BETH Study: Treatment of HER2 Positive Breast Cancer With Chemotherapy Plus Trastuzumab vs Chemotherapy Plus Trastuzumab Plus Bevacizumab

Breast Cancer Clinical Trial

— BETH  

Official title:

A Multicenter Phase III Randomized Trial of Adjuvant Therapy for Patients With HER2-Positive Node-Positive or High Risk Node-Negative Breast Cancer Comparing Chemotherapy Plus Trastuzumab With Chemotherapy Plus Trastuzumab Plus Bevacizumab

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00625898
• Other study ID #: NSABP B-44-I
• Secondary ID: CIRG (TRIO) 011R
• Status: Terminated
• Phase: Phase 3
• Start date: April 2008
• Est. completion date: July 2014

Study information

• Verified date: March 2020
• Source: NSABP Foundation Inc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The trial will determine the value of adding bevacizumab to chemotherapy plus trastuzumab in patients with resected node-positive or high risk node-negative, HER2-positive breast cancer.

Description:

This Phase III, randomized, open-label trial will determine whether the regimens of chemotherapy plus trastuzumab plus bevacizumab improve invasive disease-free survival (IDFS) relative to the regimens of chemotherapy plus trastuzumab. Secondary aims include determining whether the addition of bevacizumab to chemotherapy plus trastuzumab will improve disease-free survival (DFS), overall survival (OS), recurrence-free interval (RFI), and distant recurrence-free interval (DRFI). The benefit of adding bevacizumab for IDFS, DFS, OS, RFI, and DRFI will also be evaluated for each of the two chemotherapy regimens. The cardiac and non-cardiac toxicities of each of the regimens will also be evaluated.

Following local determination that the tumor is HER2-positive for gene amplification by in situ hybridization or is IHC 2+ or 3+, a tumor sample must be submitted for HER2 testing by a designated central laboratory. If central testing confirms that the tumor is HER2-positive (either positive by FISH or IHC 3+) and all other eligibility criteria have been met, the patient will be randomized to a regimen of chemotherapy and trastuzumab with or without bevacizumab.

Patients in the trial will be enrolled in one of two chemotherapy regimen cohorts. One cohort will receive 6 cycles of docetaxel/carboplatin plus trastuzumab (TCH) with or without bevacizumab; the other cohort will receive 3 cycles of docetaxel plus trastuzumab given with or without bevacizumab followed by 3 cycles of 5-Fluorouracil, Epirubicin, Cyclophosphamide (TH-FEC). With both regimens, patients will continue trastuzumab with or without bevacizumab following chemotherapy to complete 1 year of targeted therapy. Following completion of chemotherapy, patients will also receive adjuvant radiotherapy and endocrine therapy as clinically indicated.

The trial will be conducted by investigators affiliated with the Cancer International Research Group (CIRG) and the National Surgical Adjuvant Breast and Bowel Project (NSABP). CIRG and NSABP investigators will only enroll patients in the TCH regimen cohort. Additional investigators, referred to in the protocol as Independent Investigators, will enroll patients in both the TCH regimen or the TH-FEC regimen cohort depending on institutional preference for the one regimen that will be used by that institution for the duration of the trial.

Patients will be given the option of allowing their tumor samples to be used for the BETH translational research and correlative science studies. Also, patients will be asked to consent to the submission of blood and serum samples at scheduled time points during the study.

LVEF assessments will be performed before study entry and then at scheduled time points during therapy and at 18, 36, and 60 months following randomization.

The planned sample size for the trial is 3,000 patients randomized in the faster accruing cohort and a minimum of 3,500 patients overall.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 3509
• Est. completion date: July 2014
• Est. primary completion date: June 2013
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Life expectancy of at least 10 years, excluding their diagnosis of breast cancer.

• Women who have had breast reconstruction utilizing tissue expanders must be in agreement with delaying surgery to replace the tissue expanders with permanent implants until 3 months following the last dose of bevacizumab

• Women of reproductive potential must agree to use an effective non-hormonal method of contraception (for example condoms, some intrauterine devices, diaphragms, vasectomized partner, or abstinence) during therapy and for at least 6 months after the last dose of bevacizumab and/or trastuzumab.

• Submission of tumor samples from the breast surgery for central HER2 testing is required for all patients prior to enrollment in the BETH Trial

• Signed and dated IRB/EC-approved consent

• ECOG performance status of 0 or 1

• The tumor must be unilateral invasive adenocarcinoma of the breast on histologic examination.

• The breast cancer must be HER2-positive based on test results as follows: Local testing (if available) should demonstrate that the tumor is IHC 2+ or 3+ or is considered to be HER2-positive for gene amplification by FISH, CISH, or other in situ hybridization (ISH) method. If local ISH test results are considered equivocal, the tumor can be submitted for central HER2 testing. (If local testing is not possible, the tumor can be submitted for central HER2 testing.) Central testing (a requirement for ALL patients) must demonstrate that the tumor is HER2-positive which is defined as FISH-positive and/or IHC 3+.

• All of the following staging criteria (according to the 6th edition of the AJCC Cancer Staging Manual) must be met: By pathologic evaluation, primary tumor must be pT1-3; By pathologic evaluation, ipsilateral nodes must be pN0, pN1 (pN1mi, pN1a, pN1b, pN1c), pN2a, pN3a, or pN3b. If pN0, at least one of the following criteria must be met: Pathologic tumor size > 2.0 cm; ER negative and PgR negative; Histologic and/or nuclear grade 2 (intermediate) or 3 (high); or Age < 35 years

• Patients must have undergone either a total mastectomy or breast conserving surgery (lumpectomy).

• For patients who undergo lumpectomy, the margins of the resected specimen must be histologically free of invasive tumor and ductal carcinoma in situ (DCIS) as determined by the local pathologist. If pathologic examination demonstrates tumor at the line of resection, additional operative procedures may be performed to obtain clear margins. If tumor is still present at the resected margin after re-excision(s), the patient must undergo total mastectomy to be eligible. (Patients with margins positive for lobular carcinoma in situ [LCIS] are eligible without additional resection.)

• For patients who undergo mastectomy, margins must be free of gross residual tumor. Patients with microscopic positive margins are eligible.

• Patients must have completed one of the following procedures for evaluation of pathologic nodal status: Sentinel lymphadenectomy followed by removal of additional non-sentinel lymph nodes if the sentinel node (SN) is positive; Sentinel lymphadenectomy alone if pathologic nodal staging based on sentinel lymphadenectomy is pN0, pN1mi or pN1b; or Axillary lymphadenectomy without SN isolation procedure.

• The interval between the last surgery for breast cancer (treatment or staging) and randomization must be at least 28 days but no more than 84 days.

• Patients must have ER analysis performed on the primary tumor prior to randomization. If ER analysis is negative, then PgR analysis must also be performed.

• The most recent postoperative blood counts, performed within 6 weeks prior to randomization, must meet the following criteria: ANC must be greater than or equal to 1200/mm3; Platelet count must be greater than or equal to 100,000/mm3; and Hemoglobin must be greater than or equal to 10 g/dL.

• The following criteria for evidence of adequate hepatic function must be met based on the results of the most recent postoperative tests performed within 6 weeks prior to randomization: total bilirubin must be less than or equal to upper limit of normal (ULN) for the lab unless the patient has a bilirubin elevation > ULN to 1.5 x ULN due to Gilbert's disease or similar syndrome involving slow conjugation of bilirubin; and alkaline phosphatase must be less than or equal to 2.5 x ULN for the lab; and AST must be less than or equal to 1.5 x ULN for the lab. Alkaline phosphatase and AST may not both be > the ULN.

• Patients with AST or alkaline phosphatase > ULN are eligible for inclusion in the study if liver imaging (CT, MRI, PET scan, or PET-CT scan performed within 3 months prior to randomization) does not demonstrate metastatic disease and the requirements for evidence of adequate hepatic function are met.

• Patients with alkaline phosphatase that is > ULN but less than or equal to 2.5 x ULN are eligible for inclusion in the study if a bone scan,PET scan, or PET-CT scan (performed within 3 months prior to randomization) does not demonstrate metastatic disease.

• The following criteria for renal function must be met based on the results of the most recent postoperative tests performed within 6 weeks prior to randomization: Serum creatinine must be less than or equal to ULN for the lab. Measured or calculated creatinine clearance must be > 60 mL/min.

• A urine sample must be tested for protein by determination of the urine protein/creatinine (UPC) ratio or by urine dipstick. UPC ratio must be less than 1.0. Urine dipstick must indicate 0-1+ protein. If dipstick reading is greater than or equal to 2+, determine the UPC ratio, which must be less than 1.0, or collect a 24-hour urine specimen, which must demonstrate < 1.0 g of protein per 24 hours.

• LVEF assessment must be performed within 3 months prior to randomization. The LVEF must be greater than or equal to 55% regardless of the cardiac imaging facility's lower limit of normal (LLN).

• The ECG (performed within 3 months prior to randomization) must not have demonstrated any of the following conditions: ventricular arrhythmias except for benign premature ventricular contractions; supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication; and conduction abnormality requiring a pacemaker.

Exclusion Criteria:

• Inflammatory breast cancer.

• Definitive clinical or radiologic evidence of metastatic disease. (Chest imaging [mandatory for all patients] and other imaging [if required] must have been performed within 3 months prior to randomization.)

• Synchronous or previous contralateral invasive breast cancer (Patients with synchronous or previous contralateral DCIS or LCIS are eligible).

• History of ipsilateral invasive breast cancer regardless of treatment or ipsilateral DCIS treated with excision and RT. (Patients with history of ipsilateral LCIS are eligible.)

• History of non-breast malignancies within the 5 years prior to study entry, except for the following: carcinoma in situ of the cervix, carcinoma in situ of the colon, melanoma in situ, and basal cell and squamous cell carcinomas of the skin.

• Previous therapy with anthracyclines, taxanes, carboplatin, trastuzumab, or bevacizumab for any malignancy.

• RT, chemotherapy, and/or targeted therapy, administered for the currently diagnosed breast cancer prior to randomization.

• Continued therapy with any hormonal agent such as raloxifene or tamoxifen (or other SERM) or an aromatase inhibitor. (Patients are eligible if these medications are discontinued prior to randomization.)

• Any sex hormonal therapy, e.g., birth control pills, ovarian hormone replacement therapy, etc. Patients are eligible if these medications are discontinued prior to randomization.

• Cardiac disease (history of and/or active disease) that would preclude the use of the drugs included in the treatment regimens. This includes but is not confined to: Active cardiac disease - angina pectoris that requires the use of anti-anginal medication; ventricular arrhythmias except for benign premature ventricular contractions; supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication; conduction abnormality requiring a pacemaker; valvular disease with documented compromise in cardiac function; and symptomatic pericarditis. History of cardiac disease - myocardial infarction documented by elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LV function; history of documented CHF; and documented cardiomyopathy.

• Uncontrolled hypertension defined as systolic blood pressure (BP) > 150 mmHg or diastolic BP > 90 mmHg, with or without anti-hypertensive medication. (BP must be assessed within 28 days prior to randomization.) Patients with initial BP elevations are eligible if initiation or adjustment of BP medication lowers pressure to meet entry criteria.

• History of hypertensive crisis or hypertensive encephalopathy.

• History of TIA or CVA.

• History of any arterial thrombotic event within 12 months before randomization.

• Symptomatic peripheral vascular disease.

• Intrinsic lung disease resulting in dyspnea.

• Unstable diabetes mellitus.

• Active infection or chronic infection requiring chronic suppressive antibiotics.

• Any significant bleeding within 6 months before randomization, exclusive of menorrhagia in premenopausal women.

• Non-healing wound, skin ulcers, or incompletely healed bone fracture.

• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to planned start of study therapy.

• Anticipation of need for major surgical procedures during study therapy and for at least 3 months following completion of bevacizumab.

• Gastroduodenal ulcer(s) documented by endoscopy to be active within 6 months before randomization.

• History of GI perforation, abdominal fistulae, or intra-abdominal abscess.

• Known bleeding diathesis or coagulopathy.

• Requirement for therapeutic doses of coumadin or equivalent.

• Sensory/motor neuropathy greater than or equal to grade 2, as defined by the NCI CTCAE v3.0.

• Conditions that would prohibit administration of corticosteroids.

• Chronic daily treatment with corticosteroids (dose of > 10 mg/day methylprednisolone equivalent) (excluding inhaled steroids).

• History of hypersensitivity reaction to drugs formulated with polysorbate 80.

• Pregnancy or lactation at the time of study entry. (Note: Pregnancy testing must be performed within 14 days prior to randomization according to institutional standards for women of child-bearing potential.)

• Other non-malignant systemic disease that would preclude the patient from receiving study treatment or would prevent required follow-up.

• Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements.

• Use of any investigational product within 4 weeks prior to enrollment in the study.

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• Docetaxel
75 mg/m2 IV on day 1 every 3 weeks for cycles 1-6, Arms 1A and 1B 100 mg/m2 on day 1 every 3 weeks for cycles 1-3, Arms 2A and 2B
• Trastuzumab
First dose: 8 mg/kg IV on day 1 of cycle 1 only. Subsequent doses: 6 mg/kg IV on day 1 every 3 weeks for cycles 2-6. Following completion of chemotherapy cycles: 6 mg/kg IV every 3 weeks until 1 year following first trastuzumab dose. Arms 1A and 1B First dose: 8 mg/kg IV on day 1 of cycle 1 only. Subsequent doses: 6 mg/kg IV on day 1 every 3 weeks for cycles 2-3. 21 days after last dose of FEC: 8 mg/kg IV first post-FEC dose only; subsequent doses 6 mg/kg IV every 3 weeks for a total of 1 year. Arms 2A and 2B
• Carboplatin
6 mg/ml/min IV on day 1 every 3 weeks for cycles 1-6
• Bevacizumab
15 mg/kg IV on day 1 every 3 weeks for cycles 1-6. Following completion of chemotherapy cycles: 15 mg/kg IV on day 1 every 3 weeks until 1 year following first bevacizumab dose. Arm 1B 15 mg/kg IV on day 1 every 3 weeks for cycles 1-3. 21 days after the last dose of FEC: 15 mg/kg IV on day 1 every 3 weeks until 1 year following first bevacizumab dose. Arm 2B
• 5-Fluorouracil
600 mg/m2 IV on day 1 every 3 weeks for cycles 4-6
• Epirubicin
90 mg/m2 IV on day 1 every 3 weeks for cycles 4-6
• Cyclophosphamide
600 mg/m2 IV on day 1 every 3 weeks for cycles 4-6

Locations

Country	Name	City	State
Argentina	CEMIC	Buenos Aires
Argentina	Hospital Britanico de Buenos Aires	Buenos Aires
Argentina	Hospital Universitario Austral	Derqui	Buenos Aires
Argentina	Breast Clinica de la mama	La Plata	Buenos Aires
Argentina	Centro Oncologico Rosario (COR)	Rosario	Sante Fe
Australia	Ashford Cancer Center	Ashford	South Australia
Australia	Flinders Medical Centre	Bedford	South Australia
Australia	Macarthur Cancer Center	Campbelltown	New South Wales
Australia	Frankston Hospital	Frankston	Victoria
Australia	Royal Brisbane & Women's Hospital	Herston	Queensland
Australia	St. George Hospital	Kogarah	New South Wales
Australia	Cancer Therapy Center	Liverpool	New South Wales
Australia	The Alfred Hospital	Melbourne	Victoria
Australia	Mount Medical Center	Perth	Western Australia
Australia	Mater Adult Hospital	South Brisbane	Queensland
Australia	North Shore Private Hospital	St. Leonards	New South Wales
Australia	Royal North Shore Hospital	St. Leonards	New South Wales
Australia	Berdat Family Comprehensive Cancer Centre	Subiaco	Western Australia
Australia	Southern Medical Day Care	Wollongong	New South Wales
Austria	Krankenhaus Barmherzige Brueder Graz, Medizinische Abteilung	Graz
Austria	Medizinische Universitat Graz - Onkologie	Graz
Austria	Universitatsfrauenklinik Graz	Graz
Austria	AI University Hospital Innsbruck	Innsbruck
Austria	Bezirkskrankenhaus Kufstein, Innere Medizin	Kufstein
Austria	Landeskrankenhaus Leoben, Abteilung fur Haemato-Onkologie	Leoben
Austria	Krankenhaus Barmherzige Schwestern Linz, Kooperative Studiengruppe, Chirurgie	Linz
Austria	AI Universitätsklinikum der PMU Landeskliniken	Salzburg
Austria	AKH Vienna	Vienna
Austria	Krankenhaus Hietzing, Gynaekologische Abteilung	Vienna
Austria	Medizinische Universitaet Wien-Allgemeines Krankenhaus, Onkologie	Vienna
Austria	Landeskrankenhaus Voecklabruck, 2. Medizinische Abteilung	Voecklabruck
Austria	Klinikum Wels-Grieskirchen, Kooperative Gruppe Wels/4. Medizinische Abteilung	Wels
Belgium	AZ Klina	Brasschaat
Belgium	C. H. Notre-Dame and Reine Fabiola	Charleroi
Belgium	Clinique St Pierre	Ottignies
Belgium	Medical Institute St. Augustinus	Wilrijk
Bosnia and Herzegovina	Clinical Centre University of Sarajevo	Sarajevo
Brazil	Lifecenter Sistema de Saude S/A	Belo Horizonte	MG
Brazil	Centro Goiano de oncologia	Goiania	GO
Brazil	Assoiacao hospital de caridade de ijui	Ijui	RS
Brazil	Fundacao Dr. Amaral Carvalho	Jau	SP
Brazil	Instituto de Oncologia Clinica de Piracicaba	Piracicaba	SP
Brazil	Clinica de Oncologia de Porto Alegre	Porto Alegre	RS
Brazil	Hospital Das Clinicas de Porto Alegre-HCPA	Porto Alegre	RS
Brazil	Irmandade da Santa Casa de Misericoria de Porto Alegre Nucleo de Novos Tratamentos	Porto Alegre	RS
Brazil	Clinica Oncologistas Associados	Rio de Janeiro	RJ
Brazil	Instituto Nacional de Cancer	Rio de Janeiro	RJ
Brazil	Centro de Oncologia e Hematologia da Faculdade de Medicina do ABC	Santo Andre	SP
Brazil	Instituto do Cancer de Sao Paulo	Sao Paulo	SP
Brazil	Conjunto Hospitalar de Sorocaba	Sorocaba
Bulgaria	District Oncology Dispensary Plovdiv	Plovdiv
Bulgaria	MHAT "Tsaritsa Yoanna-ISUL" EOOD	Sofia
Canada	William Osler Health Center	Brampton	Ontario
Canada	Tom Baker Cancer Centre	Calgary	Alberta
Canada	Cross Cancer Institute, Dept of Medicine	Edmonton	Alberta
Canada	Hopital Charles LeMoyne	Greenfield Park	Quebec
Canada	Credit Valley Hospital	Mississauga	Ontario
Canada	Hopital Maisonneuve Rosemont	Montreal	Quebec
Canada	Hospital du Sacre-Coeur	Montreal	Quebec
Canada	Jewish General Hospital	Montreal	Quebec
Canada	Montreal General Hospital	Montreal	Quebec
Canada	Royal Victoria Hospital	Montreal	Quebec
Canada	University of Montreal Hospital Group	Montreal	Quebec
Canada	Southlake Regional Health Centre	New Market	Ontario
Canada	Lion's Gate Hospital	North Vancouver	British Columbia
Canada	Ottawa Hospital Regional Cancer Centre	Ottawa	Ontario
Canada	Centre Hospitalier Affilie Universitaire De Quebec, Hospital du St-Sacrement	Quebec City	Quebec
Canada	Dr. H. Bliss Murphy Cancer Centre	St. Johns	Newfoundland and Labrador
Canada	St. Michaels Hospital	Toronto	Ontario
Canada	Humber River Regional Hospital	Weston	Ontario
Canada	Windsor Regional Cancer Centre	Windsor	Ontario
Chile	Hospital Regional Rancagua	Rancagua	VI Region
China	Chinese Academy of Medical Science	Beijing
China	Chinese PLA General Hospital	Beijing
China	The Pla 307 Hospital	Beijing
China	Jilin Cancer Hospital	Changchun
China	West China Hospital, Sichuan University	Chengdu
China	Fuzhou General Hospital of Nanjing Military Area	Fuzhou
China	Sun Yat-sen University Hospital	Guangzhou
China	1st Affiliated Hospital of Zhejiang University	Hangzhou
China	Zhejiang Tumor Hospital	Hangzhou
China	Tianjin Cancer Hospital	Tianjin
Croatia	University Hospital Zagreb	Zagreb
Czechia	FN Na Bulovce	Praha 8
Egypt	National Cancer Institute	Cairo
Estonia	Tartu University Hospital Clinic of Hematology and Oncology	Tartu
France	CHU D'Amiens	Amiens
France	CH-Service Hemato-Oncologie	Beauvais
France	Clinique Bordeaux Nord Aquitaine	Bordeaux
France	CHU Morvan	Brest
France	Hopital Pasteur	Colmar
France	Ch intercommunal de creteil	Creteil
France	Centre Leonard de Vinci	Dechy
France	Institut Daniel Hollard	Grenoble
France	CHD les Oudairies	La Roche sur Yon Cedex
France	CHU Dupuytren	Limoges
France	Clinique Francois Chenieux	Limoges
France	Hopital St. Joseph	Marseille
France	Centre Regional de Lutte contre le Cancer (CRLC) Val d'Aurelle	Montpellier
France	Centre Catherine de Sienne	Nantes Cedex
France	Clinique Hartmann	Neuilly sur Seine
France	CHU Hotel Dieu	Paris
France	Hopital St. Antoine	Paris Cedex 12
France	Clinique Saint Hilaire	Rouen
France	CLCC Paul Strauss	Strasbourg
France	Pole de cancerologie prive	Strasbourg
France	Polyclinique du Parc	Toulous
France	Institution Claudius Regaud	Toulouse Cedex
Germany	Klinikum St. Marien Amberg	Amberg
Germany	Hochwaldkrankenhaus	Bad Nauheim
Germany	Klinikverbund Suedwest - Sindelfingen-Böeblingen Clinical Centre	Böeblingen
Germany	Klinikum Chemnitz	Chemnitz
Germany	Universitaetsklinikum Dresden	Dresden
Germany	Luisenkrankenhaus	Duesseldorf
Germany	Universitaetsfrauenklinik	Essen
Germany	Zentrum fur Frauenheilkunde und Geburtshilfe	Frankfurt
Germany	Medizinisches Versorgungszentrum Osthessen	Fulda
Germany	Kreiskrankenhaus Hameln	Hameln
Germany	Klinikum Stadt Hanau	Hanau
Germany	Klinikum Hannover Nordstadt	Hannover
Germany	Universitat Frauenklinik Jena	Jena
Germany	Onkologische schwerpunktpraxis	Leer
Germany	Klinikum Lippe Lemgo	Lemgo
Germany	Asklepios Kliniken Lich GmbH	Lich
Germany	St. Vincenz u. Elisabeth Hospital	Mainz
Germany	Universitaetsklinikum Mainz	Mainz
Germany	Ev Krankenhaus Bethesda	Mönchengladbach
Germany	RotKreuzKlinikum München GmbH	Munich
Germany	Universitaetsklinikum Munster	Munster
Germany	Praxis und Tagesklinik fuer Onkologie und	Recklinghausen
Germany	Klinikum Rosenheim	Rosenheim
Germany	Klinikum Schaumburg	Stadhagen
Germany	Johanniter Krankenhaus	Stendal
Germany	Robert-Bosch-Krankenhaus	Stuttgart
Germany	Fachärzte fürlnnere Medizin, Hämatologie	Traunstein
Greece	P.G. Hospital of Thessaloniki "Papageorgiou"	Thessaloniki
Hong Kong	Prince of Wales Hospital	Hong Kong
Hong Kong	Queen Elizabeth Hospital	Hong Kong
Hungary	Semmelweis Egyetem Clinic of Radiology	Budapest
Hungary	DEOEC Onkologiai Tanszek	Debrecen
Hungary	Petz Aladar Megyei Oktato	Gyor
Hungary	Kaposi Mor oktato korhaz Onkologiai tanszek	Kaposvar
Ireland	Cork University Hospital	Cork
Ireland	Adelaide and Meath National Childrens Hospital	Dublin
Ireland	Beaumont Hospital	Dublin
Ireland	Institute for Cancer Research	Dublin
Ireland	Mater Private Hospital	Dublin
Ireland	St. James's Hospital	Dublin
Ireland	St. Vincent's University Hospital	Dublin 4
Ireland	University College Hospital Galway	Galway
Ireland	Midwestern Regional Hospital	Limerick
Ireland	Sligo General Hospital	Sligo
Israel	The Lady Davis Carmel Medical Center/Lynn	Haifa
Israel	Meir Medical Center	Kfar
Israel	Kaplan Medical Center	Rehovot
Israel	Sourasky (Ichilov) Medical Center	Tel Aviv
Israel	Ziv Medical Center	Zefat
Israel	Assaf Harofeh Medical Center	Zerifin
Italy	Humanitas Centro Catanese	Catania
Italy	(Azienda u.s.I. chieti) - Policinico Ospedaliero	Chieti
Italy	Ospedale vito fazzi	Lecce
Italy	Ospedale di Mirano	Mirano
Italy	IRCCS - Instituto Nazionale per lo Studio e la Cura	Napoli
Italy	Fondazione Salvatore Maugeri	Pavia
Italy	Ospedale S. Filippo Neri	Roma
Italy	Regina Elena Cancer Institute	Rome
Italy	Ospedale casa sollievo della sofferenza	San-Giovanni
Italy	Universita-istituto Clinica Medica	Sassari
Italy	Asl n. 5 -Ospedale s. Vincenzo	Taormina
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	Seoul
Latvia	P. Stradina Clinical University Hospital	Riga
Mexico	Opcion Oncologia	Monterrey
Peru	Hospital Nacional Carlos Alberto Seguin	Arequipa
Peru	Hospital Nacional Edgardo Rebagliati Martins	Lima
Philippines	Cebu Doctors University Hospital	Cebu City
Poland	Regional Oncology Center	Bialystok
Poland	Centrum Onkologii Instytut im. M.	Gliwice
Poland	Olsztynski Osrodek Onkologiczny "Kopernik"	Olsztyn
Poland	ZOZ MSWiA z Warminsko-Mazurskim Centrum	Olsztyn
Poland	Samodzielny Publiczny Zaklad Opieki	Rybnik
Poland	Breast Cancer Clinic	Warsaw
Portugal	HUC	Coimbra
Portugal	IPO Francisco Gentil-Porto	Porto
Romania	County Hospital Alba-Iulia	Alba-Iulia
Romania	Institute of Oncology "AI.Trestioreanu"	Bucharest
Romania	Institutul Oncologic "Prof. Dr. I. Chiricuta" Cluj-Napoca	Cluj-Napoca
Russian Federation	State Medical Institution "Republican Clinical Oncology Dispensary Ministry of Health of Republic Tatarstan"	Kazan
Russian Federation	State Institution "Russian Oncological Research Center n.a. N.N. Blokhin of RAMS"	Moscow
Russian Federation	Federal State Institution "Research Institute of Oncology n.a. N.N. Petrov Rosmedtechnologiy"	Saint Petersburg
Russian Federation	Saint-Petersburg State Medical Institution "City Clinical Oncology Dispensary"	Saint Petersburg
Serbia	Clinical Hospital Center Bezanijska Kosa	Belgrade
Serbia	Clinic of Oncology, Clinical Center nis	Nis
Slovenia	University Clinical Centre	Maribor
South Africa	Department of Oncotherapy National Hospital	Bloemfontein
South Africa	Hopelands Cancer Centre	Durban
South Africa	Johannesburg Hospital	Johannesburg
Spain	Fundacion Hospitalaria de Alcorcon	Alcorcon
Spain	Hospital General de Alicante	Alicante
Spain	Hospital Perpetuo Socorro	Badajoz
Spain	Hospital Germans Trias l Pujol	Badalona (Barcelona)
Spain	Hospital Comarcal de Barbastro	Barbastro
Spain	Althaia Xarxa Assistencial de Manresa	Barcelona
Spain	Consorci Sanitari de Terrassa	Barcelona
Spain	Hospital Clinic i Provincial	Barcelona
Spain	Hospital Del Mar	Barcelona
Spain	Hospital Espiritu Santo	Barcelona
Spain	Hospital Santa Crue l San Pau	Barcelona
Spain	Hospital De San Pedro de Alcantara	Caceres
Spain	Hospital Gral. De Elche	Elche
Spain	Hospital de Cabueñes, Oncologia Médica	Gijon
Spain	Instituto Catalan Oncologia de Girona	Girona
Spain	Complejo Hospitalario de Jaen	Jaen
Spain	Complejo Hospitalario Universitario A Coruna	La Coruna
Spain	Centro Oncologico de Galicia	La Coruña
Spain	Hospital Universitario de Canarias	La Laguna
Spain	Hospital Universitario Insular de Gran Canaria	Las Palmas	Canary Islands
Spain	Hospital Xera Calde	Lugo
Spain	Centro Integral de Oncologia "Clara Campal"	Madrid
Spain	Fundacion Jimenez Diaz	Madrid
Spain	Hospital Ruber International	Madrid
Spain	Hospital Universitario Gregorio Maranon	Madrid
Spain	Hospital Universitario San Carlos	Madrid
Spain	Hospital Clinico Virgen de la Victoria	Malaga
Spain	Hospital Univesitario Carlos Haya	Malaga
Spain	Hospital Santa Maria Nai Dr. Cabaleiro	Ourense
Spain	Complejo Hospitalario de Pontevedra	Pontevedra
Spain	Hospital del Parc Tauli	Sabadell
Spain	Hospital Universitario de Salamanca	Salamanca
Spain	Instituto Oncologico de Guipuzcoa	San Sebastian
Spain	Hospital Universitario Virgen del Rocio	Sevilla
Spain	Hospital Torrevieja Salud, UTE	Torrevieja
Spain	Hospital Clinico Universitario de Valencia	Valencia
Spain	Hospital Clinico Universitario Lozano Blesa	Zaragoza
Spain	Hospital U. Miguel Servet	Zaragoza
Sweden	Sahlgrenska University Hospital	Goteborg
Sweden	Karolinska University Hospital	Stockholm
Taiwan	Changhua Christian Hospital	Changhua
Taiwan	Kaohsiung Medical University Chung	Kaohsiung
Taiwan	National Cheng Kung University	Tainan
Taiwan	Sun Yat-Sen Cancer Center	Taipei
Taiwan	Taipei Veterans General Hospital	Taipei
Taiwan	Chang Gung Memorial Hospital	Taoyuan
Thailand	National Cancer Institute	Bangkok
Thailand	Chulalongkorn Hospital	Patumwan	Bangkok
Thailand	Songklanagarind Hospital	Songkhla
United Kingdom	Royal Bournemouth Hospital	Bournemouth
United Kingdom	Bristol Hematology - Oncology Centre	Bristol
United Kingdom	Ipswich Hospital	Ipswich
United Kingdom	Christie Hospital NHS Trust	Manchester
United Kingdom	Nottingham City Hospital	Nottingham
United Kingdom	Peterborough District Hospital	Peterborough
United Kingdom	Sunrise Cancer Centre	Truro
United States	Bixby Medical Center	Adrian	Michigan
United States	Akron City Hospital	Akron	Ohio
United States	Akron General Medical Center	Akron	Ohio
United States	New York Oncology Hematology PC-Albany	Albany	New York
United States	NY Oncology Hematology PC at Albany Medical Center	Albany	New York
United States	Phoebe Putney Memorial Hospital	Albany	Georgia
United States	Central Hematology/Oncology Medical Group, Inc.	Alhambra	California
United States	Lehigh Valley Hospital	Allentown	Pennsylvania
United States	Alliance Cancer Center	Alliance	Ohio
United States	Amsterdam Community Cancer Program	Amsterdam	New York
United States	CCOP, St. Joseph Mercy Hospital	Ann Arbor	Michigan
United States	Cancer Care & Hematology Specialists of Chicagoland	Arlington	Illinois
United States	Cancer Care of Western North Carolina	Asheville	North Carolina
United States	Cancer Center of NC at Asheville	Asheville	North Carolina
United States	CCOP, Mission Hospitals, Inc.	Asheville	North Carolina
United States	Northeast Georgia Cancer Care, LLC	Athens	Georgia
United States	Emory University	Atlanta	Georgia
United States	Grady Healthsystem	Atlanta	Georgia
United States	Augusta Oncology Associates	Augusta	Georgia
United States	University of Colorado Cancer Center	Aurora	Colorado
United States	Northwest Georgia Oncology Centers PC	Austell	Georgia
United States	Oncology Associates P.C.-Avon	Avon	Connecticut
United States	Comprehensive Blood and Cancer Center	Bakersfield	California
United States	Kaiser Permanente-Baldwin Park	Baldwin Park	California
United States	Franklin Square Hospital Center	Baltimore	Maryland
United States	Greater Baltimore Medical Center	Baltimore	Maryland
United States	Harry & Jeannette Weinberg Cancer Institute	Baltimore	Maryland
United States	Hematology-Oncology Associates	Baltimore	Maryland
United States	Mercy Medical Center	Baltimore	Maryland
United States	Eastern Maine Medical Center	Bangor	Maine
United States	Baton Rouge General Medical Center	Baton Rouge	Louisiana
United States	Battle Creek Health System	Battle Creek	Michigan
United States	Bay Regional Medical Center	Bay City	Michigan
United States	Dr. Cook and Abramson - Bay City	Bay City	Michigan
United States	Overlake Internal Medicine	Bellevue	Washington
United States	Kaiser Permanente-Bellflower	Bellflower	California
United States	Summit Medical Group	Berkeley Heights	New Jersey
United States	Carolyn Hendricks, MD	Bethesda	Maryland
United States	Suburban Hospital	Bethesda	Maryland
United States	Hematology and Medical Oncology Consultants-Bettendorf	Bettendorf	Iowa
United States	Hematology Oncology Centers of the Northern Rockies	Billings	Montana
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Cancer Care of Southern Indiana	Bloomington	Indiana
United States	Lynn Cancer Institute	Boca Raton	Florida
United States	Florida Cancer Specialists-Bonita Springs	Bonita Springs	Florida
United States	Florida Cancer Specialists-Bradenton	Bradenton	Florida
United States	Florida Cancer Specialists, Brandon	Brandon	Florida
United States	Bridgeport Hospital	Bridgeport	Connecticut
United States	Medical Specialists of SWIM	Bridgeport	Connecticut
United States	St. Joseph Mercy Woodland Health Center	Brighton	Michigan
United States	Josephone Ford Cancer Center	Brownstown	Michigan
United States	Providence Saint Joseph Medical Center	Burbank	California
United States	Oncology Alliance-Burlington	Burlington	Wisconsin
United States	Minnesota Oncology Hematology-Burnsville	Burnsville	Minnesota
United States	Park Nicollet Clinic	Burnsville	Minnesota
United States	Interlakes Oncology & Hematology, P.C.	Canandaigua	New York
United States	Aultman Hospital	Canton	Ohio
United States	Tri County Hematology/Oncology	Canton	Ohio
United States	Florida Cancer Specialists-Cape Coral Del Prado	Cape Coral	Florida
United States	Florida Cancer Specialists-Cape Coral Parkway	Cape Coral	Florida
United States	Northwest Georgia Oncology Centers PC	Carrollton	Georgia
United States	Northwest Georgia Oncology Centers PC	Cartersville	Georgia
United States	Carolinas Hematology Oncology Associates - Harris Blvd.	Charlotte	North Carolina
United States	Carolinas Hematology-Oncology - John J. Delaney	Charlotte	North Carolina
United States	Carolinas Hematology-Oncology Associates - Tyron St	Charlotte	North Carolina
United States	Carolinas Medical Center - Blumenthal Cancer Center	Charlotte	North Carolina
United States	CCOP Presbyterian Hospital	Charlotte	North Carolina
United States	Mecklenburg Medical Group - Cameron Valley Pkwy	Charlotte	North Carolina
United States	Mecklenburg Medical Group - Morehead Medical Dr	Charlotte	North Carolina
United States	The Office of Frederik Smith	Chevy Chase	Maryland
United States	Washington Oncology-Hematology Center, PC-Chevy Chase	Chevy Chase	Maryland
United States	MBCCOP, John H. Stroger, JR., Hospital of Cook County-Chicago	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	Kenwood Office	Cincinnati	Ohio
United States	North Treatment Center - Blue Ash Medical Center	Cincinnati	Ohio
United States	Oncology/Hematology Care Clinical Trials LLC	Cincinnati	Ohio
United States	Oncology/Hematology Care Clinical Trials LLC	Cincinnati	Ohio
United States	Oncology/Hematology Care Clinical Trials LLC, Cincinnati, OH Blue Ash Med. Cntr. (Administrative Only)	Cincinnati	Ohio
United States	Florida Cancer Specialists	Clearwater	Florida
United States	Case Western Reserve/University Hospitals-Ireland Cancer Cntr.	Cleveland	Ohio
United States	Kootenai Cancer Center	Coeur d'Alene	Idaho
United States	Penrose Cancer Center	Colorado Springs	Colorado
United States	University of Missouri-Ellis Fischel	Columbia	Missouri
United States	Hubert H. Humphrey Cancer Center - Coon Rapids	Coon Rapids	Minnesota
United States	Corydon Hospital Medical Plaza	Corydon	Indiana
United States	Texas Oncology- Sammons CC	Dallas	Texas
United States	Geisinger Clinic	Danville	Pennsylvania
United States	Hematology and Medical Oncology Consultants-Davenport	Davenport	Iowa
United States	Dayton Physicians-LLC-Hematology & Medical Oncology Division	Dayton	Ohio
United States	Henry Ford Medical Center-Fairlane	Dearborn	Michigan
United States	Cancer Care Specialists-Central Illinois	Decatur	Illinois
United States	Clearview Cancer Institute-Decatur	Decatur	Alabama
United States	Crossroads Cancer Center	Decatur	Illinois
United States	Decatur Memorial Hospital	Decatur	Illinois
United States	CCOP-Colorado Cancer Research Prog. Inc.(Administrative Only)	Denver	Colorado
United States	Cypress Hematology/Oncology	Denver	Colorado
United States	Kaiser Permanente-Franklin	Denver	Colorado
United States	Rocky Mountain Cancer Center - Midtown	Denver	Colorado
United States	Henry Ford Hospital	Detroit	Michigan
United States	Hematology Oncology Associates of NE PA	Donora	Pennsylvania
United States	Hematology Oncology Assaociates of CNY, CCOP	East Syracuse	New York
United States	Fairview Southdale Medical Oncology Clinic	Edina	Minnesota
United States	Minnesota Oncology Hematology-Edina	Edina	Minnesota
United States	Shaw Regional Cancer Center	Edwards	Colorado
United States	Elkhart Clinic	Elkhart	Indiana
United States	Michiana Hematology-Oncology, P.C. (Elkhart)	Elkhart	Indiana
United States	Hematology-Encinitas	Encinitas	California
United States	Scripps Clinic Encinitas	Encinitas	California
United States	Drs. Forte, Schleider, Attas and Condemi, PA	Englewood	New Jersey
United States	Florida Cancer Specialists-Englewood	Englewood	Florida
United States	Ephrata Cancer Center at Ephrata Community Hospital	Ephrata	Pennsylvania
United States	UP Hematology/Oncology Assoc.-Doctor's Park Family Physicians	Escanaba	Michigan
United States	Healthplex	Fairfield	Ohio
United States	Medical Specialists of Fairfield	Fairfield	Connecticut
United States	Oncology Associates of Bridgeport-Fairfield	Fairfield	Connecticut
United States	Northern Arizona Hematology & Onclogy Associates	Flagstaff	Arizona
United States	CCOP Hurley Medical Center	Flint	Michigan
United States	Genesys Hurley	Flint	Michigan
United States	Sing and Arora	Flint	Michigan
United States	Kaiser Permanente-Fontana	Fontana	California
United States	Florida Cancer Specialists-Fort Myers Broadway	Fort Myers	Florida
United States	Florida Cancer Specialists-Fort Myers Summerlin	Fort Myers	Florida
United States	The Center for Cancer and Blood Disorders	Fort Worth	Texas
United States	Oncology Alliance-Franklin	Franklin	Wisconsin
United States	Hubert H. Humphrey Cancer Center - Fridley	Fridley	Minnesota
United States	St. Jude Heritage Healthcare	Fullerton	California
United States	Robert R. Carroll, MD, PA	Gainesville	Florida
United States	Waverly Hematology Oncology	Gary	Indiana
United States	Oncology Alliance	Glendale	Wisconsin
United States	CCOP, Wayne Memorial Hospital	Goldsboro	North Carolina
United States	Genesys Regional Medical Center	Grand Blanc	Michigan
United States	Grand Rapids Clinical Oncology Program	Grand Rapids	Michigan
United States	Spectrum Health Hospitals	Grand Rapids	Michigan
United States	St. Mary's Health Services	Grand Rapids	Michigan
United States	North Colorado Medical Center	Greeley	Colorado
United States	Aurora BayCare Medical Center	Green Bay	Wisconsin
United States	Moses Cone Regional Cancer Center	Greensboro	North Carolina
United States	UPMC Cancer Centers Arnold Palmer Pavilion-Mountainview	Greensburg	Pennsylvania
United States	UPMC Cancer Centers Arnold Palmer-Oakbrook	Greensburg	Pennsylvania
United States	Dayton Physicians, LLC - Greenville	Greenville	Ohio
United States	CCOP, St. John Hospital and Medical Center	Grosse Pointe Woods	Michigan
United States	Cancer Institute of New Jersey at Hamilton	Hamilton	New Jersey
United States	Hamilton Office	Hamilton	Ohio
United States	Portage Internal Medical Associates	Hancock	Michigan
United States	Connecticut Multi Specialty Group-Hartford	Hartford	Connecticut
United States	Hartford Hospital	Hartford	Connecticut
United States	Oncology Associates P.C.-Hartford	Hartford	Connecticut
United States	Breastlink Medical Group, Inc	Hawthorne	California
United States	Comprehensive Cancer Centers of Nevada (Siena)	Henderson	Nevada
United States	Northwestern Carolina Oncology & Hematology, PA	Hickory	North Carolina
United States	Oncare Hawaii, Inc-KMP	Honolulu	Hawaii
United States	Oncare Hawaii, Inc-POB2	Honolulu	Hawaii
United States	Straub Clinic and Hospital	Honolulu	Hawaii
United States	University of Hawaii	Honolulu	Hawaii
United States	Baylor College of Medicine	Houston	Texas
United States	Ben Taub General Hospital	Houston	Texas
United States	NY Oncology Hematology PC-Hudson Carvell Cancer Tx Prog.	Hudson	New York
United States	Carolina BioOncology Institute	Huntersville	North Carolina
United States	Pacific Shores Medical Group	Huntington Beach	California
United States	Clearview Cancer Institute	Huntsville	Alabama
United States	Clearview Cancer Institute- Huntsville	Huntsville	Alabama
United States	UPMC Cancer Centers-Indiana	Indiana	Pennsylvania
United States	University of Iowa	Iowa City	Iowa
United States	UP Hematology/Oncology Associates	Iron Mountain	Michigan
United States	UP Hematology/Oncology Associates-Gogebic Range	Ironwood	Michigan
United States	Kaiser Permanente-Irvine	Irvine	California
United States	Integrated Community Oncology Network	Jacksonville	Florida
United States	Clark Medical Building	Jeffersonville	Indiana
United States	UPMC Cancer Centers-John P. Murtha Cancer Center	Johnstown	Pennsylvania
United States	Freeman Cancer Institute	Joplin	Missouri
United States	St. John's Regional Health Center-Joplin	Joplin	Missouri
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	CCOP, Kansas City (Administrative Only)	Kansas City	Missouri
United States	Saint Luke's Hospital	Kansas City	Missouri
United States	Oncology Alliance-Kenosha North	Kenosha	Wisconsin
United States	Oncology Alliance-Kenosha South	Kenosha	Wisconsin
United States	Dayton Clinical Oncology Program-Kettering	Kettering	Ohio
United States	Marian A. Llenado Lee, MD, Inc.	Kettering	Ohio
United States	Thompson Cancer Survival Center	Knoxville	Tennessee
United States	Thompson Cancer Survival Center-Dowell Springs	Knoxville	Tennessee
United States	Thompson Oncology Group-Blount	Knoxville	Tennessee
United States	Thompson Oncology Group-West	Knoxville	Tennessee
United States	Howard Regional Health System	Kokomo	Indiana
United States	Hematology-La Jolla	La Jolla	California
United States	Sabina R. Wallach, MD., AMC	La Jolla	California
United States	Scripps Cancer Center-San Diego	La Jolla	California
United States	Kaiser Permanente Rock Creek	Lafayette	Colorado
United States	Lakeland Regional Cancer Center	Lakeland	Florida
United States	Hematology/Oncology Associates of OH and MI, PC	Lambertville	Michigan
United States	Antelope Valley Cancer Center	Lancaster	California
United States	CCOP, Sparrow Health System	Lansing	Michigan
United States	Michigan State University - Breslin Cancer Center	Lansing	Michigan
United States	Hematology Oncology-Lapeer	Lapeer	Michigan
United States	Lapeer Regional Hospital	Lapeer	Michigan
United States	Michiana Hematology-Oncology, P.C. (LaPorte)	LaPorte	Indiana
United States	Cancer and Blood Specialists- Shadow Lane	Las Vegas	Nevada
United States	Cancer Consultants	Las Vegas	Nevada
United States	Nevada Cancer Institute	Las Vegas	Nevada
United States	University Medical Center of Southern Nevada	Las Vegas	Nevada
United States	NY Oncology Hematology PC- Latham- Capital District Oncology Hematology	Latham	New York
United States	Keewanaw Memorial Hospital	Laurium	Michigan
United States	Lawrence Memorial Hospital	Lawrence	Kansas
United States	Suburban Hematology-Oncology Associates	Lawrenceville	Georgia
United States	University of Kentucky Medical Center	Lexington	Kentucky
United States	St. Mary Mercy Hospital - Livonia	Livonia	Michigan
United States	Monmouth Medical Center	Long Branch	New Jersey
United States	Kaiser Permanente-Sunset	Los Angeles	California
United States	Kaiser Permanente-West Los Angeles	Los Angeles	California
United States	Norton Medical Plaza II	Louisville	Kentucky
United States	Norton Medical Plaza West	Louisville	Kentucky
United States	NortonHealthcare Pavillion	Louisville	Kentucky
United States	Old Brownsboro Crossing	Louisville	Kentucky
United States	McKee Medical Center	Loveland	Colorado
United States	Covenant Health System dba Joe Arrington Cancer Research & Treatment Center	Lubbock	Texas
United States	Central Georgia Cancer Care	Macon	Georgia
United States	Georgia Cancer Specialists	Macon	Georgia
United States	Minnesota Oncology Hematology PA - Maplewood	Maplewood	Minnesota
United States	Georgia Cancer Specialists	Marietta	Georgia
United States	Marquette General Hospital	Marquette	Michigan
United States	Upper Peninsula Hematology/Oncology Associates	Marquette	Michigan
United States	CCOP, Marshfield Clinic	Marshfield	Wisconsin
United States	Northwest Ohio Oncology Center	Maumee	Ohio
United States	UPMC Cancer Centers - McKeesport Hospital	McKeesport	Pennsylvania
United States	Riddle Memorial Hospital	Media	Pennsylvania
United States	The West Clinic	Memphis	Tennessee
United States	Oncology Alliance-Menomonee Falls	Menomonee Falls	Wisconsin
United States	Oncology Alliance-Mequon	Mequon	Wisconsin
United States	Medical Oncology and Hematology, P.C.	Meriden	Connecticut
United States	Mountain States Tumor Institute	Meridian	Idaho
United States	Oncology Alliance-South	Milwaukee	Wisconsin
United States	Minnesota Oncology Hematology-Minneapolis	Minneapolis	Minnesota
United States	West Virginia University Hospitals Inc.	Morgantown	West Virginia
United States	Morristown Memorial Hospital	Morristown	New Jersey
United States	Community Cancer Care Specialists-Mt. Clemens	Mount Clemens	Michigan
United States	Mount Clemens Regional Medical Center	Mount Clemens	Michigan
United States	UPMC Cancer Centers Arnold Palmer-Mt. Pleasant	Mount Pleasant	Pennsylvania
United States	Intermountain Medical Center	Murray	Utah
United States	Hackley Hospital	Muskegon	Michigan
United States	Edward Hospital	Naperville	Illinois
United States	Florida Cancer Specialists-NAPA Ridge	Naples	Florida
United States	Florida Cancer Specialists-Naples Goodlette	Naples	Florida
United States	Cancer Care Center	New Albany	Indiana
United States	Cancer Institute of New Jersey	New Brunswick	New Jersey
United States	Beth Israel Medical Center	New York	New York
United States	St. Luke's-Roosevelt Hospital Center	New York	New York
United States	CCOP, Christiana Care Health Services Inc.	Newark	Delaware
United States	Newark Beth Israel Medical Center	Newark	New Jersey
United States	University of Medicine and Dentistry of New Jersey	Newark	New Jersey
United States	Michiana Hematology-Oncology PC	Niles	Michigan
United States	Berkshire Hematology Oncology, P.C.-North Adams	North Adams	Massachusetts
United States	Eastern Connecticut Hematology & Oncology Associates	Norwich	Connecticut
United States	Kaiser Permanente-Oakland	Oakland	California
United States	North County Oncology Medical Clinic, Inc.	Oceanside	California
United States	McKay-Dee Hospital	Ogden	Utah
United States	Integrated Community Oncology Network	Orange Park	Florida
United States	UHHS - Chagrin Highlands	Orange Village	Ohio
United States	Florida Hospital Cancer Institute	Orlando	Florida
United States	Florida Cancer Specialists, Cornerstone	Palm Harbor	Florida
United States	Kaiser Permanente-Orange County	Panorama City	California
United States	Kaiser Permanente-Panorama City	Panorama City	California
United States	Wilshire Oncology Medical Group	Pasadena	California
United States	Albert Einstein Healthcare Network	Philadelphia	Pennsylvania
United States	Cancer Center at Center One	Philadelphia	Pennsylvania
United States	Kimmel Cancer Center at Jefferson	Philadelphia	Pennsylvania
United States	Allegheny General Hospital/Allegheny-Singer Research Institute	Pittsburgh	Pennsylvania
United States	Hillman Cancer Center	Pittsburgh	Pennsylvania
United States	NSABP Foundation, Inc	Pittsburgh	Pennsylvania
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	UPMC Cancer Centers - UPMC Passavant	Pittsburgh	Pennsylvania
United States	UPMC Cancer Centers - UPMC St. Margaret	Pittsburgh	Pennsylvania
United States	Berkshire Hematology Oncology, P.C.	Pittsfield	Massachusetts
United States	Edward Cancer Center Plainfield	Plainfield	Illinois
United States	North Texas Regional Cancer Center	Plano	Texas
United States	Michiana Hematology-Oncology PC	Plymouth	Indiana
United States	Oncology, P.C. Plymouth	Plymouth	Indiana
United States	Florida Cancer Specialists-Port Charlotte	Port Charlotte	Florida
United States	Adventist Medical Center	Portland	Oregon
United States	CCOP, Columbia River Oncology	Portland	Oregon
United States	Northwest Cancer Specialists-Adventist Office	Portland	Oregon
United States	Northwest Cancer Specialists-Portland	Portland	Oregon
United States	Providence Oncology and Hematology Care Clinic	Portland	Oregon
United States	Providence Portland Medical Center	Portland	Oregon
United States	Providence St. Vincent Medical Center	Portland	Oregon
United States	Utah Valley Regional Medical Center	Provo	Utah
United States	Oncology Alliance-Racine	Racine	Wisconsin
United States	Cancer Care Associates Medical Group, Inc.	Redondo Beach	California
United States	Alpine Hematology-Oncology	Reno	Nevada
United States	Renown Regional Medical Center	Reno	Nevada
United States	Riverview Cancer Care Medical Association	Rexford	New York
United States	MBCCOP, Virginia Commonwealth University	Richmond	Virginia
United States	VCU Massey Cancer Center at Stony Point	Richmond	Virginia
United States	Kaiser Permanente-Riverside	Riverside	California
United States	Hubert H. Humphrey Cancer Center-Robbinsdale	Robbinsdale	Minnesota
United States	Associates in Oncology/Hematology	Rockville	Maryland
United States	Hematology Oncology Associates of CNY, CCOP	Rome	New York
United States	Kaiser Permanente-Roseville	Roseville	California
United States	Kaiser Permanente-Sacramento	Roseville	California
United States	Sutter Roseville Medical Center	Roseville	California
United States	CCOP, William Beaumont Hospital	Royal Oak	Michigan
United States	Sutter Medical Center	Sacramento	California
United States	Sutter Medical Group	Sacramento	California
United States	CCOP, St. Mary's Medical Center	Saginaw	Michigan
United States	Dixie Medical Center	Saint George	Utah
United States	Lakeside Cancer Specialists, PLLC	Saint Joseph	Michigan
United States	Michiana Hematology-Oncology, PC Lakeland	Saint Joseph	Michigan
United States	Park Nicollet Health Services	Saint Louis Park	Minnesota
United States	Minnesota Hematology Oncology-St. Paul	Saint Paul	Minnesota
United States	Florida Cancer Specialists-Park Place	Saint Petersburg	Florida
United States	Peninsula Regional Medical Center	Salisbury	Maryland
United States	Peninsula Regional Oncology & Hematology	Salisbury	Maryland
United States	LDS Hospital	Salt Lake City	Utah
United States	Kaiser Permanente-San Diego	San Diego	California
United States	Peter T. Reissman, MD, Inc	San Diego	California
United States	Scripps Clinic-Rancho Bernardo	San Diego	California
United States	Sharp Rees-Stealy	San Diego	California
United States	William Stanton, MD, Inc	San Diego	California
United States	Kaiser Permanente-Hayward	San Francisco	California
United States	Kaiser Permanente-San Francisco	San Francisco	California
United States	Sansum Clinic	Santa Barbara	California
United States	Santa Barbara Hematology Oncology Medical Group	Santa Barbara	California
United States	Kaiser Permanente-Santa Clara	Santa Clara	California
United States	Central Coast Medical Oncology Corporation	Santa Maria	California
United States	Florida Cancer Specialist-Cattleman	Sarasota	Florida
United States	Florida Cancer Specialists-Downtown	Sarasota	Florida
United States	Chippewa Medical Associates	Sault Sainte-Marie	Michigan
United States	Hematology and Oncology Associates	Scranton	Pennsylvania
United States	Mercy Hospital	Scranton	Pennsylvania
United States	Scranton Hematology Oncology	Scranton	Pennsylvania
United States	Northern Arizona Hematology & Oncology Associates	Sedona	Arizona
United States	Osteopathic Medical Oncology Hematology	Shelby	Michigan
United States	Holy Cross Hospital	Silver Spring	Maryland
United States	Suburban Hematology Oncology Associates PC	Snellville	Georgia
United States	Michiana Hematology-Oncology, P.C. (Main Office)	South Bend	Indiana
United States	Michiana Hematology-Oncology, P.C. Cedar St.	South Bend	Indiana
United States	Northern Indiana Cancer Research Consortium	South Bend	Indiana
United States	South Bend Clinic	South Bend	Indiana
United States	UHHS Green Road-Ireland Cancer Center	South Euclid	Ohio
United States	Kaiser Permanente-South San Francisco	South San Francisco	California
United States	University of Tennessee Cancer Institute	Southaven	Mississippi
United States	Sparta Cancer Treatment Center	Sparta	New Jersey
United States	Rockwood Cancer Treatment Center	Spokane	Washington
United States	Rockwood Cancer Treatment Center - Sinto Ave	Spokane	Washington
United States	Cox Health Systems	Springfield	Missouri
United States	St. John's Regional Health Center	Springfield	Missouri
United States	Stanford University Medical Center	Stanford	California
United States	Mount Nittany Medical Center	State College	Pennsylvania
United States	University Hospital and Medical Center - SUNY	Stony Brook	New York
United States	University Hospital and Medical Center-SUNY	Stony Brook	New York
United States	Overlook Hospital	Summit	New Jersey
United States	Flower Memorial Hospital	Sylvania	Ohio
United States	Hematology Oncology Assoc. of CNY, CCOP (Comm. General Hospital Satellite Office)	Syracuse	New York
United States	Florida Cancer Specialists	Tampa	Florida
United States	Florida Cancer Specialists	Tampa	Florida
United States	Providence Medical Group	Terre Haute	Indiana
United States	Bayview Oncology Associates	Toledo	Ohio
United States	Toledo Clinic	Toledo	Ohio
United States	Munson Medical Center	Traverse City	Michigan
United States	Troy Cancer Treatment Program	Troy	New York
United States	Black Rock Medical Group	Trumbull	Connecticut
United States	Oncology Associates of Bridgeport-Trumbull	Trumbull	Connecticut
United States	Mountain States Tumor Institute	Twin Falls	Idaho
United States	UPMC Cancer Centers-Uniontown	Uniontown	Pennsylvania
United States	UCLA/Santa Clarita Valley Cancer Center	Valencia	California
United States	Kaiser Permanente-Vallejo	Vallejo	California
United States	Northwest Cancer Specialists-134th St.	Vancouver	Washington
United States	Northwest Cancer Specialists-136th Ave	Vancouver	Washington
United States	Southwest Washington Hospital	Vancouver	Washington
United States	Florida Cancer Specialists-Venice	Venice	Florida
United States	Florida Cancer Specialists-Venice Island	Venice	Florida
United States	San Diego Pacific Oncology & Hematology-Vista	Vista	California
United States	Minnesota Oncology Hematology-Waconia	Waconia	Minnesota
United States	Kaiser Permanente-Walnut Creek	Walnut Creek	California
United States	CCOP, St. John Macomb Hospital	Warren	Michigan
United States	Sibley Memorial Hospital	Washington	District of Columbia
United States	Washington Cancer Institute	Washington	District of Columbia
United States	Washington Oncology-Hematology Center, PC-Washington	Washington	District of Columbia
United States	Medical Oncology & Hematology, P.C.	Waterbury	Connecticut
United States	Oncology Alliance-Waukeska	Waukesha	Wisconsin
United States	Henry Ford Medical Center-West Bloomfield	West Bloomfield	Michigan
United States	Palm Beach Cancer Institute	West Palm Beach	Florida
United States	UHHS Westlake-Ireland Cancer Center	Westlake	Ohio
United States	Marshfield Clinic Weston Center	Weston	Wisconsin
United States	Connecticut Multi Specialty Group-Wethersfield	Wethersfield	Connecticut
United States	UPMC Cancer Centers - Wexford	Wexford	Pennsylvania
United States	Exempla Lutheran Medical Center	Wheat Ridge	Colorado
United States	Oncology Care Associates	Wheaton	Maryland
United States	Oncology Associates P.C.-Willimantic	Willimantic	Connecticut
United States	Cancer Care and Hematology Specialists of Chicagoland	Winfield	Illinois
United States	Minnesota Oncology Hematology	Woodbury	Minnesota
United States	Kaiser Permanente-Woodland Hills	Woodland Hills	California
United States	Metro Health Hospital	Wyoming	Michigan
United States	York Hospital	York	Pennsylvania
United States	Yorkville Family Practice	Yorkville	Illinois

Sponsors (4)

Lead Sponsor	Collaborator
NSABP Foundation Inc	Cancer International Research Group (CIRG), Genentech, Inc., Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Bosnia and Herzegovina,  Brazil,  Bulgaria,  Canada,  Chile,  China,  Croatia,  Czechia,  Egypt,  Estonia,  France,  Germany,  Greece,  Hong Kong,  Hungary,  Ireland,  Israel,  Italy,  Korea, Republic of,  Latvia,  Mexico,  Peru,  Philippines,  Poland,  Portugal,  Romania,  Russian Federation,  Serbia,  Slovenia,  South Africa,  Spain,  Sweden,  Taiwan,  Thailand,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Invasive Disease-free Survival (IDFS)		up to 10 years
Secondary	Invasive disease-free survival (IDFS) within chemotherapy cohorts		up to 10 years
Secondary	Disease-free survival (DFS)		up to 10 years
Secondary	Overall survival (OS)		Time from randomization until death from any cause or up to a maximum of 10 years from study entry
Secondary	Recurrence-free interval (RFI)		Time from randomization until local, regional or distant recurrence or up to a maximum of 10 years from study entry
Secondary	Distant recurrence-free interval (DRFI)		Time from randomization until distant disease recurrence only or up to a maximum of 10 years from study entry
Secondary	Cardiac toxicity. Cumulative incidence of severe cardiac events defined as definite or probable cardiac death, or NYHA Class III or IV CHF		2-3 weeks after cycle 3; 2-3 weeks after last chemotherapy dose; 7, 10, 18, 36, and 60 months from randomization
Secondary	Non-cardiac toxicity. Frequencies of adverse events categorized using the NCI CTCAE v3.0.		within 3 days of each chemotherapy cycle; 2-3 weeks following last chemotherapy dose; every 6 weeks during targeted therapy; every 6 months through year 5; every 12 months years 6 - 10
Secondary	Identification of biomarkers (from tumor and serum/plasma) predictive for the level of benefit from the addition of bevacizumab to standard adjuvant systemic treatment for HER2-positive breast cancer as well as for cardiac toxicity		baseline, during therapy and follow-up, within 2 weeks of LVEF assessments, any protocol-specified cardiac event, and after diagnosis of recurrence