Study of Pembrolizumab (MK-3475) Plus Chemotherapy vs Placebo Plus Chemotherapy as Neoadjuvant Therapy and Pembrolizumab vs Placebo as Adjuvant Therapy in Participants With Triple Negative Breast Cancer (TNBC) (MK-3475-522/KEYNOTE-522)

Sponsor

Merck Sharp & Dohme LLC (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03036488

Collaborator

(none)

1,174

Enrollment

193

Locations

Arms

102.8

Anticipated Duration (Months)

6.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy and safety of pembrolizumab (MK-3475) plus chemotherapy vs placebo plus chemotherapy as neoadjuvant therapy and pembrolizumab vs placebo as adjuvant therapy in participants who have triple negative breast cancer (TNBC).

After a screening phase of approximately 28 days, each participant will receive neoadjuvant study treatment (Pembrolizumab + Chemotherapy OR Placebo + Chemotherapy) based on the randomization schedule for approximately 24 weeks (8 cycles). Each participant will then undergo definitive surgery 3-6 weeks after conclusion of the last cycle of the neoadjuvant study treatment. After definitive surgery, each participant will receive adjuvant study treatment (Pembrolizumab OR Placebo) for approximately 27 weeks (9 cycles). Following adjuvant study treatment, each participant will be monitored for safety, survival and disease recurrence.

The primary study hypothesis is that pembrolizumab is superior to placebo, in combination with chemotherapy, as measured by the rate of Pathological Complete Response (pCR) and/or Event-free Survival (EFS), in participants with locally advanced TNBC.

Condition or Disease	Intervention/Treatment	Phase
Triple Negative Breast Neoplasms	Biological: Pembrolizumab Drug: Carboplatin Drug: Paclitaxel Drug: Doxorubicin Drug: Epirubicin Drug: Cyclophosphamide Drug: Placebo Biological: Granulocyte colony stimulating factor: Filgrastim or Pegfilgastrim	Phase 3

Study Design

Study Type:

Interventional

Actual Enrollment :

1174 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

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

Primary Purpose:

Treatment

Official Title:

A Phase III, Randomized, Double-blind Study to Evaluate Pembrolizumab Plus Chemotherapy vs Placebo Plus Chemotherapy as Neoadjuvant Therapy and Pembrolizumab vs Placebo as Adjuvant Therapy for Triple Negative Breast Cancer (TNBC)

Actual Study Start Date :

Mar 7, 2017

Anticipated Primary Completion Date :

Sep 30, 2025

Anticipated Study Completion Date :

Sep 30, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pembrolizumab + Chemotherapy Participants receive pembrolizumab every 3 weeks (Q3W) + paclitaxel weekly + carboplatin (weekly or Q3W) x 4 cycles, followed by pembrolizumab Q3W + (doxorubicin OR epirubicin) + cyclophosphamide Q3W x 4 cycles as neoadjuvant therapy prior to surgery; followed by 9 cycles of pembrolizumab Q3W as adjuvant therapy post-surgery. Each cycle is 21 days.	Biological: Pembrolizumab On Day 1 of each cycle in the neoadjuvant and adjuvant phases of the study for a total of 17 cycles; intravenous (IV) infusion. Other Names: MK-3475 KEYTRUDA® Drug: Carboplatin On Day 1 of Cycles 1-4 of the neoadjuvant phase of the study OR on Days 1, 8, 15 of Cycles 1-4 of the neoadjuvant phase of the study; IV infusion. Other Names: PARAPLATIN® Drug: Paclitaxel On Days 1, 8 and 15 of Cycles 1-4 in the neoadjuvant phase of the study; IV infusion. Other Names: TAXOL® Drug: Doxorubicin On Day 1 of Cycles 5-8 of the neoadjuvant phase of the study; IV injection. Other Names: ADRIAMYCIN® Drug: Epirubicin On Day 1 of Cycles 5-8 of the neoadjuvant phase of the study; IV injection. Other Names: ELLENCE® Drug: Cyclophosphamide On Day 1 of Cycles 5-8 of the neoadjuvant phase of the study; IV infusion. Other Names: CYTOXAN® Biological: Granulocyte colony stimulating factor: Filgrastim or Pegfilgastrim For prevention of neutropenia, filgrastim 5 μg/kg/day via subcutaneous (SC) injection administered per standard of care after chemotherapy OR pegfilgastrim 100 µg/kg (individualized) or 6 mg (general approach) via SC injection administered per standard of care. Other Names: NEUPOGEN® NEULASTA®
Active Comparator: Placebo + Chemotherapy Participants receive placebo (normal saline solution) Q3W + paclitaxel weekly + carboplatin (weekly or Q3W) x 4 cycles, followed by placebo + (doxorubicin OR epirubicin) + cyclophosphamide Q3W x 4 cycles as neoadjuvant therapy prior to surgery; followed by 9 cycles of placebo Q3W as adjuvant therapy post-surgery. Each cycle is 21 days.	Drug: Carboplatin On Day 1 of Cycles 1-4 of the neoadjuvant phase of the study OR on Days 1, 8, 15 of Cycles 1-4 of the neoadjuvant phase of the study; IV infusion. Other Names: PARAPLATIN® Drug: Paclitaxel On Days 1, 8 and 15 of Cycles 1-4 in the neoadjuvant phase of the study; IV infusion. Other Names: TAXOL® Drug: Doxorubicin On Day 1 of Cycles 5-8 of the neoadjuvant phase of the study; IV injection. Other Names: ADRIAMYCIN® Drug: Epirubicin On Day 1 of Cycles 5-8 of the neoadjuvant phase of the study; IV injection. Other Names: ELLENCE® Drug: Cyclophosphamide On Day 1 of Cycles 5-8 of the neoadjuvant phase of the study; IV infusion. Other Names: CYTOXAN® Drug: Placebo normal saline solution or dextrose: On Day 1 of each cycle in the neoadjuvant and adjuvant phases of the study for a total of 17 cycles; IV infusion Biological: Granulocyte colony stimulating factor: Filgrastim or Pegfilgastrim For prevention of neutropenia, filgrastim 5 μg/kg/day via subcutaneous (SC) injection administered per standard of care after chemotherapy OR pegfilgastrim 100 µg/kg (individualized) or 6 mg (general approach) via SC injection administered per standard of care. Other Names: NEUPOGEN® NEULASTA®

Arm

Intervention/Treatment

Experimental: Pembrolizumab + Chemotherapy

Participants receive pembrolizumab every 3 weeks (Q3W) + paclitaxel weekly + carboplatin (weekly or Q3W) x 4 cycles, followed by pembrolizumab Q3W + (doxorubicin OR epirubicin) + cyclophosphamide Q3W x 4 cycles as neoadjuvant therapy prior to surgery; followed by 9 cycles of pembrolizumab Q3W as adjuvant therapy post-surgery. Each cycle is 21 days.

Biological: Pembrolizumab

On Day 1 of each cycle in the neoadjuvant and adjuvant phases of the study for a total of 17 cycles; intravenous (IV) infusion.

Other Names:

MK-3475

KEYTRUDA®

Drug: Carboplatin

On Day 1 of Cycles 1-4 of the neoadjuvant phase of the study OR on Days 1, 8, 15 of Cycles 1-4 of the neoadjuvant phase of the study; IV infusion.

Other Names:

PARAPLATIN®

Drug: Paclitaxel

On Days 1, 8 and 15 of Cycles 1-4 in the neoadjuvant phase of the study; IV infusion.

Other Names:

TAXOL®

Drug: Doxorubicin

On Day 1 of Cycles 5-8 of the neoadjuvant phase of the study; IV injection.

Other Names:

ADRIAMYCIN®

Drug: Epirubicin

On Day 1 of Cycles 5-8 of the neoadjuvant phase of the study; IV injection.

Other Names:

ELLENCE®

Drug: Cyclophosphamide

On Day 1 of Cycles 5-8 of the neoadjuvant phase of the study; IV infusion.

Other Names:

CYTOXAN®

Biological: Granulocyte colony stimulating factor: Filgrastim or Pegfilgastrim

For prevention of neutropenia, filgrastim 5 μg/kg/day via subcutaneous (SC) injection administered per standard of care after chemotherapy OR pegfilgastrim 100 µg/kg (individualized) or 6 mg (general approach) via SC injection administered per standard of care.

Other Names:

NEUPOGEN®

NEULASTA®

Active Comparator: Placebo + Chemotherapy

Participants receive placebo (normal saline solution) Q3W + paclitaxel weekly + carboplatin (weekly or Q3W) x 4 cycles, followed by placebo + (doxorubicin OR epirubicin) + cyclophosphamide Q3W x 4 cycles as neoadjuvant therapy prior to surgery; followed by 9 cycles of placebo Q3W as adjuvant therapy post-surgery. Each cycle is 21 days.

Drug: Carboplatin

On Day 1 of Cycles 1-4 of the neoadjuvant phase of the study OR on Days 1, 8, 15 of Cycles 1-4 of the neoadjuvant phase of the study; IV infusion.

Other Names:

PARAPLATIN®

Drug: Paclitaxel

On Days 1, 8 and 15 of Cycles 1-4 in the neoadjuvant phase of the study; IV infusion.

Other Names:

TAXOL®

Drug: Doxorubicin

On Day 1 of Cycles 5-8 of the neoadjuvant phase of the study; IV injection.

Other Names:

ADRIAMYCIN®

Drug: Epirubicin

On Day 1 of Cycles 5-8 of the neoadjuvant phase of the study; IV injection.

Other Names:

ELLENCE®

Drug: Cyclophosphamide

On Day 1 of Cycles 5-8 of the neoadjuvant phase of the study; IV infusion.

Other Names:

CYTOXAN®

Drug: Placebo

normal saline solution or dextrose: On Day 1 of each cycle in the neoadjuvant and adjuvant phases of the study for a total of 17 cycles; IV infusion

Biological: Granulocyte colony stimulating factor: Filgrastim or Pegfilgastrim

Other Names:

NEUPOGEN®

NEULASTA®

Outcome Measures

Primary Outcome Measures

Pathological complete response (pCR) rate using the definition of ypT0/Tis ypN0 (i.e., no invasive residual in breast or nodes; noninvasive breast residuals allowed) at the time of definitive surgery [Up to approximately 27-30 weeks]
pCR rate (ypT0/Tis ypN0) is defined as the percentage of participants without residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy by current American Joint Committee on Cancer (AJCC) staging criteria assessed by the local pathologist at the time of definitive surgery.
Event-free Survival (EFS) as assessed by Investigator [Up to approximately 8 years]
EFS is defined as the time from randomization to any of the following events: progression of disease that precludes surgery, local or distant recurrence, second primary malignancy (breast or other cancers) or death due to any cause.

Secondary Outcome Measures

pCR rate using an alternative definition, ypT0 ypN0 (i.e., no invasive or noninvasive residual in breast or nodes) at the time of definitive surgery [Up to approximately 27-30 weeks]
pCR rate (ypT0 ypN0) is defined as the percentage of participants without residual invasive and in situ cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy by current AJCC staging criteria assessed by the local pathologist at the time of definitive surgery in all participants and in participants with tumors expressing Programmed Death-Ligand 1 (PD-L1).
pCR rate using the definition of ypT0/Tis ypN0 (i.e., no invasive residual in breast or nodes; noninvasive breast residuals allowed) at the time of definitive surgery [Up to approximately 27-30 weeks]
pCR rate (ypT0/Tis) is defined as the percentage of participants without invasive cancer in the breast irrespective of ductal carcinoma in situ or nodal involvement following completion of neoadjuvant systemic therapy by current AJCC staging criteria assessed by the local pathologist at the time of definitive surgery in participants with tumors expressing PD-L1.
EFS in participants with tumors expressing PD-L1 [Up to approximately 8 years]
EFS is defined as the time from randomization to any of the following events: progression of disease that precludes surgery, local or distant recurrence, second primary malignancy (breast or other cancers) or death due to any cause.
pCR rate using an alternative definition, ypT0/Tis (i.e., absence of invasive cancer in the breast irrespective of ductal carcinoma in situ or nodal involvement) at the time of definitive surgery [Up to approximately 27-30 weeks]
pCR rate (ypT0/Tis) is defined as the percentage of participants without invasive cancer in the breast irrespective of ductal carcinoma in situ or nodal involvement following completion of neoadjuvant systemic therapy by current AJCC staging criteria assessed by the local pathologist at the time of definitive surgery in all participants and in participants with tumors expressing PD-L1.
Overall survival (OS) [Up to approximately 8 years]
OS is defined as the time from randomization to death due to any cause. Participants without documented death at the time of the analysis will be censored at the date of the last follow-up.
Percentage of participants who experience an adverse event (AE) [Up to approximately 61 weeks]
An AE is defined as any untoward medical occurrence in a participant administered study treatment which does not necessarily have to have a causal relationship with this treatment. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study treatment or protocol-specified procedure, whether or not considered related to study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of study treatment, is also an AE.
Percentage of participants who discontinue study treatment due to an AE [Up to approximately 57 weeks]
An AE is defined as any untoward medical occurrence in a participant administered study treatment which does not necessarily have to have a causal relationship with this treatment. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study treatment or protocol-specified procedure, whether or not considered related to study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of study treatment, is also an AE.
European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Core 30 Questionnaire (QLQ-C30) score [Up to approximately 27-30 weeks]
The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Individual responses are given on a 4-point scale (1=Not at All to 4=Very Much), with a lower score indicating a better outcome. The EORTC-QLQ-C30 score will be presented for all participants and for participants with tumors expressing PD-L1.
EORTC Breast Cancer-Specific QoL Questionnaire (QLQ-BR23) score [Up to approximately 27-30 weeks]
The EORTC-QLQ-BR23 is a 23-item questionnaire developed to assess the quality of life of breast cancer patients. Individual responses are given on a 4-point scale (1=Not at All to 4=Very Much), with a lower score indicating a better outcome. The EORTC-QLQ-BR23 score will be presented for all participants and for participants with tumors expressing PD-L1.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Has newly diagnosed, locally advanced, centrally confirmed TNBC, as defined by the most recent American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines.
Has previously untreated locally advanced non-metastatic (M0) TNBC defined as the following combined primary tumor (T) and regional lymph node (N) staging per current American Joint Committee of Cancer (AJCC) staging criteria for breast cancer as assessed by the investigator based on radiological and/or clinical assessment:
T1c, N1-N2
T2, N0-N2
T3, N0-N2
T4a-d, N0-N2
Provides a core needle biopsy consisting of at least 2 separate tumor cores from the primary tumor at screening to the central laboratory.
Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 performed within 10 days of treatment initiation.
Demonstrates adequate organ function.
Males and female participants of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 12 months after the last dose of study treatment for participants who have received cyclophosphamide, and 6 months after the last dose of study treatment for participants who did not.

Exclusion Criteria:

Has a history of invasive malignancy ≤5 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.
Has received prior chemotherapy, targeted therapy, and radiation therapy within the past 12 months.
Has received prior therapy with an anti-programmed cell death protein 1 (anti-PD-1), anti-programmed death - ligand 1 (anti-PD-L1), or anti-PD-L2 agent or with an agent directed to another co-inhibitory T-cell receptor (e.g., cytotoxic T-lymphocyte-associated antigen-4 [CTLA-4], OX-40, CD137 [tumor necrosis factor receptor superfamily member 9 (TNFRSF9)]) or has previously participated in a pembrolizumab (MK-3475) clinical study.
Is currently participating in or has participated in an interventional clinical study with an investigational compound or device within 4 weeks of the first dose of treatment in this current study.
Has received a live vaccine within 30 days of the first dose of study treatment.
Has an active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (i.e., dosing exceeding 10 mg daily of prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment.
Has a known history of Human Immunodeficiency Virus (HIV).
Has known active Hepatitis B or Hepatitis C.
Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
Has an active infection requiring systemic therapy.
Has significant cardiovascular disease, such as: history of myocardial infarction, acute coronary syndrome or coronary angioplasty/stenting/bypass grafting within the last 6 months OR congestive heart failure (CHF) New York Heart Association (NYHA) Class II-IV or history of CHF NYHA Class III or IV.
Is pregnant or breastfeeding, or expecting to conceive children within the projected duration of the study, starting with the screening visit through 12 months after the last dose of study treatment for participants who have received cyclophosphamide, and for 6 months after the last dose of study treatment for participants who have not.
Has a known hypersensitivity to the components of the study treatment or its analogs.
Has a known history of active tuberculosis (TB, Bacillus Tuberculosis).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Virginia G. Piper Cancer Center Pharmacy - Scottsdale Healthcare ( Site 0089)	Scottsdale	Arizona	United States	85268
2	Arizona Oncology Associates PC- HOPE ( Site 8001)	Tucson	Arizona	United States	85711
3	Cedars Sinai Medical Center ( Site 0091)	Los Angeles	California	United States	90048
4	Pacific Cancer Care ( Site 0069)	Monterey	California	United States	93940
5	ICRI ( Site 0072)	Whittier	California	United States	90603
6	University of Colorado Cancer Center ( Site 0021)	Aurora	Colorado	United States	80045
7	Yale University School of Medicine ( Site 0054)	New Haven	Connecticut	United States	06510
8	Christiana Hospital ( Site 0029)	Newark	Delaware	United States	19713
9	Univ of Miami-Sylvester Comprehensive Cancer Center- Kendall satellite ( Site 0079)	Miami	Florida	United States	33176
10	The University of Chicago Medical Center ( Site 0047)	Chicago	Illinois	United States	60637-1447
11	North Shore University Health System ( Site 0081)	Evanston	Illinois	United States	60201
12	Orchard Healthcare Research Inc. ( Site 0049)	Skokie	Illinois	United States	60077
13	Goshen Center for Cancer Care ( Site 0010)	Goshen	Indiana	United States	46526
14	University of Iowa Hospital and Clinics ( Site 0038)	Iowa City	Iowa	United States	52242
15	New England Cancer Specialists ( Site 0005)	Scarborough	Maine	United States	04074
16	Henry Ford Hospital ( Site 0003)	Detroit	Michigan	United States	48202
17	Minnesota Oncology Hematology, PA ( Site 8013)	Minneapolis	Minnesota	United States	55404
18	Rutgers Cancer Institute of New Jersey ( Site 0073)	New Brunswick	New Jersey	United States	08903
19	Broome Oncology, LLC ( Site 8002)	Johnson City	New York	United States	13790
20	Nyack Hospital Infusion Center ( Site 0059)	Nyack	New York	United States	10960
21	TriHealth Cancer Institute-Good Samaritan Hospital ( Site 0044)	Cincinnati	Ohio	United States	45220
22	Oncology Hematology Care, Inc. ( Site 8011)	Cincinnati	Ohio	United States	45242
23	Providence Portland Medical Center ( Site 0052)	Portland	Oregon	United States	97213
24	Northwest Cancer Specialists, P.C. ( Site 8008)	Portland	Oregon	United States	97227
25	Magee - Women's Hospital ( Site 0011)	Pittsburgh	Pennsylvania	United States	15213
26	Rhode Island Hospital ( Site 0060)	Providence	Rhode Island	United States	02903
27	The West Clinic, P.C. ( Site 0078)	Germantown	Tennessee	United States	38138
28	Texas Oncology-Austin Central ( Site 8005)	Austin	Texas	United States	78731
29	Parkland Health and Hospital System ( Site 0093)	Dallas	Texas	United States	75235
30	Texas Oncology-Baylor Charles A. Sammons Cancer Center ( Site 8006)	Dallas	Texas	United States	75246
31	Simmons Cancer Center ( Site 0094)	Dallas	Texas	United States	75390-9015
32	UT Southwestern Medical Center ( Site 0030)	Dallas	Texas	United States	75390-9179
33	Moncrief Cancer Institute ( Site 0092)	Fort Worth	Texas	United States	76104
34	Texas Oncology-Memorial City ( Site 8003)	Houston	Texas	United States	77024
35	Houston Methodist Cancer Center ( Site 0013)	Houston	Texas	United States	77030
36	Texas Oncology- Plano East ( Site 8010)	Plano	Texas	United States	75075
37	Texas Oncology-San Antonio Northeast ( Site 8012)	San Antonio	Texas	United States	78217
38	Texas Oncology-Tyler ( Site 8007)	Tyler	Texas	United States	75702
39	University of Virginia ( Site 0022)	Charlottesville	Virginia	United States	22903
40	Virginia Cancer Specialists, PC ( Site 8009)	Fairfax	Virginia	United States	22031
41	Bon Secours Cancer Institute Medical Oncology at St. Mary's ( Site 0033)	Midlothian	Virginia	United States	23114
42	Peninsula Cancer Institute, LLC ( Site 0041)	Newport News	Virginia	United States	23601
43	Virginia Oncology Associates ( Site 8000)	Norfolk	Virginia	United States	23502
44	Kadlec Clinic Hematology and Oncology ( Site 0087)	Kennewick	Washington	United States	99336
45	Seattle Cancer Care Alliance ( Site 0068)	Seattle	Washington	United States	98109
46	Medical Oncology Associates (Summit Cancer Centers) ( Site 0014)	Spokane	Washington	United States	99208
47	YVMH dba Vrigina Mason Memorial/North Star Lodge Cancer Center ( Site 8004)	Yakima	Washington	United States	98902
48	Royal North Shore Hospital ( Site 2000)	Sydney	New South Wales	Australia	2065
49	Westmead Hospital ( Site 2002)	Sydney	New South Wales	Australia	2145
50	Royal Adelaide Hospital ( Site 2008)	Adelaide	South Australia	Australia	5000
51	Cabrini Health ( Site 2009)	East Malvern	Victoria	Australia	3145
52	Frankston Hospital ( Site 2010)	Franskton		Australia	3199
53	Royal Brisbane and Women s Hospital ( Site 2003)	Herston		Australia	4029
54	St John of God Subiaco Hospital ( Site 2006)	Perth		Australia	6008
55	Hospital Nossa Senhora da Conceicao ( Site 0203)	Porto Alegre	Rio Grande Do Sul	Brazil	91350-200
56	UOPECCAN - Uniao Oeste Paranaense de Estudos e Combate ao Cancer ( Site 0206)	Cascavel		Brazil	85806-300
57	Universidade de Caxias do Sul ( Site 0201)	Caxias do Sul		Brazil	95070-560
58	Hospital Erasto Gaertner ( Site 0207)	Curitiba		Brazil	81520-060
59	Instituto do Cancer do Ceara ( Site 0205)	Fortaleza		Brazil	60430-230
60	Hospital Araujo Jorge ( Site 0204)	Goiania		Brazil	74605-070
61	Hospital Sao Lucas da PUCRS ( Site 0200)	Porto Alegre		Brazil	90610-900
62	Fundacao Faculdade Regional de Medicina de Sao Jose do Rio Preto ( Site 0208)	Sao Jose do Rio Preto		Brazil	15090-000
63	Instituto do Cancer de Sao Paulo - ICESP ( Site 0211)	Sao Paulo		Brazil	01246-000
64	Tom Baker Cancer Centre ( Site 0105)	Calgary	Alberta	Canada	T2N 4N2
65	The Ottawa Hospital - Cancer Care ( Site 0100)	Ottawa	Ontario	Canada	K1H 8L6
66	Princess Margaret Cancer Centre ( Site 0103)	Toronto	Ontario	Canada	M5G 2M9
67	Centre Hospitalier de l Universite de Montreal - CHUM ( Site 0106)	Montreal	Quebec	Canada	H2X 0C1
68	Jewish General Hospital ( Site 0101)	Montreal	Quebec	Canada	H3T 1E2
69	CIUSSS de l'Estrie-CHUS ( Site 0102)	Sherbrooke	Quebec	Canada	J1H 5N4
70	CHU de Quebec Universite Laval - Hopital du Saint-Sacrement ( Site 0104)	Quebec		Canada	G1S 4L8
71	Oncomedica S.A. ( Site 0404)	Monteria	Cordoba	Colombia	230002
72	Oncologos del Occidente S.A. ( Site 0405)	Pereira	Risaralda	Colombia	661002
73	Hospital Universitario San Ignacio ( Site 0401)	Bogota		Colombia	110231
74	Instituto Nacional de Cancerologia [Bogota-Colombia] ( Site 0403)	Bogota		Colombia	110411
75	Hemato Oncologos S.A. ( Site 0400)	Cali		Colombia	760001
76	Instituto De Cancerologia S.A. ( Site 0406)	Medellin		Colombia	050024
77	CHU Jean Minjoz ( Site 0917)	Besancon		France	25000
78	Polyclinique Bordeaux Nord Aquitaine ( Site 0911)	Bordeaux		France	33077
79	Centre Francois Baclesse ( Site 0907)	Caen		France	14000
80	Centre Jean Perrin ( Site 0903)	Clermont-Ferrand Cedex 01		France	63001
81	Clinique Victor Hugo ( Site 0901)	Le Mans		France	72015
82	Hopital prive du Confluent ( Site 0902)	Nantes		France	44277
83	Institut Curie ( Site 0909)	Paris		France	75005
84	Hopital Saint Louis ( Site 0908)	Paris		France	75010
85	Hopital Diaconesses Croix Saint Simon ( Site 0905)	Paris		France	75020
86	CHU de la Miletrie Poitiers ( Site 0913)	Poitiers		France	86021
87	Institut Claudius Regaud IUCT Oncopole ( Site 0914)	Toulouse Cedex 9		France	31059
88	HELIOS Klinikum Berlin-Buch ( Site 1005)	Berlin		Germany	13125
89	Gynaekologisches Zentrum ( Site 1004)	Bonn		Germany	53111
90	Universitaetsklinikum Erlangen ( Site 1001)	Erlangen		Germany	91054
91	Kliniken Essen Mitte ( Site 1012)	Essen		Germany	45136
92	Universitaetsklinik und Poliklinik Halle/Saale ( Site 1008)	Halle		Germany	06120
93	Universitaetsklinikum Hamburg-Eppendorf ( Site 1007)	Hamburg		Germany	20246
94	Klinikum der Universit. Muenchen ( Site 1002)	Muenchen		Germany	80337
95	Caritasklinik St. Theresia ( Site 1011)	Saarbruecken		Germany	66113
96	Universitaets-Frauenklinik Tuebingen ( Site 1003)	Tubingen		Germany	72076
97	Bon Secours Hospital ( Site 1551)	Cork		Ireland	T12 DV56
98	St Vincents University Hospital ( Site 1550)	Dublin		Ireland	D04 T6F4
99	Oncology institute ( Site 1601)	Beer Sheva		Israel	8410101
100	Assaf Harofeh MC ( Site 1605)	Beer Yaakov-Zerifin		Israel	7030001
101	Hadassah Ein Karem - Sharett Institute of Oncology ( Site 1600)	Jerusalem		Israel	9112001
102	Rabin-Medical Center ( Site 1604)	Petah Tikva		Israel	4941492
103	Sheba Medical Center ( Site 1602)	Ramat-Gan		Israel	5265601
104	Sourasky Medical Center ( Site 1603)	Tel Aviv		Israel	6423906
105	Istituto Scientifico Romagnolo per Studio e Cura Tumori IRST ( Site 1101)	Meldola	FC	Italy	47014
106	Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia ( Site 1103)	Brescia		Italy	25100
107	Ospedale San Luca, AZIENDA USL2 TOSCANA NORD OVEST ( Site 1105)	Lucca		Italy	55100
108	Ospedale Civile di Macerata ( Site 1104)	Macerata		Italy	62100
109	Istituto Europeo di Oncologia ( Site 1106)	Milano		Italy	20141
110	Istituto Nazionale Tumori IRCCS Fondazione Pascale ( Site 1102)	Napoli		Italy	80131
111	Aichi Cancer Center Hospital ( Site 2502)	Nagoya	Aichi	Japan	464-8681
112	National Cancer Center Hospital East ( Site 2518)	Kashiwa	Chiba	Japan	277-8577
113	National Hospital Organization Hokkaido Cancer Center ( Site 2512)	Sapporo	Hokkaido	Japan	003-0804
114	Hyogo College of Medicine Hospital ( Site 2506)	Nishinomiya	Hyogo	Japan	663-8501
115	Tokai University Hospital ( Site 2517)	Isehara	Kanagawa	Japan	259-1193
116	St. Marianna University School of Medicine Hospital ( Site 2516)	Kawasaki	Kanagawa	Japan	216-8511
117	Kindai University Hospital ( Site 2507)	Osakasayama	Osaka	Japan	589-8511
118	Saitama Medical University International Medical Center ( Site 2513)	Hidaka	Saitama	Japan	350-1298
119	Saitama Cancer Center ( Site 2510)	Kitaadachi-gun	Saitama	Japan	362-0806
120	Shizuoka Cancer Center Hospital and Research Institute ( Site 2514)	Sunto-gun	Shizuoka	Japan	411-8777
121	Chiba Cancer Center ( Site 2519)	Chiba		Japan	260-8717
122	Hiroshima City Hiroshima Citizens Hospital ( Site 2501)	Hiroshima		Japan	730-8518
123	Social medical corporation Hakuaikai Sagara Hospital ( Site 2508)	Kagoshima		Japan	892-0833
124	Kumamoto University Hospital ( Site 2515)	Kumamoto		Japan	860-8556
125	National Hospital Organization Osaka National Hospital ( Site 2505)	Osaka		Japan	540-0006
126	National Cancer Center Hospital ( Site 2500)	Tokyo		Japan	104-0045
127	St.Luke's International Hospital ( Site 2511)	Tokyo		Japan	104-8560
128	Toranomon Hospital ( Site 2503)	Tokyo		Japan	105-8470
129	The Cancer Institute Hospital of JFCR ( Site 2509)	Tokyo		Japan	135-8550
130	Seoul National University Hospital ( Site 2101)	Seoul		Korea, Republic of	03080
131	Severance Hospital Yonsei University Health System ( Site 2100)	Seoul		Korea, Republic of	03722
132	Asan Medical Center ( Site 2102)	Seoul		Korea, Republic of	05505
133	Samsung Medical Center ( Site 2103)	Seoul		Korea, Republic of	06351
134	Mazowiecki Szpital Onkologiczny ( Site 1713)	Wieliszew	Mazowieckie	Poland	05-135
135	Centrum Onkologii Instytut im. Marii Skłodowskiej Curie ( Site 1717)	Gliwice	Slaskie	Poland	44-101
136	Centrum Onkologii im. Prof. Franciszka Lukaszczyka ( Site 1708)	Bydgoszcz		Poland	85-796
137	Centrum Onkologii im. Prof. Franciszka Lukaszczyka ( Site 1712)	Bydgoszcz		Poland	85-796
138	Szpital Morski im. PCK. Szpitale Pomorskie Sp. Z o.o ( Site 1701)	Gdynia		Poland	81-519
139	Centrum Onkologii Instytut im. Marii Sklodowskiej Curie ( Site 1719)	Krakow		Poland	31-115
140	Centrum Onkologii Ziemi Lubelskiej im. sw. Jana z Dukli ( Site 1700)	Lublin		Poland	20-090
141	Dolnoslaskie Centrum Onkologii. ( Site 1702)	Wroclaw		Poland	53-413
142	Fundacao Champalimaud ( Site 2444)	Lisboa		Portugal	1400-038
143	Hospital de Santa Maria, E.P.E. ( Site 2445)	Lisboa		Portugal	1600-190
144	Instituto Portugues de Oncologia Do Porto Francisco Gentil E.P.E. ( Site 2446)	Porto		Portugal	4200-072
145	Arkhangelsk Clinical Oncological Dispensary ( Site 1810)	Arkhangelsk		Russian Federation	163045
146	Chelyabinsk Regional Clinical Oncological Dispensary ( Site 1805)	Chelyabinsk		Russian Federation	454087
147	Republican Clinical Oncology Dispensary of Tatarstan MoH ( Site 1806)	Kazan		Russian Federation	420029
148	Russian Oncological Research Center n.a. N.N.Blokhin of MoH ( Site 1801)	Moscow		Russian Federation	115478
149	GBU RO Regional Clinical Oncological Dispensary ( Site 1808)	Ryazan		Russian Federation	390046
150	Scientific Research Oncology Institute n.a. N.N.Petrov ( Site 1803)	Saint Petersburg		Russian Federation	197758
151	Republican Clinical Oncology Dispensary of Republic of Bashkortostan ( Site 1804)	Ufa		Russian Federation	450054
152	National Cancer Centre Singapore ( Site 2600)	Singapore		Singapore	169610
153	ICO L Hospitalet ( Site 1305)	Hospitalet de Llobregat	Barcelona	Spain	08908
154	Hospital Quiron de Madrid ( Site 1303)	Pozuelo de Alarcon	Madrid	Spain	28223
155	Hospital del Mar ( Site 1306)	Barcelona		Spain	08003
156	Instituto Oncologico Baselga.Hospital Quiron. ( Site 1312)	Barcelona		Spain	08023
157	Hospital General Universitari Vall d Hebron ( Site 1301)	Barcelona		Spain	08035
158	Hospital Universitario Reina Sofia ( Site 1304)	Cordoba		Spain	14004
159	Hospital Universitario Ramon y Cajal ( Site 1300)	Madrid		Spain	28034
160	Complejo Hospitalario Universitario de Santiago ( Site 1308)	Santiago de Compostela		Spain	15706
161	Hospital Universitario Virgen del Rocio ( Site 1314)	Sevilla		Spain	41013
162	Hospital Clinico Univ de Valencia ( Site 1313)	Valencia		Spain	46011
163	Linkopings Universitetssjukhus ( Site 1402)	Linkoping		Sweden	581 85
164	Karolinska Universitetssjukhuset Solna ( Site 1404)	Solna		Sweden	171 64
165	Norrlands Universitetssjukhus ( Site 1401)	Umea		Sweden	901 85
166	Akademiska Sjukhuset ( Site 1403)	Uppsala		Sweden	751 85
167	Taipei Veterans General Hospital ( Site 2302)	Taipei	Beitou	Taiwan	11217
168	National Cheng Kung University Hospital ( Site 2305)	Tainan		Taiwan	704
169	National Taiwan University Hospital ( Site 2301)	Taipei		Taiwan	100
170	MacKay Memorial Hospital ( Site 2303)	Taipei		Taiwan	105
171	Koo Foundation Sun Yat-Sen Cancer Center ( Site 2304)	Taipei		Taiwan	11259
172	Linkou Chang Gung Memorial Hospital ( Site 2300)	Taoyuan		Taiwan	333
173	Samsun Ondokuz Mayıs Universitesi Tıp Fakultesi Hastanesi ( Site 1910)	Samsun	Atakum	Turkey	55280
174	Adana Acıbadem Hospital Department of Medical Oncology ( Site 1906)	Adana		Turkey	01130
175	Baskent Unıversity Adana Kısla Hospital ( Site 1903)	Adana		Turkey	01250
176	Hacettepe Universitesi Tip Fakultesi Hastanesi ( Site 1912)	Ankara		Turkey	06100
177	Abdurrahman Yurtaslan Oncology Training and Research Hospital ( Site 1909)	Ankara		Turkey	06200
178	Ozel Medicana International Ankara Hastanesi ( Site 1915)	Ankara		Turkey	06510
179	Antalya Memorial Hospital Department of Medical Oncology ( Site 1908)	Antalya		Turkey	07020
180	Trakya University Medical Faculty Balkan Oncology Hospital ( Site 1901)	Edirne		Turkey	22030
181	Acibadem Altunizade Hastanesi ( Site 1900)	Istambul		Turkey	34662
182	İstanbul University Cerrahpaşa Medical Faculty ( Site 1904)	Istanbul		Turkey	34098
183	Amerikan Hospital Medical ( Site 1902)	Istanbul		Turkey	34365
184	Memorial Sisli Hastanesi ( Site 1913)	Istanbul		Turkey	34384
185	Ege University Medical Faculty Tulay Aktas Oncology Hospital ( Site 1905)	Izmir		Turkey	35040
186	Izmir Medical Park Hospital Department of Medical Oncology ( Site 1907)	Izmir		Turkey	35575
187	Colchester General Hospital ( Site 1508)	Colchester	Essex	United Kingdom	CO4 5JL
188	Barts Cancer Institute ( Site 1500)	London		United Kingdom	EC1M 6BQ
189	St George s Hospital ( Site 1516)	London		United Kingdom	SW17 0QT
190	Maidstone Hospital ( Site 1511)	Maidstone		United Kingdom	ME16 9QQ
191	The James Cook University Hospital ( Site 1515)	Middlesbrough		United Kingdom	TS4 3BW
192	Nottingham University Hospitals NHS Trust ( Site 1505)	Nottingham		United Kingdom	NG5 1PB
193	Royal Cornwall Hospitals NHS Trust ( Site 1504)	Truro		United Kingdom	TR1 3LJ