IMpassion132: A Study of the Efficacy and Safety of Atezolizumab Plus Chemotherapy for Patients With Early Relapsing Recurrent Triple-Negative Breast Cancer

Sponsor

Hoffmann-La Roche (Industry)

Overall Status

Recruiting

CT.gov ID

NCT03371017

Collaborator

(none)

572

Enrollment

164

Locations

Arms

80.6

Anticipated Duration (Months)

3.5

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study will evaluate the efficacy and safety of atezolizumab plus chemotherapy compared with placebo plus chemotherapy in patients with inoperable recurrent triple-negative breast cancer (TNBC).

Condition or Disease	Intervention/Treatment	Phase
Triple Negative Breast Neoplasms	Drug: Atezolizumab Drug: Placebo Drug: Gemcitabine Drug: Capecitabine Drug: Carboplatin	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

572 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

A Phase III, Randomised, Double-Blind, Placebo-Controlled, Multicentre Study Of The Efficacy And Safety Of Atezolizumab Plus Chemotherapy For Patients With Early Relapsing Recurrent (Inoperable Locally Advanced Or Metastatic) Triple-Negative Breast Cancer

Actual Study Start Date :

Jan 11, 2018

Anticipated Primary Completion Date :

Mar 31, 2023

Anticipated Study Completion Date :

Sep 30, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Atezolizumab Participants will receive Atezolizumab on day 1 of each 3-week treatment cycle	Drug: Atezolizumab Atezolizumab will be administered, 1200 mg by IV infusion with : gemcitabine 1000 mg/m2, followed by carboplatin target area under the curve (AUC) 2 mg/ml/min, both administered by IV infusion on Days 1 and 8 of each 3-week treatment cycle or with capecitabine 1000 mg/m2, twice daily orally on Days 1 to 14, followed by a 7-day rest period in each 3-week treatment cycle Drug: Gemcitabine Gemcitabine 1000 mg/m2, followed by carboplatin target area under the curve (AUC) 2 mg/ml/min, both administered by IV infusion on Days 1 and 8 of each 3-week treatment cycle Drug: Capecitabine Capecitabine 1000 mg/m2, twice daily orally on Days 1 to 14, followed by a 7-day rest period in each 3-week treatment cycle Drug: Carboplatin Carboplatin target area under the curve (AUC) 2 mg/ml/min, both administered by IV infusion on Days 1 and 8 of each 3-week treatment cycle
Placebo Comparator: Placebo Participants will receive Placebo on day 1 of each 3-week treatment cycle	Drug: Placebo Placebo will be administered, 1200 mg by IV infusion with : gemcitabine 1000 mg/m2, followed by carboplatin target area under the curve (AUC) 2 mg/ml/min, both administered by IV infusion on Days 1 and 8 of each 3-week treatment cycle or with capecitabine 1000 mg/m2, twice daily orally on Days 1 to 14, followed by a 7-day rest period in each 3-week treatment cycle Drug: Gemcitabine Gemcitabine 1000 mg/m2, followed by carboplatin target area under the curve (AUC) 2 mg/ml/min, both administered by IV infusion on Days 1 and 8 of each 3-week treatment cycle Drug: Capecitabine Capecitabine 1000 mg/m2, twice daily orally on Days 1 to 14, followed by a 7-day rest period in each 3-week treatment cycle Drug: Carboplatin Carboplatin target area under the curve (AUC) 2 mg/ml/min, both administered by IV infusion on Days 1 and 8 of each 3-week treatment cycle

Arm

Intervention/Treatment

Experimental: Atezolizumab

Participants will receive Atezolizumab on day 1 of each 3-week treatment cycle

Drug: Atezolizumab

Atezolizumab will be administered, 1200 mg by IV infusion with : gemcitabine 1000 mg/m2, followed by carboplatin target area under the curve (AUC) 2 mg/ml/min, both administered by IV infusion on Days 1 and 8 of each 3-week treatment cycle or with capecitabine 1000 mg/m2, twice daily orally on Days 1 to 14, followed by a 7-day rest period in each 3-week treatment cycle

Drug: Gemcitabine

Gemcitabine 1000 mg/m2, followed by carboplatin target area under the curve (AUC) 2 mg/ml/min, both administered by IV infusion on Days 1 and 8 of each 3-week treatment cycle

Drug: Capecitabine

Capecitabine 1000 mg/m2, twice daily orally on Days 1 to 14, followed by a 7-day rest period in each 3-week treatment cycle

Drug: Carboplatin

Carboplatin target area under the curve (AUC) 2 mg/ml/min, both administered by IV infusion on Days 1 and 8 of each 3-week treatment cycle

Placebo Comparator: Placebo

Participants will receive Placebo on day 1 of each 3-week treatment cycle

Drug: Placebo

Placebo will be administered, 1200 mg by IV infusion with : gemcitabine 1000 mg/m2, followed by carboplatin target area under the curve (AUC) 2 mg/ml/min, both administered by IV infusion on Days 1 and 8 of each 3-week treatment cycle or with capecitabine 1000 mg/m2, twice daily orally on Days 1 to 14, followed by a 7-day rest period in each 3-week treatment cycle

Drug: Gemcitabine

Gemcitabine 1000 mg/m2, followed by carboplatin target area under the curve (AUC) 2 mg/ml/min, both administered by IV infusion on Days 1 and 8 of each 3-week treatment cycle

Drug: Capecitabine

Capecitabine 1000 mg/m2, twice daily orally on Days 1 to 14, followed by a 7-day rest period in each 3-week treatment cycle

Drug: Carboplatin

Carboplatin target area under the curve (AUC) 2 mg/ml/min, both administered by IV infusion on Days 1 and 8 of each 3-week treatment cycle

Outcome Measures

Primary Outcome Measures

Overall Survival (OS) in Population With Programmed Death-Ligand 1 (PD-L1)-Positive Tumour Status [Baseline to end of study (approximately 58 months)]
OS will be tested hierarchically in the following fixed order: In the population with programmed deathligand 1 (PD-L1)-positive tumour status In the modified intent-to-treat (mITT) population
Overall Survival (OS) in Modified Intent-To-Treat (mITT) Popluation [Baseline to end of study (approximately 58 months)]
OS will be tested hierarchically in the following fixed order: In the population with programmed deathligand 1 (PD-L1)-positive tumour status In the modified intent-to-treat (mITT) population

Secondary Outcome Measures

Proportion of Participants Alive 12 Months [Randomization to 12 months post randomization]
Proportion of Participants Alive 18 Months [Randomization to 18 months post randomization]
Progression-Free Survival (PFS) in Population With Programmed Death-Ligand 1 (PD-L1)-Positive Tumour Status [Randomisation to the first occurrence of disease progression or death (through the end of study, approximately 58 months)]
PFS defined as the time from randomisation to the first occurrence of disease progression, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), or death from any cause, whichever occurs first. PFS will be tested hierarchically in the following fixed order: In the PD-L1-positive population In the mITT population
Progression-Free Survival (PFS) in mITT population [Randomisation to the first occurrence of disease progression or death (through the end of study, approximately 58 months)]
PFS defined as the time from randomisation to the first occurrence of disease progression, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), or death from any cause, whichever occurs first. PFS will be tested hierarchically in the following fixed order: In the PD-L1-positive population In the mITT population
Objective Response Rate (ORR) in Population With Programmed Death-Ligand 1 (PD-L1)-Positive Tumour Status [Baseline; every 8 weeks for the first 12 months after randomisation, and every 12 weeks thereafter until disease progression, withdrawal of consent, death, or study termination (approximately 58 months)]
ORR defined as the proportion of patients with an objective response, defined as a complete response (CR) or a partial response (PR), as determined by the investigator according to RECIST 1.1. ORR will be tested hierarchically in the following fixed order: In the PD-L1-positive population In the mITT population
Objective Response Rate (ORR) in Modified Intent-To-Treat (mITT) Popluation [Baseline; every 8 weeks for the first 12 months after randomisation, and every 12 weeks thereafter until disease progression, withdrawal of consent, death, or study termination (approximately 58 months)]
ORR defined as the proportion of patients with an objective response, defined as a complete response (CR) or a partial response (PR), as determined by the investigator according to RECIST 1.1. ORR will be tested hierarchically in the following fixed order: In the PD-L1-positive population In the mITT population
Duration of Objective Response (DoR) [Time from the first occurrence of a documented objective response to disease progression or death (through the end of study, approximately 58 months)]
DoR as determined by the investigator according to RECIST 1.1.
Clinical Benefit Rate (CBR) [8 weeks for the first 12 months after treatment initiation and every 12 weeks thereafter until disease progression (through the end of study, approximately 58 months)]
CBR is defined as the proportion of participants with a CR or a PR or stable disease as determined by the investigator according to RECIST 1.1.
Confirmed Objective Response Rate (C-ORR) [Baseline; every 8 weeks for the first 12 months after randomisation, and every 12 weeks thereafter until disease progression, withdrawal of consent, death, or study termination (approximately 58 months)]
Duration of Response for Confirmed Responders (C-DoR) [Time from the first occurrence of a documented objective response to disease progression or death (through the end of study, approximately 58 months)]
Time to Confirmed Deterioration (TTD) of GHS/QoL [Baseline to end of study (approximately 58 months)]
TTD of GHS/QoL, defined by a minimally important decrease of ≥10 points at two consecutive assessment time-points on the GHS/QoL scale (Items 29, 30) of the EORTC QLQ-C30.
Percentage of Participants With Adverse Events [Baseline to end of study (approximately 58 months)]
Maximum Serum Concentration (Cmax) of Atezolizumab [At pre-defined intervals from Day 1, Cycle 1 through Cycle 4 (cycle = 21 days)]
Minimum Serum Concentration (Cmin) of Atezolizumab [At pre-defined intervals from Day 1, Cycle 1 through Cycle 4 (cycle = 21 days)]
Incidence of Anti-Drug Antibodies (ADAs) to Atezolizumab [Baseline to end of study (approximately 58 months)]
Relationship Between PD-L1 Protein Expression in Screening Tumour Tissue and Clinical Outcomes [Baseline to end of study (approximately 58 months)]
Overall Survival (OS) in China Population With Programmed Death-Ligand 1 (PD-L1)-Positive Tumour Status [Baseline to end of study (approximately 58 months)]
OS will be tested hierarchically in the following fixed order: In the population with programmed deathligand 1 (PD-L1)-positive tumour status In the modified intent-to-treat (mITT) population
Overall Survival (OS) in mITT China Popluation [Baseline to end of study (approximately 58 months)]
OS will be tested hierarchically in the following fixed order: In the population with programmed deathligand 1 (PD-L1)-positive tumour status In the modified intent-to-treat (mITT) population
Proportion of Participants Alive 12 Months in China Population [Randomization to 12 months post randomization]
Proportion of Participants Alive 18 Months in China Population [Randomization to 18 months post randomization]
Progression Free Survival (PFS) in China Population With Programmed Death-Ligand 1 (PD-L1)-Positive Tumour Status [Randomisation to the first occurrence of disease progression or death (through the end of study, approximately 58 months)]
PFS defined as the time from randomisation to the first occurrence of disease progression, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), or death from any cause, whichever occurs first. PFS will be tested hierarchically in the following fixed order: In the PD-L1-positive population In the mITT population
Progression Free Survival (PFS) in mITT China Population [Randomisation to the first occurrence of disease progression or death (through the end of study, approximately 58 months)]
PFS defined as the time from randomisation to the first occurrence of disease progression, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), or death from any cause, whichever occurs first. PFS will be tested hierarchically in the following fixed order: In the PD-L1-positive population In the mITT population
Objective Response Rate (ORR) in China Population With Programmed Death-Ligand 1 (PD-L1)-Positive Tumour Status [Baseline; every 8 weeks for the first 12 months after randomisation, and every 12 weeks thereafter until disease progression, withdrawal of consent, death, or study termination (approximately 58 months)]
ORR defined as the proportion of patients with an objective response, defined as a complete response (CR) or a partial response (PR), as determined by the investigator according to RECIST 1.1. ORR will be tested hierarchically in the following fixed order: In the PD-L1-positive population In the mITT population
ORR in Modified Intent-To-Treat (mITT) China Popluation [Baseline; every 8 weeks for the first 12 months after randomisation, and every 12 weeks thereafter until disease progression, withdrawal of consent, death, or study termination (approximately 58 months)]
ORR defined as the proportion of patients with an objective response, defined as a complete response (CR) or a partial response (PR), as determined by the investigator according to RECIST 1.1. ORR will be tested hierarchically in the following fixed order: In the PD-L1-positive population In the mITT population
Duration of Objective Response (DoR) in China Population [Time from the first occurrence of a documented objective response to disease progression or death (through the end of study, approximately 58 months)]
DoR as determined by the investigator according to RECIST 1.1.
Clinical Benefit Rate (CBR) in China Population [8 weeks for the first 12 months after treatment initiation and every 12 weeks thereafter until disease progression (through the end of study, approximately 58 months)]
CBR is defined as the proportion of participants with a CR or a PR or stable disease as determined by the investigator according to RECIST 1.1.
Confirmed Objective Response Rate (C-ORR) in China Population [Baseline; every 8 weeks for the first 12 months after randomisation, and every 12 weeks thereafter until disease progression, withdrawal of consent, death, or study termination (approximately 58 months)]
Duration of Response for Confirmed Responders (C-DoR) in China Population [Time from the first occurrence of a documented objective response to disease progression or death (through the end of study, approximately 58 months)]
Time to Confirmed Deterioration (TTD) of GHS/QoL in China Population [Baseline to end of study (approximately 58 months)]
TTD of GHS/QoL, defined by a minimally important decrease of ≥10 points at two consecutive assessment time-points on the GHS/QoL scale (Items 29, 30) of the EORTC QLQ-C30.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically confirmed triple negative breast cancer (TNBC) that is either locally recurrent, inoperable and cannot be treated with curative intent or is metastatic
Documented disease progression occurring within 12 months from the last treatment with curative intent
Prior treatment (of early breast cancer) with an anthracycline and taxane
Have not received prior chemotherapy or targeted systemic therapy for their locally advanced inoperable or metastatic recurrence. Prior radiation therapy for recurrent disease is permitted
Measurable or non-measurable disease, as defined by RECIST 1.1
Availability of a representative formalin-fixed, paraffin-embedded (FFPE) tumour block (preferred) or at least 17 unstained slides obtained from relapsed metastatic or locally advanced diseases may be submitted, if clinically feasible, with an associated pathology report, if available. If a fresh tumour sample is not clinically feasible, either the diagnosis sample, the primary surgical resection sample, or the most recent FFPE tumour biopsy sample should be used.
Eastern Cooperative Oncology Group performance status 0-1
Life expectancy ≥ 12 weeks
Adequate haematologic and end-organ function
Negative human immunodeficiency virus (HIV) test ---Negative hepatitis B surface antigen (HBsAg) test at screening
Negative total hepatitis B core antibody (HBcAb) test at screening, or positive HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening
The HBV DNA test will be performed only for patients who have a negative HBsAg and a positive HBcAb test.
Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening.
Women of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method with a failure rate of ≤1% per year during the treatment period and for at least 5 months after the last dose of atezolizumab or 6 months after the last dose of capecitabine, whichever is later. In addition, women must refrain from donating eggs during the same time period.
Men must agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agree to refrain from donating sperm

Inclusion criteria for patients enrolled after the recruitment of all-comers is complete:

-PD-L1-positive tumour status (assessed centrally prior to randomisation), defined as PD-L1 expression on tumour-infiltrating immune cells (IC) of 1% or greater.

Exclusion Criteria:

Spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for > 2 weeks prior to randomisation
Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases.
Symptomatic or rapid visceral progression
No prior treatment with an anthracycline and taxane
History of leptomeningeal disease
Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently) (patients with indwelling catheters such as PleurX® are allowed)
Uncontrolled tumour-related pain
Uncontrolled or symptomatic hypercalcemia
Malignancies other than TNBC within 5 years prior to randomisation)
Significant cardiovascular disease, within 3 months prior to randomisation, unstable arrhythmias, or unstable angina
Presence of an abnormal ECG
Severe infection requiring oral or IV antibiotics within 4 weeks prior to randomisation, including but not limited to hospitalization for complications of infection, bacteraemia, or severe pneumonia.
Current treatment with anti-viral therapy for HBV.
Major surgical procedure within 4 weeks prior to randomisation or anticipation of the need for a major surgical procedure during the course of the study other than for diagnosis
Treatment with investigational therapy within 28 days prior to randomisation
Pregnant or lactating, or intending to become pregnant during or within 5 months after the last dose of atezolizumab, or within 6 months after the last dose of capecitabine, whichever is later.

Exclusion Criteria Related to Atezolizumab:

History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanised antibodies or fusion proteins
Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or to any component of the atezolizumab formulation
History of autoimmune disease
Prior allogeneic stem cell or solid organ transplantation
History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e. bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest computerised tomography (CT) scan History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
Active tuberculosis
Receipt of a live, attenuated vaccine within 4 weeks prior to randomisation or anticipation that a live, attenuated vaccine will be required during atezolizumab/placebo treatment or within 5 months after the last dose of atezolizumab/placebo
Prior treatment with CD137 agonists, anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway targeting agents
Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin [IL]-2) within 4 weeks or five half-lives of the drug (whichever is longer) prior to randomisation
Treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 weeks prior to start of study treatment, or anticipated requirement for systemic immunosuppressive medications during the trial

Exclusion Criteria Related to Capecitabine:

Inability to swallow pills
Malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach or small bowel, or ulcerative colitis
Known dihydropyrimidine dehydrogenase (DPD) deficiency or history of severe and unexpected reactions to fluoropyrimidine therapy in patients selected to receive capecitabine

Exclusion Criteria Related to Carboplatin/Gemcitabine:

-Hypersensitivity to platinum containing compounds or any component of carboplatin or gemcitabine drug formulations in patients selected to receive carboplatin and Gemcitabine

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Florida Cancer Specialists - Fort Myers (Broadway)	Fort Myers	Florida	United States	33901
2	Florida Cancer Specialists & Research Institute	Saint Petersburg	Florida	United States	33705
3	Northwest Georgia Oncology Centers PC - Marietta	Marietta	Georgia	United States	30060
4	HCA Midwest Division	Kansas City	Missouri	United States	64132
5	The Valley Hospital	Paramus	New Jersey	United States	07652
6	Magee-Woman's Hospital; UPMC Pinnacle Cancer Center	Harrisburg	Pennsylvania	United States	17109
7	Magee-Woman's Hospital	Pittsburgh	Pennsylvania	United States	15213
8	Tennessee Oncology; Sarah Cannon Research Institute	Nashville	Tennessee	United States	37203
9	Inova Schar Cancer Institute	Falls Church	Virginia	United States	22042
10	Centre hospitalo-univerisitaire de Rouiba;Service d'oncologie médicale	Algiers		Algeria	16016
11	Centre Anti Cancer Beau-fraisier;Service d'oncologie médicale	Algiers		Algeria	16340
12	CHU Constantine; Service d'Oncologie Médicale	Constantine		Algeria	25000
13	Fundación CENIT para la Investigación en Neurociencias	Buenos Aires		Argentina	C1125ABD
14	Instituto de Investigaciones Metabolicas (Idim)	Ciudad Autonoma de Buenos Aires		Argentina	C1012AAR
15	Instituto de Oncología de Rosario	Rosario		Argentina	S2000KZE
16	Hospital Provincial del Centenario	Rosario		Argentina	S2002KDS
17	University Clinical Center of the Republic of Srpska	Banja Luka		Bosnia and Herzegovina	78000
18	Clinic of Oncology, University Clinical Center Sarajevo	Sarajevo		Bosnia and Herzegovina	7100
19	Oncocentro Serviços Medicos E Hospitalares Ltda	Fortaleza	CE	Brazil	60135-237
20	Hospital Araujo Jorge; Departamento de Ginecologia E Mama	Goiania	GO	Brazil	74605-070
21	Hospital do Cancer de Pernambuco - HCP	Recife	PE	Brazil	50040-000
22	Hospital Sao Vicente de Paulo	Passo Fundo	RS	Brazil	99010-090
23	Hospital Nossa Senhora da Conceicao	Porto Alegre	RS	Brazil	91350-200
24	Centro de Oncologia de Santa Catarina LTDA	Chapeco	SC	Brazil	89801-222
25	Instituto de Pesquisa Grupo NotreDame Intermedica	Sao Paulo	SP	Brazil	01229-010
26	Hospital Perola Byington	Sao Paulo	SP	Brazil	01317-000
27	Núcleo de Pesquisa São Camilo; ONCOLOGIA CLINICA / QUIMIOTERAPIA	Sao Paulo	SP	Brazil	04014-002
28	Patagonia Research	Puerto Montt		Chile	5480000
29	Bradford Hill Centro de Investigaciones Clinicas; Bradford Hill Centro de Investigaciones Clinicas	Recoleta		Chile	8420383
30	Fundacion Arturo Lopez Perez	Santiago		Chile	7500921
31	Clinica Vespucio	Santiago		Chile	8241479
32	James Lind Centro de Investigación Del Cáncer	Temuco		Chile	4800827
33	ONCOCENTRO APYS; Oncología	Vina Del Mar		Chile	2520598
34	Cancer Hospital , Chinese Academy of Medical	Beijing City		China	100021
35	Peking University People's Hospital	Beijing		China	100044
36	Beijing Cancer Hospital	Beijing		China	100142
37	the First Affiliated Hospital of Bengbu Medical College	Bengbu City		China	233000
38	Jilin Cancer Hospital	Changchun		China	132013
39	Hunan Cancer Hospital	Changsha City		China	410013
40	The First Affiliated Hospital, Chongqing Medical University	Chongqing		China	400016
41	Fujian Medical University Union Hospital	Fuzhou City		China	350001
42	Sun Yat-sen Memorial Hospital	Guangzhou		China	510000
43	Sun Yet-sen University Cancer Center	Guangzhou		China	510060
44	Sir Run Run Shaw Hospital Zhejiang University	Hangzhou City		China	310016
45	Harbin Medical University Cancer Hospital	Harbin		China	150081
46	The First Affiliated Hospital Of Jinzhou Medical University	Jinzhou City		China	121001
47	Jiangsu Province Hospital	Nanjing		China	210036
48	The Affiliated Hospital of Medical College Qingdao University	Qingdao		China	266003
49	Fudan University Shanghai Cancer Center; Medical Oncology	Shanghai City		China	201315
50	Hebei Medical University Fourth Hospital;(Tumor Hospital of Hebei Province)	Shijiazhuang		China	050035
51	Shanxi Province Cancer Hospital	Taiyuan City		China	030013
52	Tianjin Cancer Hospital	Tianjin		China	300060
53	The First Affiliated Hospital of The Fourth Military Medical University (Xijing Hospital)	Xi'an		China	710032
54	Zhejiang Cancer Hospital	Zhejiang		China	310022
55	Hospital Hermanos Ameijeiras	La Habana		Cuba	10300
56	Instituto Nacional de Oncología y Radiología (INOR)	La Habana		Cuba	10400
57	AirForce Specialized Hospital; Clinical Oncology	Cairo		Egypt	11391
58	Ain Shams University Hospital; Oncology	Cairo		Egypt
59	Helsinki University Central Hospital; Dept of Oncology	Helsinki		Finland	00250
60	Tampere University Hospital; Dept of Oncology	Tampere		Finland	33520
61	Turku Uni Central Hospital; Oncology Clinics	Turku		Finland	20520
62	Centre Georges-François Lecler; Ctr de Lutte Contre le Canc	Dijon		France	21034
63	Centre Leon Berard; Oncologie Genetique	Lyon		France	69373
64	Institut Paoli-Calmettes; Oncologie Medicale 1	Marseille Cedex 09		France	13273
65	Centre Régional de Lutte Contre Le Cancer Val D'aurelle Paul Lamarque	Montpellier		France	34298
66	INSTITUT CURIE_SITE PARIS - Service d'Oncologie Médicale.	Paris		France	75005
67	Centre Eugene Marquis; Service d'oncologie	Rennes		France	35042
68	Centre Alexis Vautrin; Oncologie Medicale	Vandoeuvre-les-nancy		France	54519
69	IGR	Villejuif		France	94800
70	Praxisklinik Krebsheilkunde für Frauen / Brustzentrum (Dres. Kittel/Klare)	Berlin		Germany	10367
71	Universitätsklinikum "Carl Gustav Carus"; Frauenheilkunde und Geburtshilfe	Dresden		Germany	01307
72	Klinikum Essen-Mitte Ev. Huyssens-Stiftung / Knappschafts GmbH; Klinik für Senologie / Brustzentrum	Essen		Germany	45136
73	Klinikum Frankfurt Höchst GmbH; Klinik für Gynäkologie und Geburtshilfe	Frankfurt		Germany	65929
74	Universitätsklinikum Halle (Saale); Universitätsklinik Und Poliklinik Für Gynäkologie	Halle		Germany	06120
75	Onkologische Schwerpunktpraxis Eppendorf	Hamburg		Germany	20249
76	Medizinische Hochschule Hannover, Klinik für Frauenheilkunde und Geburtshilfe	Hannover		Germany	30625
77	Nationales Centrum für Tumorerkrankungen (NCT) ; Gyn. Onk. Frauenklinik; Uniklinikum Heidelberg	Heidelberg		Germany	69120
78	Kliniken der Stadt Köln gGmbH Krankenhaus Holweide; Brustzentrum	Köln		Germany	51067
79	Gemeinschaftspraxis Prof. Dr.med. Christoph Salat und Dr.med. Oliver J. Stötzer	München		Germany	80638
80	Caritas-Krankenhaus St. Josef; Klinik für Frauenheilkunde und Geburtshilfe	Regensburg		Germany	93053
81	Szent Margit Hospital	Budapest		Hungary	1032
82	Orszagos Onkologiai Intezet; B Belgyogyaszati Osztaly	Budapest		Hungary	1122
83	Uzsoki Utcai Korhaz	Budapest		Hungary	1145
84	Borsod-Abauj-Zemplen Megyei Korhaz es Egyetemi Oktato Korhaz;Sugarterapias Klinikai Onkologiai Intez	Miskolc		Hungary	3526
85	Pécsi Tudományegyetem; Klinikai Központ Onkoterápiás Intézet	Pécs		Hungary	7623
86	Istituto Nazionale per lo Studio e la Cura dei Tumori Fondazione G. Pascale	Napoli	Campania	Italy	80131
87	Azienda Ospedaliero Universitaria San Martino	Genova	Liguria	Italy	16132
88	Ospedale San Raffaele S.r.l.	Milano	Lombardia	Italy	20132
89	Irccs Istituto Europeo Di Oncologia (IEO); Ricerca Di Senologia Medica	Milano	Lombardia	Italy	20141
90	Ospedale San Gerardo	Monza	Lombardia	Italy	20900
91	Fondazione Del Piemonte Per L'oncologia Ircc Di Candiolo; Dipartimento Oncologico	Candiolo	Piemonte	Italy	10060
92	Ospedale Antonio Perrino; Oncologia Medica	Brindisi	Puglia	Italy	72100
93	Azienda Ospedaliero-Universitaria Careggi; SOD Radioterapia	Firenze	Toscana	Italy	50134
94	IRCCS Istituto Oncologico Veneto (IOV); Oncologia Medica Seconda	Padova	Veneto	Italy	35128
95	Kazakh Scientific Research Institution Of Oncology and Radiology; Chemotherapy department	Almaty		Kazakhstan	050022
96	Almaty Cancer Hospital; Chemotherapy department	Almaty		Kazakhstan	050054
97	Multidisciplinary medical center; Chemotherapy department	Astana		Kazakhstan	010000
98	Seoul National University Bundang Hospital	Seongnam-si		Korea, Republic of	13605
99	Seoul National University Hospital	Seoul		Korea, Republic of	03080
100	Severance Hospital, Yonsei University Health System	Seoul		Korea, Republic of	03722
101	Asan Medical Center	Seoul		Korea, Republic of	05505
102	Samsung Medical Center	Seoul		Korea, Republic of	06351
103	Centro Medico Dalinde	Cdmx	Mexico CITY (federal District)	Mexico	06760
104	Instituto Nacional de Cancerologia; Oncology	Distrito Federal		Mexico	14080
105	Consultorio de Medicina Especializada; Dentro de Condominio San Francisco	Mexico City		Mexico	03100
106	Clinical Center of Montenegro; Clinic for Oncology and Radiotherapy	Podgorica		Montenegro	81000
107	Centre Hospitalier Universitaire Hassan II	FES		Morocco	30000
108	Centre Hospitalier Universitaire Mohamed VI; Oncologie-Hématologie	Marrakech		Morocco	40000
109	Clinique specialise Menara; Oncology Medical	Marrakech		Morocco	40000
110	Institut National D'oncologie Sidi Med Benabdellah	Rabat		Morocco	6213
111	Centro Hemato Oncologico Panama	Panama		Panama	0832
112	Hospital Nacional Edgardo Rebagliati Martins	Jesus Maria		Peru	Lima 11
113	Clinica San Felipe; Centro de Investigacion Unidad de Oncologia Medica	Lima		Peru	Lima 11
114	Instituto Nacional de Enfermedades Neoplasicas	Lima		Peru	Lima 34
115	Clinica Internacional, Sede San Borja; Unidad de Investigacion de Clínica Internacional	Lima		Peru	Lima 41
116	Świętokrzyskie Centrum Onkologii; Dział Chemioterapii	Kielce		Poland	25-734
117	Narodowy Inst.Onkologii im.Sklodowskiej-Curie Panstw.Inst.Bad; Klinika Nowtw.Piersi i Chir.Rekonstr	Warszawa		Poland	02-781
118	Hospital de Santa Maria; Servico de Oncologia Medica	Lisboa		Portugal	1649-035
119	Centro Hospitalar do Porto - Hospital de Santo António; Oncologia	Porto		Portugal	4099-001
120	IPO do Porto; Servico de Oncologia Medica	Porto		Portugal	4200-072
121	Arkhangelsk Regional Clinical Oncology Dispensary	Arkhangelsk	Arhangelsk	Russian Federation	163045
122	Moscow City Oncology Hospital #62	Moscovskaya Oblast	Moskovskaja Oblast	Russian Federation	143423
123	Moscow Clinical Scientific Center	Moscow	Moskovskaja Oblast	Russian Federation	111123
124	Private Healthcare Institution Clinical Hospital RZhD Medicine	St. Petersburg	Sankt Petersburg	Russian Federation	195271
125	FSBI "National Medical Research Center of Oncology N.N. Blokhin"	Moscow		Russian Federation	115478
126	S-Pb clinical scientific practical center of specialized kinds of medical care (oncological)	Saint-Petersburg		Russian Federation	197758
127	City Clinical Oncology Dispensary, SPb SBIH CCOD	Saint-Petersburg		Russian Federation	198255
128	FBI "Scientific Research Institute of Oncology n. a. N. N. Petrov"	Saint-Petersburg		Russian Federation
129	Institute of Oncology and Radiology of Serbia	Belgrade		Serbia	11000
130	University Hospital Medical Center Bezanijska kosa	Belgrade		Serbia	11080
131	Clinical Centre Nis, Clinic for Oncology	Nis		Serbia	18000
132	Oncology Institute of Vojvodina	Sremska Kamenica		Serbia	21204
133	National University Hospital; National University Cancer Institute, Singapore (NCIS)	Singapore		Singapore	119228
134	National Cancer Centre; Medical Oncology	Singapore		Singapore	169610
135	Cape Town Oncology Trials	Cape Town		South Africa	7570
136	The Oncology centre,Durban; Clinical Oncology	Durban		South Africa	4001
137	Wits Clinical Research; Charlotte Maxeke Johannesburg Academic Hospital	Johannesburg		South Africa	2193
138	Medical Oncology Centre of Rosebank; Oncology	Johannesburg		South Africa	2196
139	Richards Bay Oncology Centre	KwaZulu Natal		South Africa	3900
140	University of Pretoria Oncology Department; Medical Oncology	Pretoria		South Africa	0002
141	Private Oncology Centre	Pretoria		South Africa	0081
142	Eugene Marais Hospital; Oncology	Pretoria		South Africa
143	Hospital de Cruces; Servicio de Oncologia	Bilbao	Vizcaya	Spain	48903
144	Hospital Universitari Vall d'Hebron; Oncology	Barcelona		Spain	08035
145	Hospital General Universitario Gregorio Marañon; Servicio de Oncologia	Madrid		Spain	28007
146	Hospital Ramon y Cajal; Servicio de Oncologia	Madrid		Spain	28034
147	Hospital Clinico Universitario Virgen de la Victoria; Servicio de Oncologia	Malaga		Spain	29010
148	Hospital Clínico Universitario de Valencia; Servicio de Oncología	Valencia		Spain	46010
149	Hacettepe University Medical Faculty; Department of Internal Medicine	Ankara		Turkey	06100
150	Ankara Oncology Hospital; Medical Oncology Department	Ankara		Turkey	06200
151	Ege University Medical Faculty; Medical Oncology Department	Bornova, İ̇zmi̇r		Turkey	35100
152	Trakya Universitesi Tip Fakultesi, Medikal Onkoloji Bilim Dali, Balkan Yerleskesi	Edirne		Turkey	22030
153	Medipol University MF; Oncology Department	Istanbul		Turkey	34214
154	Pendik Training and Research Hospital; Medical Oncology	Istanbul		Turkey	34890
155	Necmettin Erbakan University Meram Medical Faculty ; Internal Diseases	Konya		Turkey	42080
156	Velindre Cancer Centre; Oncology Dept	Cardiff		United Kingdom	CF14 2TL
157	University Hospital Coventry	Coventry		United Kingdom	CV2 2DX
158	Western General Hospital; Edinburgh Cancer Center	Edinburgh		United Kingdom	EH4 2XU
159	Royal Lancaster Infirmary, Morecambe Bay Hospitals Nhs Trust	Lancaster		United Kingdom	LA1 4RP
160	Barts	London		United Kingdom	EC1M6BQ
161	Guys and St Thomas NHS Foundation Trust, Guys Hospital	London		United Kingdom	SE1 9RT
162	Christie Hospital NHS Trust	Manchester		United Kingdom	M20 4BX
163	Mount Vernon Cancer Centre	Northwood		United Kingdom	HA6 2RN
164	Royal Stoke University Hospital	Stoke-on-Trent		United Kingdom	ST4 6QG