlington	Massachusetts
United States	Medical University of South Carolina; Division of Hematology-Oncology	Charleston	South Carolina
United States	Virginia Oncology Associates - Chesapeake	Chesapeake	Virginia
United States	Oncology & Hematology Associates of SW Va Inc. - Market Street	Christiansburg	Virginia
United States	Maryland Oncology Hematology, P.A.	Columbia	Maryland
United States	Missouri Cancer Associates	Columbia	Missouri
United States	Wilshire Oncology Medical Group	Corona	California
United States	Texas Oncology, P.A. - Dallas Presbyterian	Dallas	Texas
United States	Texas Oncology-Medical City Dallas	Dallas	Texas
United States	Sylvester Comprehensive Cancer Center - Deerfield Beach; Sylvester Cancer Center	Deerfield Beach	Florida
United States	Virginia Cancer Specialists, PC	Fairfax	Virginia
United States	Florida Cancer Specialists - Broadway	Fort Myers	Florida
United States	Texas Oncology, P.A. - Fort Worth	Fort Worth	Texas
United States	Texas Oncology- Southwest Fort Worth	Fort Worth	Texas
United States	Hematology Oncology Associates of Fredericksburg, Inc.	Fredericksburg	Virginia
United States	Virginia Cancer Specialists - Gainsville	Gainesville	Virginia
United States	Univ of Texas Medical Branch	Galveston	Texas
United States	Texas Oncology, P.A. - Garland	Garland	Texas
United States	Wilshire Oncology Medical Group	Glendora	California
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Virginia Oncology Associates - Hampton	Hampton	Virginia
United States	Kaiser Foundation Hospital; Dr. Eron's Office	Honolulu	Hawaii
United States	IU Cancer Pavilion	Indianapolis	Indiana
United States	Cancer Care Centers of S Texas	Kerrville	Texas
United States	Wilshire Oncology Medical Group	La Verne	California
United States	Virginia Cancer Specialists - Leesburg	Leesburg	Pennsylvania
United States	Long Beach Memorial Medical Center; Oncology	Long Beach	California
United States	Texas Oncology- Longview Cancer Center	Longview	Texas
United States	Oncology and Hematology Assoc. of SW VA, Inc. - Low Moor	Low Moor	Virginia
United States	Texas Oncology, P.A. - McAllen; South Texas Cancer Center-McAllen	McAllen	Texas
United States	Signal Point Clinical; Research Center, LLC	Middletown	Ohio
United States	West Virginia University; Endocrinology	Morgantown	West Virginia
United States	SCRI-Tennessee Oncology	Nashville	Tennessee
United States	The Jones Clinic, PC	New Albany	Mississippi
United States	Virginia Oncology Associates - New Port News	Newport News	Virginia
United States	Virginia Oncology Associates	Norfolk	Virginia
United States	Tenet Health System Desert Inc	Palm Springs	California
United States	Pennsylvania Oncology Hematology Associates, Inc.; PA Oncology & Hematology	Philadelphia	Pennsylvania
United States	Texas Oncology Plano West	Plano	Texas
United States	BRCR Medical Center, Inc.	Plantation	Florida
United States	Wilshire Oncology Medical Group; Oncology	Pomona	California
United States	Hematology Oncology Associates of the Treasure Coast	Port Saint Lucie	Florida
United States	Wilshire Oncology Medical Group	Rancho Cucamonga	California
United States	Oncology & Hematolgy Associates of SW Va Inc. - Roanoke	Roanoke	Virginia
United States	Washington University; Center for Adv Medicine	Saint Louis	Missouri
United States	Oncology and Hematology Assoc. of SW VA, Inc.	Salem	Virginia
United States	Cancer Care Centers of South Texas	San Antonio	Texas
United States	Cancer Care Centers of South Texas	San Antonio	Texas
United States	CancerCare Centers of South Texas	San Antonio	Texas
United States	ProMedica Hickman Cancer Center at Flower Hospital; Hickman Cancer Center	Sylvania	Ohio
United States	Northwest Medical Specialties, PLLC; Research Department	Tacoma	Washington
United States	Texas Oncology, P.A.	The Woodlands	Texas
United States	Texas Oncology, P.A. - Tyler	The Woodlands	Texas
United States	University of Toledo; Dept. of Medicine	Toledo	Ohio
United States	Arizona Cancer Center	Tucson	Arizona
United States	Virginia Oncology Associates - Virginia Beach	Virginia Beach	Virginia
United States	Washington Hospital	Washington	District of Columbia
United States	Wilshire Oncology Medical Group	West Covina	California
United States	Oncology and Hematology Assoc. of SW VA, Inc. - Wytheville	Wytheville	Virginia

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Argentina,  Belgium,  Brazil,  Bulgaria,  Chile,  Germany,  Italy,  Japan,  Korea, Republic of,  Panama,  Romania,  Russian Federation,  South Africa,  Ukraine,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Progression or Death in Intent-to-Treat (ITT) Population	Tumor assessment was performed as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by investigator. Disease progression was defined as at least 20 percent (%) increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 millimeter (mm), unequivocal progression of existing non-target lesions, or presence of new lesions.	Baseline, every 8 weeks until documented disease progression, death or clinical cut-off (up to 117.7 weeks)
Primary	Progression Free Survival (PFS) in ITT Population	PFS was defined as the interval between the date of randomization and the first documentation of progressive disease or death from any cause. Tumor assessment was performed as per RECIST v1.1 by investigator. Disease progression was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, unequivocal progression of existing non-target lesions, or presence of new lesions. PFS was estimated using Kaplan Meier method.	Baseline, every 8 weeks until documented disease progression, death or clinical cut-off (up to 117.7 weeks)
Primary	Percentage of Participants With Progression or Death in High Baseline Plasma Vascular Endothelial Growth Factor-A (VEGF-A) ITT Population	Tumor assessment was performed as per RECIST v1.1 by investigator. Disease progression was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, unequivocal progression of existing non-target lesions, or presence of new lesions.	Baseline, every 8 weeks until documented disease progression, death or clinical cut-off (up to 111.3 weeks)
Primary	PFS in High Baseline Plasma VEGF-A ITT Population	PFS was defined as the interval between the date of randomization and the first documentation of progressive disease or death from any cause. Tumor assessment was performed as per RECIST v1.1 by investigator. Disease progression was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, unequivocal progression of existing non-target lesions, or presence of new lesions. PFS was estimated using Kaplan Meier method.	Baseline, every 8 weeks until documented disease progression, death or clinical cut-off (up to 111.3 weeks)
Secondary	Percentage of Participants Who Died - ITT Population		From randomization till death or clinical cut-off (up to 244 weeks)
Secondary	Overall Survival (OS) - ITT Population	OS was defined as the interval between the date of randomization and death from any cause. OS was estimated using Kaplan Meier method.	From randomization till death or clinical cut-off (up to 244 weeks)
Secondary	Percentage of Participants Who Died - High Baseline Plasma VEGF-A ITT Population		From randomization till death or clinical cut-off (up to 244 weeks)
Secondary	OS - High Baseline Plasma VEGF-A ITT Population	OS was defined as the interval between the date of randomization and death from any cause. OS was estimated using Kaplan Meier method.	From randomization till death or clinical cut-off (up to 244 weeks)
Secondary	Percentage of Participants With an Objective Response - ITT Population	Objective response was defined as having a Complete Response (CR) or Partial Response (PR) according to a RECIST criteria v 1.1. CR was defined as disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to <10 mm in short axis and normalization of tumor marker level. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesions, and no new lesions. Measurable disease was defined by the presence of at least one measurable lesion by clinical measurement, chest x-ray, computed tomography (CT), or magnetic resonance imaging (MRI).	Baseline, every 8 weeks until documented disease progression, death or clinical cut-off (up to 117.7 weeks)
Secondary	Percentage of Participants With an Objective Response - High Baseline Plasma VEGF-A ITT Population	Objective response was defined as having a CR or PR according to a RECIST criteria v 1.1. CR was defined as disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to <10 mm in short axis and normalization of tumor marker level. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesions, and no new lesions. Measurable disease was defined by the presence of at least one measurable lesion by clinical measurement, chest x-ray, CT, or MRI.	Baseline, every 8 weeks until documented disease progression, death or clinical cut-off (up to 111.3 weeks)
Secondary	Duration of Response - ITT Population	Duration of response was defined as the time from the initial date of the objective response to documented disease progression or death (whichever occurred first). Objective response was defined as having a CR or PR according to a RECIST criteria v 1.1. CR was defined as disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to <10 mm in short axis and normalization of tumor marker level. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesions, and no new lesions. Disease progression was defined as at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, unequivocal progression of existing non-target lesions, or presence of new lesions. Analysis was performed using Kaplan Meier method.	Baseline, every 8 weeks until documented disease progression or clinical cut-off (up to 117.7 weeks)
Secondary	Duration of Response - High Baseline Plasma VEGF-A ITT Population	Duration of response was defined as the time from the initial date of the objective response to documented disease progression or death (whichever occurred first). Objective response was defined as having a CR or PR according to a RECIST criteria v 1.1. CR was defined as disappearance of all target and non-target lesions and no new lesions, all pathological lymph nodes must have decreased to <10 mm in short axis and normalization of tumor marker level. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters), no progression in non-target lesions, and no new lesions. Disease progression was defined at least 20% increase in the sum of diameters of target lesions compared to smallest sum of diameters on-study and absolute increase of at least 5 mm, unequivocal progression of existing non-target lesions, or presence of new lesions. Analysis was performed using Kaplan Meier method.	Baseline, every 8 weeks until documented disease progression or clinical cut-off (up to 111.3 weeks)
Secondary	Percentage of Participants Who Were Alive at 1 Year - ITT Population		1 year
Secondary	Secondary: Percentage of Participants Who Were Alive at 1 Year - High Baseline Plasma VEGF-A ITT Population		1 year