Everolimus in Combination With Exemestane in the Treatment of Postmenopausal Women With Estrogen Receptor Positive Locally Advanced or Metastatic Breast Cancer Who Are Refractory to Letrozole or Anastrozole

Breast Cancer Clinical Trial

— BOLERO-2  

Official title:

A Randomized Double-Blind, Placebo-Controlled Study of Everolimus in Combination With Exemestane in the Treatment of Postmenopausal Women With Estrogen Receptor Positive Locally Advanced or Metastatic Breast Cancer Who Are Refractory to Letrozole or Anastrozole

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00863655
• Other study ID #: CRAD001Y2301
• Secondary ID: 2008-008698-69
• Status: Completed
• Phase: Phase 3
• First received: March 16, 2009
• Last updated: November 25, 2015
• Start date: June 2009
• Est. completion date: December 2014

Study information

• Verified date: November 2015
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationAustralia: Department of Health and Ageing Therapeutic Goods AdministrationAustria: Agency for Health and Food SafetyBelgium: The Federal Public Service (FPS) Health, Food Chain Safety and EnvironmentBrazil: National Health Surveillance AgencyCanada: Health CanadaCzech Republic: State Institute for Drug ControlEgypt: Ministry of Health, Drug Policy and Planning CenterFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Germany: Federal Institute for Drugs and Medical DevicesHong Kong: Department of HealthHungary: National Institute of PharmacyItaly: National Institute of HealthJapan: Pharmaceuticals and Medical Devices AgencyNetherlands: Medicines Evaluation Board (MEB)New Zealand: Food Safety AuthorityNorway: Norwegian Medicines AgencyPoland: Office for Registration of Medicinal Products, Medical Devices and Biocidal ProductsSouth Korea: Korea Food and Drug Administration (KFDA)Spain: Spanish Agency of MedicinesSweden: Medical Products AgencyThailand: Food and Drug AdministrationTurkey: Ministry of HealthUnited Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial Summary

There are no treatments specifically approved after recurrence or progression on a non steroidal aromatase inhibitors (NSAI). In light of the need for new treatment options for postmenopausal women after failure of prior NSAI therapy, the purpose of this Phase III study is to compare efficacy and safety of a treatment with exemestane + everolimus to exemestane + placebo in postmenopausal women with estrogen receptor positive locally advanced or metastatic breast cancer refractory to NSAI.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 724
• Est. completion date: December 2014
• Est. primary completion date: December 2014
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Adult women (= 18 years of age) with metastatic or locally advanced breast cancer not amenable to curative treatment by surgery or radiotherapy.

• Histological or cytological confirmation of estrogen-receptor positive (ER+) breast cancer

• Postmenopausal women.

• Disease refractory to non steroidal aromatase inhibitors (NSAI),

• Radiological or clinical evidence of recurrence or progression on or after the last systemic therapy prior to randomization.

• Patients must have at least one lesion that can be accurately measured or bone lesions in the absence of measurable disease as defined above.

Exclusion Criteria:

• HER2-overexpressing patients

• Patients with only non-measurable lesions other than bone metastasis (e.g. pleural effusion, ascites etc.).

• Patients who received more than one chemotherapy line for Advanced Breast Cancer.

• Previous treatment with exemestane or mTOR inhibitors.

• Known hypersensitivity to mTOR inhibitors, e.g. sirolimus (rapamycin).

• Radiotherapy within four weeks prior to randomization

• Currently receiving hormone replacement therapy,

Other protocol-defined inclusion/exclusion criteria may apply

Study Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• Everolimus
Everolimus was formulated as tablets of 5-mg strength and was packaged into blister packs . Everolimus (two 5 mg tablets daily) were administered in a blinded manner on their respective treatment arms by continuous oral daily dosing.
• Exemestane
Exemestane 25 mg orally daily.
• Everolimus Placebo
Placebo was formulated to be indistinguishable from the everolimus tablets. Matching placebo (two tablets daily) were administered in a blinded manner on their respective treatment arms by continuous oral daily dosing.

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	Bedford Park	South Australia
Australia	Novartis Investigative Site	Nambour	Queensland
Australia	Novartis Investigative Site	Parkville	Victoria
Australia	Novartis Investigative Site	Redcliffe	Queensland
Australia	Novartis Investigative Site	Subiaco	Western Australia
Austria	Novartis Investigative Site	Innsbruck
Austria	Novartis Investigative Site	Linz
Austria	Novartis Investigative Site	Salzburg
Austria	Novartis Investigative Site	Wels
Austria	Novartis Investigative Site	Wien
Belgium	Novartis Investigative Site	Brussel
Belgium	Novartis Investigative Site	Bruxelles
Belgium	Novartis Investigative Site	Leuven
Belgium	Novartis Investigative Site	Liege
Belgium	Novartis Investigative Site	Sint-Niklaas
Belgium	Novartis Investigative Site	Wilrijk
Brazil	Novartis Investigative Site	Porto Alegre	RS
Brazil	Novartis Investigative Site	Rio de Janeiro	RJ
Brazil	Novartis Investigative Site	Salvador	BA
Brazil	Novartis Investigative Site	São Paulo	SP
Brazil	Novartis Investigative Site	Uberlândia	MG
Canada	Novartis Investigative Site	Calgary	Alberta
Canada	Novartis Investigative Site	Cambridge	Ontario
Canada	Novartis Investigative Site	Greenfield Park	Quebec
Canada	Novartis Investigative Site	Halifax	Nova Scotia
Canada	Novartis Investigative Site	London	Ontario
Canada	Novartis Investigative Site	Moncton	New Brunswick
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Newmarket	Ontario
Canada	Novartis Investigative Site	Quebec
Canada	Novartis Investigative Site	Sherbrooke	Quebec
Canada	Novartis Investigative Site	St. Catharines	Ontario
Canada	Novartis Investigative Site	Toronto	Ontario
Canada	Novartis Investigative Site	Toronto	Ontario
Canada	Novartis Investigative Site	Weston	Ontario
Czech Republic	Novartis Investigative Site	Brno
Czech Republic	Novartis Investigative Site	Olomouc	CZE
Czech Republic	Novartis Investigative Site	Praha
Egypt	Novartis Investigative Site	Alexandria
Egypt	Novartis Investigative Site	Cairo
Egypt	Novartis Investigative Site	Menoufiya
France	Novartis Investigative Site	La Roche sur Yon Cedex
France	Novartis Investigative Site	Le Mans
France	Novartis Investigative Site	Lyon Cedex
France	Novartis Investigative Site	Marseille
France	Novartis Investigative Site	Paris
France	Novartis Investigative Site	Rouen
France	Novartis Investigative Site	Rouen Cedex 1
France	Novartis Investigative Site	Saint-Herblain Cédex
France	Novartis Investigative Site	Saint-Nazaire
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Duesseldorf
Germany	Novartis Investigative Site	Frankfurt
Germany	Novartis Investigative Site	Mannheim
Germany	Novartis Investigative Site	Muenchen
Germany	Novartis Investigative Site	Muenchen
Germany	Novartis Investigative Site	Muenster
Germany	Novartis Investigative Site	Trier
Hong Kong	Novartis Investigative Site	Hong Kong SAR
Hungary	Novartis Investigative Site	Budapest
Hungary	Novartis Investigative Site	Szeged
Hungary	Novartis Investigative Site	Szolnok
Italy	Novartis Investigative Site	Antella - Bagno a Ripoli	FI
Italy	Novartis Investigative Site	Brindisi	BR
Italy	Novartis Investigative Site	Catania	CT
Italy	Novartis Investigative Site	Genova	GE
Italy	Novartis Investigative Site	Macerata	MC
Italy	Novartis Investigative Site	Perugia	PG
Italy	Novartis Investigative Site	Saronno	Va
Italy	Novartis Investigative Site	Terni	TR
Italy	Novartis Investigative Site	Torino	TO
Italy	Novartis Investigative Site	Varese	VA
Japan	Novartis Investigative Site	Bunkyo-ku	Tokyo
Japan	Novartis Investigative Site	Chuo-ku	Tokyo
Japan	Novartis Investigative Site	Chuo-ku	Tokyo
Japan	Novartis Investigative Site	Fukuoka
Japan	Novartis Investigative Site	Hidaka	Saitama
Japan	Novartis Investigative Site	Isehara-city	Kanagawa
Japan	Novartis Investigative Site	Kagoshima
Japan	Novartis Investigative Site	Kashiwa	Chiba
Japan	Novartis Investigative Site	Kitaadachi-gun	Saitama
Japan	Novartis Investigative Site	Kitakyushu	Fukuoka
Japan	Novartis Investigative Site	Koto	Tokyo
Japan	Novartis Investigative Site	Kumamoto City	Kumamoto
Japan	Novartis Investigative Site	Kyoto-city	Kyoto
Japan	Novartis Investigative Site	Maebashi-city	Gunma
Japan	Novartis Investigative Site	Matsuyama	Ehime
Japan	Novartis Investigative Site	Nagoya	Aichi
Japan	Novartis Investigative Site	Osaka
Japan	Novartis Investigative Site	Osaka
Japan	Novartis Investigative Site	Sapporo-city	Hokkaido
Japan	Novartis Investigative Site	Suita-city	Osaka
Korea, Republic of	Novartis Investigative Site	Hwasun-gun	Jeollanam-do
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Korea, Republic of	Novartis Investigative Site	Seoul
Netherlands	Novartis Investigative Site	Alkmaar
Netherlands	Novartis Investigative Site	Amsterdam
Netherlands	Novartis Investigative Site	Den Haag
Netherlands	Novartis Investigative Site	Dordrecht
Netherlands	Novartis Investigative Site	Eindhoven
Netherlands	Novartis Investigative Site	Sittard-Geleen
New Zealand	Novartis Investigative Site	Christchurch
Norway	Novartis Investigative Site	Lørenskog
Poland	Novartis Investigative Site	Krakow
Poland	Novartis Investigative Site	Rzeszow
Poland	Novartis Investigative Site	Warszawa
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	La Coruna	Galicia
Spain	Novartis Investigative Site	Lleida	Cataluna
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Malaga	Andalucia
Spain	Novartis Investigative Site	Mallorca	Islas Baleares
Spain	Novartis Investigative Site	Palma De Mallorca	Islas Baleares
Spain	Novartis Investigative Site	Santiago de Compostela	Galicia
Spain	Novartis Investigative Site	Sevilla	Andalucia
Spain	Novartis Investigative Site	Terrassa	Cataluña
Sweden	Novartis Investigative Site	Stockholm
Sweden	Novartis Investigative Site	Stockholm
Sweden	Novartis Investigative Site	Uppsala
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Bangkok
Thailand	Novartis Investigative Site	Chiang Mai
Thailand	Novartis Investigative Site	Songkla
Turkey	Novartis Investigative Site	Altunizade
Turkey	Novartis Investigative Site	Ankara
Turkey	Novartis Investigative Site	Izmir
United Kingdom	Novartis Investigative Site	Broomfield	Chelmsford
United Kingdom	Novartis Investigative Site	Cardiff
United Kingdom	Novartis Investigative Site	Nottingham
United Kingdom	Novartis Investigative Site	Sheffield
United Kingdom	Novartis Investigative Site	Southampton
United Kingdom	Novartis Investigative Site	Truro	Cornwall
United States	University of New Mexico Cancer Research Center Dept of UNM Cancer & Research	Albuquerque	New Mexico
United States	Kaiser Permanente Medical Group Kaiser Permanente-Moanalua M.C	Anaheim	California
United States	Anne Arundel Health System Research Institute Wayson Pavilion	Annapolis	Maryland
United States	Comprehensive Blood and Cancer Center Dept. of CBCC (3)	Bakersfield	California
United States	Maryland Hematology/Oncology Associates, P.A.	Baltimore	Maryland
United States	Mercy Medical Center Medical Oncology & Hematology	Baltimore	Maryland
United States	Weinberg Cancer Institute at Franklin Square Hospital	Baltimore	Maryland
United States	Hematology Oncology Clinic Hematology Oncology Clinic (2)	Baton Rouge	Louisiana
United States	Comprehensive Cancer Center - Boca Raton Deerfield Beach	Boca Raton	Florida
United States	Lahey Clinic Dept of Lahey Clinic (2)	Burlington	Massachusetts
United States	Ironwood Cancer and Research Centers	Chandler	Arizona
United States	Medical University of South Carolina -Hollings Cancer Center Dept. MUSC/HollingsCancerCtr	Charleston	South Carolina
United States	Regional Cancer Care Associates Dept. of the CCHD	Cherry Hill	New Jersey
United States	Rush University Medical Center Study Coordinator	Chicago	Illinois
United States	University of Texas Southwestern Medical Center SimmonsComprehensiveCancerCtr.	Dallas	Texas
United States	Florida Cancer Research Institute	Davie	Florida
United States	Georgia Cancer Specialists. Drug Ship	Decatur	Georgia
United States	Fairview Southdale Medical Oncology Clinic	Edina	Minnesota
United States	Trinitas Comprehensive Cancer Center Dept. of Trinitas	Elizabeth	New Jersey
United States	Highlands Oncology Group DeptofHighlandsOncologyGrp(2)	Fayetteville	Arkansas
United States	Florida Cancer Specialists DeptofFloridaCancerSpecialists	Fort Myers	Florida
United States	The Center for Cancer and Blood Disorders Dept. of The Ctr for C & BD(2)	Fort Worth	Texas
United States	Frederick Memorial Hospital Dept. of FMH-IRB	Frederick	Maryland
United States	Cancer Care Associates Dept.ofCancerCareAssoc. (2)	Fresno	California
United States	Grass Valley Hematology Oncology Medical Group Dept. of Grass Valley Hem/Onc	Grass Valley	California
United States	Penn State University / Milton S. Hershey Medical Center Division of Oncology (2)	Hershey	Pennsylvania
United States	Memorial Hospital Memorial Cancer Institute	Hollywood	Florida
United States	University of Texas/MD Anderson Cancer Center Dept.ofMDAndersonCancerCtr(2)	Houston	Texas
United States	Hematology Oncology of Indiana	Indianapolis	Indiana
United States	Scripps Clinic SC	La Jolla	California
United States	Horizon Oncology Center	Lafayette	Indiana
United States	Clinical Research Alliance Dept.ofArenaOncologyAssoc(2)	Lake Success	New York
United States	ProHealth Care	Lake Success	New York
United States	Cancer Centers of Southwest Oklahoma Cancer Research Dept.of Southwest Oklahoma	Lawton	Oklahoma
United States	Southeast Nebraska Oncology Cancer Center	Lincoln	Nebraska
United States	The Angeles Clinic and Research Institute	Los Angeles	California
United States	USC/Kenneth Norris Comprehensive Cancer Center Regulatory Contact 3	Los Angeles	California
United States	University of Louisville / James Graham Brown Cancer Center SC	Louisville	Kentucky
United States	University of Wisconsin Hospital & Clinics UW ComprehensiveCancerCtr(2)	Madison	Wisconsin
United States	Crescent City Research Consortium, LLC Dept of Hem&Onc Specialist - 2	Metairie	Louisiana
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	Weill Cornell Medical College Weill Cornell Med. Ctr.	New York	New York
United States	Hematology Oncology Association of Rockland	Nyack	New York
United States	Northern Utah Cancer Associates SC	Ogden	Utah
United States	MD Anderson Cancer Center - Orlando Dept.ofMDACC-Orlando(2)	Orlando	Florida
United States	Oncology Specialists, SC Dept.of Oncology Specialists	Park Ridge	Illinois
United States	Central Utah Clinic CRAD001Y2301	Provo	Utah
United States	Medical Oncology & Hematology Associates of Northern VA Med. Onc&Hem Assoc. of No.VA	Reston	Virginia
United States	Hope Oncology HOPE Richardson	Richardson	Texas
United States	University of Utah / Huntsman Cancer Institute Dept.ofHuntsmanCancerInst.(2)	Salt Lake City	Utah
United States	Utah Cancer Specialists Dept.of Utah Cancer Spec. (2)	Salt Lake City	Utah
United States	Sharp Memorial Hospital SharpClinicalOncologyResearch	San Diego	California
United States	University of California San Francisco UCSF Medical Center	San Francisco	California
United States	Premiere Oncology/Pinnacle Oncology Hematology Dept.ofPremiereOncologyAZ	Santa Monica	California
United States	St Joseph Heritage Healthcare Dept. of RRMG (4)	Santa Rosa	California
United States	Holy Cross Hospital Holy Cross	Silver Spring	Maryland
United States	St. Louis Cancer & Breast Institute Dept.ofSt.LouisCancer&Breast	St. Louis	Missouri
United States	Cancer Care Associates SC	Tulsa	Oklahoma
United States	Marion L. Shepard Cancer Center	Washington	North Carolina
United States	Palm Beach Cancer Institute	West Palm Beach	Florida
United States	Cancer Center of Kansas Dept.ofCancerCtr.ofKansas	Wichita	Kansas
United States	Florida Medical Clinic PA Dept.ofFloridaMedicalClinic	Zephyrhills	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Brazil,  Canada,  Czech Republic,  Egypt,  France,  Germany,  Hong Kong,  Hungary,  Italy,  Japan,  Korea, Republic of,  Netherlands,  New Zealand,  Norway,  Poland,  Spain,  Sweden,  Thailand,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free Survival (PFS) Based on Local Radiology Review of Tumor Assessments.	Tumor response was assessed using Response Evaluation Criteria in Solid Tumors (RECIST 1.0). For patients with no target lesion, in the absence of new lesions, the overall lesion response at each assessment was one of following: Complete Response CR), Stable Disease SD), Unknown, or Progressive Disease (PD) based on non-target lesion responses. The following is considered progression among patients with lytic or mixed (lytic+sclerotic) bone lesions: appearance of =1 new lytic lesions in bone; the appearance of = new lesions outside of bone and unequivocal progression of existing bone lesions.	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, 27 July 2009, until cut-off date 11 February 2011.	No
Secondary	Overall Survival (OS)	Overall survival, the key secondary endpoint in this study, is defined as the time from date of randomization to the date of death due to any cause.	Every 3 months after End of Treatment + 28 days (every 6 weeks before)	No
Secondary	Overall Response Rate (ORR)	ORR is defined as the proportion of patients whose best overall response is either complete response (CR) or partial response (PR) according to RECIST.	Every 6 weeks	No
Secondary	Incidence of Adverse Events (AEs)/Serious Adverse Events (SAEs)	In addition to AEs/SAEs, shift from baseline in vital signs and laboratory results (hematology, blood chemistry) will be reported.	Continuous and every 6 weeks	Yes
Secondary	Qol Scores ECOG Performance Status	Change in QoL scores over time and time to deterioration of ECOG performance status.	Every 6 weeks	Yes
Secondary	Clinical Benefit Rate (CBR)	CBR is defined as the proportion of patients 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.	Every 6 weeks	No

External Links

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