Study of Pembrolizumab Given Prior to Surgery and in Combination With Radiotherapy Given Post-surgery for Advanced Head and Neck Squamous Cell Carcinoma (MK-3475-689)

Sponsor

Merck Sharp & Dohme LLC (Industry)

Overall Status

Recruiting

CT.gov ID

NCT03765918

Collaborator

(none)

704

Enrollment

177

Locations

Arms

91.4

Anticipated Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a randomized, active-controlled, open-label study of pembrolizumab (Pembro) given prior to surgery and pembrolizumab in combination with standard of care radiotherapy (with or without cisplatin), as post-surgical therapy in treatment naïve participants with newly diagnosed Stage III/IVA, resectable, locoregionally advanced, head and neck squamous cell carcinoma (LA-HNSCC). Efficacy outcomes will be stratified by programmed cell death ligand 1 (PD-L1) combined positive score (CPS) status. The primary hypothesis is that pembrolizumab given before surgery and after surgery in combination with radiotherapy (with or without cisplatin) improves major pathological response and event-free survival compared to radiotherapy (with or without cisplatin) given after surgery alone.

Condition or Disease	Intervention/Treatment	Phase
Head and Neck Neoplasms	Biological: Pembrolizumab 200 mg Radiation: Radiotherapy 60 Gray/day Radiation: Radiotherapy 66 Gray/day Radiation: Radiotherapy 70 Gray/day Drug: Cisplatin 100 mg/m^2	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

704 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase III, Randomized, Open-label Study to Evaluate Pembrolizumab as Neoadjuvant Therapy and in Combination With Standard of Care as Adjuvant Therapy for Stage III-IVA Resectable Locoregionally Advanced Head and Neck Squamous Cell Carcinoma (LA HNSCC)

Actual Study Start Date :

Dec 17, 2018

Anticipated Primary Completion Date :

Jul 30, 2025

Anticipated Study Completion Date :

Jul 30, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pembro Neoadjuvant+Pembro SOC Adjuvant Participants receive 200 mg pembrolizumab by intravenous (IV) infusion administered on Day 1 of a 21-day cycle for 2 cycles as a neoadjuvant prior to surgery. Following surgical resection, high risk participants receive 200 mg pembrolizumab by IV infusion administered on Day 1 every 3 weeks (Q3W) for fifteen 21-day cycles plus standard of care radiotherapy plus cisplatin 100 mg/m^2 by IV infusion on Day 1 Q3W for three 21-day cycles as adjuvant therapy. Following surgical resection, low risk participants receive 200 mg pembrolizumab by IV infusion administered on Day 1 Q3W for fifteen 21-day cycles plus standard of care radiotherapy as adjuvant therapy.	Biological: Pembrolizumab 200 mg 200 mg administered by intravenous (IV) infusion on Day 1 of each 21-day cycle Other Names: KEYTRUDA® MK-3475 Radiation: Radiotherapy 60 Gray/day Low risk participants administered 2 Gray/day in 30 fractions. Administered using intensity modulated radiation therapy. Radiation: Radiotherapy 66 Gray/day High risk participants administered 2 Gray/day in 33 fractions. Administered using intensity modulated radiation therapy. Radiation: Radiotherapy 70 Gray/day Participants with gross residual disease administered 2 Gray/day in 35 fractions. Administered using intensity modulated radiation therapy. Drug: Cisplatin 100 mg/m^2 100 mg/m^2 administered by IV infusion on Day 1 of each 21-day cycle Other Names: Platinol® Platinol-AQ®
Active Comparator: No Neoadjuvant+SOC Adjuvant Participants receive no neoadjuvant prior to surgery. Following surgical resection, high risk participants receive standard of care radiotherapy plus cisplatin 100 mg/m^2 by IV infusion on Day 1 Q3W for three 21-day cycles as adjuvant therapy. Following surgical resection, low risk participants receive standard of care radiotherapy as adjuvant therapy.	Radiation: Radiotherapy 60 Gray/day Low risk participants administered 2 Gray/day in 30 fractions. Administered using intensity modulated radiation therapy. Radiation: Radiotherapy 66 Gray/day High risk participants administered 2 Gray/day in 33 fractions. Administered using intensity modulated radiation therapy. Radiation: Radiotherapy 70 Gray/day Participants with gross residual disease administered 2 Gray/day in 35 fractions. Administered using intensity modulated radiation therapy. Drug: Cisplatin 100 mg/m^2 100 mg/m^2 administered by IV infusion on Day 1 of each 21-day cycle Other Names: Platinol® Platinol-AQ®

Arm

Intervention/Treatment

Experimental: Pembro Neoadjuvant+Pembro SOC Adjuvant

Participants receive 200 mg pembrolizumab by intravenous (IV) infusion administered on Day 1 of a 21-day cycle for 2 cycles as a neoadjuvant prior to surgery. Following surgical resection, high risk participants receive 200 mg pembrolizumab by IV infusion administered on Day 1 every 3 weeks (Q3W) for fifteen 21-day cycles plus standard of care radiotherapy plus cisplatin 100 mg/m^2 by IV infusion on Day 1 Q3W for three 21-day cycles as adjuvant therapy. Following surgical resection, low risk participants receive 200 mg pembrolizumab by IV infusion administered on Day 1 Q3W for fifteen 21-day cycles plus standard of care radiotherapy as adjuvant therapy.

Biological: Pembrolizumab 200 mg

200 mg administered by intravenous (IV) infusion on Day 1 of each 21-day cycle

Other Names:

KEYTRUDA®

MK-3475

Radiation: Radiotherapy 60 Gray/day

Low risk participants administered 2 Gray/day in 30 fractions. Administered using intensity modulated radiation therapy.

Radiation: Radiotherapy 66 Gray/day

High risk participants administered 2 Gray/day in 33 fractions. Administered using intensity modulated radiation therapy.

Radiation: Radiotherapy 70 Gray/day

Participants with gross residual disease administered 2 Gray/day in 35 fractions. Administered using intensity modulated radiation therapy.

Drug: Cisplatin 100 mg/m^2

100 mg/m^2 administered by IV infusion on Day 1 of each 21-day cycle

Other Names:

Platinol®

Platinol-AQ®

Active Comparator: No Neoadjuvant+SOC Adjuvant

Participants receive no neoadjuvant prior to surgery. Following surgical resection, high risk participants receive standard of care radiotherapy plus cisplatin 100 mg/m^2 by IV infusion on Day 1 Q3W for three 21-day cycles as adjuvant therapy. Following surgical resection, low risk participants receive standard of care radiotherapy as adjuvant therapy.

Radiation: Radiotherapy 60 Gray/day

Low risk participants administered 2 Gray/day in 30 fractions. Administered using intensity modulated radiation therapy.

Radiation: Radiotherapy 66 Gray/day

High risk participants administered 2 Gray/day in 33 fractions. Administered using intensity modulated radiation therapy.

Radiation: Radiotherapy 70 Gray/day

Participants with gross residual disease administered 2 Gray/day in 35 fractions. Administered using intensity modulated radiation therapy.

Drug: Cisplatin 100 mg/m^2

100 mg/m^2 administered by IV infusion on Day 1 of each 21-day cycle

Other Names:

Platinol®

Platinol-AQ®

Outcome Measures

Primary Outcome Measures

Major Pathological Response (mPR) [Up to 30 days post-sugery]
The proportion of participants with a major pathological response (mPR) as assessed by the Central Pathologist at the time of definitive surgery. mPR is defined as ≤10% invasive squamous cell carcinoma within the resected primary tumor specimen and all the sampled regional lymph nodes.
Event-free Survival (EFS) [Up to 5 years]
EFS is the time from the date of randomization to the date of first record of any of the following events: disease progression; local or distant recurrence as assessed with imaging or biopsy as indicated; or death due to any cause.

Secondary Outcome Measures

Overall Survival (OS) [Up to 5 years]
OS is the time from randomization to death due to any cause.
Pathological Complete Response (pCR) [Up to 30 days post-sugery]
Pathological complete response (pCR) is measured as the proportion of participants with a pathological complete response as assessed by the central pathologist at the time of definitive surgery. pCR is defined as having no residual invasive squamous cell carcinoma within the resected primary tumor specimen and all sampled regional lymph nodes.
Change From Baseline in Global Health Status/Quality of Life Scale (GHS/QoL) [Prior to the first dose of study therapy (Baseline) and at the time of last follow-up (up to 5 years)]
Change from baseline in the combined score of GHS/QoL using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (EORTC QLQ-C30) items 29 and 30
Change From Baseline in Global Health Status/Physical Functioning Scales [Prior to the first dose of study therapy (Baseline) and at the time of last follow-up (up to 5 years)]
Change from baseline in the combined score of physical functioning scale using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core Questionnaire (EORTC QLQ-C30) items 1 through 5
Change from Baseline in Swallowing, Speech, and Pain Symptoms [Prior to the first dose of study therapy (Baseline) and at the time of last follow-up (up to 5 years)]
Change from baseline in the combined score of swallowing, speech, and pain symptoms using the European Organization for Research and Treatment of Cancer Head and Neck Questionnaire (EORTC QLQ-H&N35) items 31-38, 46, and 53-54
Percentage of Participants Experiencing An Adverse Event (AEs) [From time of first dose of study treatment until the end of follow-up (up to 5 years)]
Percentage of participants experiencing any sign, symptom, disease, or worsening of preexisting condition temporally associated with study therapy and irrespective of causality to study therapy
Percentage of Participants Discontinuing Study Drug Due to AEs [From time of first dose of study treatment until the end of treatment (up to 12 months)]
Percentage of participants discontinuing study drug due to an AE

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Has histologically confirmed new diagnosis of resectable, non-metastatic, squamous cell carcinoma that is either: Stage III Human Papillomavirus (HPV) positive oropharyngeal primary that is tumor size (T) 4, lymph node involvement (N) 0-2, no distant metastases (M0); Stage III or IVA oropharyngeal HPV negative; or Stage III or IVA larynx/hypopharynx/oral cavity primaries.
Is eligible for primary surgery based on investigator decision and per local practice
Female and male participants of reproductive potential must agree to use adequate contraception throughout the study period and for up to 180 days after the last dose of study therapy.
Male participants must refrain from donating sperm throughout the study period and for up to 180 days after the last dose of study therapy
Female participant that is not pregnant or breastfeeding
Has evaluable tumor burden (measurable and/or non-measurable tumor lesions) assessed by computed tomography (CT) scan or magnetic resonance imaging (MRI), based on RECIST version 1.1
Has provided newly obtained core or excisional biopsy of a tumor lesion not previously irradiated
Has results from testing of HPV status for oropharyngeal cancer defined as p16
Has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 performed within 10 days of randomization

Exclusion Criteria:

Has Stage T4B and/or N3 LA HNSCC and/or distant metastases
Has cancer outside of the oropharynx, larynx, and hypopharynx or oral cavity. such as nasopharyngeal, sinus, other para-nasal, or other unknown primary head and neck cancer (HNC)
Female participant who has a positive urine pregnancy test within 72 hours prior to study start or within 24 hours prior to the start of radiotherapy with or without cisplatin.
Has received prior therapy with an anti-programmed cell death receptor 1(PD-1), anti-programmed cell death receptor ligand 1(PD-L1), or anti-programmed cell death receptor ligand 2 (PD-L2) agent or with an agent directed to another co-inhibitory T-cell receptor
Has received prior radiotherapy treatment or systemic anti-cancer therapy including investigational agents for the HNC under study prior to study start
Has received a live vaccine within 30 days prior to randomization
Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to randomization
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to randomization
Has a known additional malignancy that is progressing or has required active treatment within the past 3 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. in situ cervical cancer or breast carcinoma) that have undergone potentially curative therapy
Has radiographically detectable (even if asymptomatic and/or previously treated) central nervous system metastases and/or carcinomatous meningitis
Has Grade ≥2 audiometric hearing loss
Has Grade ≥2 neuropathy
Has Grade 3-4 bleeding due to the underlying malignancy
Has received major surgery or has not recovered adequately from the toxicity and/or complications from the intervention prior to study start
Has had previous allogeneic tissue/solid organ transplant
Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients, radiotherapy, cisplatin or their analogs
Has an active autoimmune disease that has required systemic treatment in past 2 years
Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
Has an active infection requiring systemic therapy
Has a known history of human immunodeficiency virus (HIV) infection
Has a known history of or is positive for Hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active Hepatitis C (defined as Hepatitis C virus [HCV] ribonucleic acid is detected).
Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the investigator
Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Moores Cancer Center ( Site 1885)	La Jolla	California	United States	92093-0698
2	University of Southern California Norris Comprehensive Cancer Center ( Site 1850)	Los Angeles	California	United States	90033
3	UC Davis Health System ( Site 1864)	Sacramento	California	United States	95817
4	St. Joseph Heritage Healthcare ( Site 1806)	Santa Rosa	California	United States	95403
5	University of Colorado Cancer Center ( Site 1838)	Aurora	Colorado	United States	80045
6	George Washington University Medical Faculty Associates ( Site 2035)	Washington	District of Columbia	United States	20037
7	University of Florida ( Site 1832)	Gainesville	Florida	United States	32608
8	University of Miami, Sylvester Comprehensive Cancer Center ( Site 2008)	Miami	Florida	United States	33136
9	AdventHealth Orlando-AdventHealth Medical Group Hematology & Oncology at Orlando ( Site 2054)	Orlando	Florida	United States	32804
10	Saint Alphonsus Regional Medical Center ( Site 2021)	Boise	Idaho	United States	83706
11	Beacon Cancer Care ( Site 2052)	Coeur d'Alene	Idaho	United States	83814
12	Rush University Medical Center ( Site 1823)	Chicago	Illinois	United States	60612
13	NorthShore University HealthSystem ( Site 1812)	Evanston	Illinois	United States	60201
14	Loyola University Medical Center [Maywood, IL] ( Site 1817)	Maywood	Illinois	United States	60153
15	University of Kansas Cancer Center ( Site 2004)	Westwood	Kansas	United States	66205
16	Ochsner Cancer Institute ( Site 2045)	New Orleans	Louisiana	United States	70121
17	University of Maryland ( Site 2031)	Baltimore	Maryland	United States	21201
18	Dana Farber Cancer Center ( Site 1873)	Boston	Massachusetts	United States	02215
19	University of Massachusetts Memorial Medical Center ( Site 1875)	Worcester	Massachusetts	United States	01655
20	Karmanos Cancer Institute ( Site 1870)	Detroit	Michigan	United States	48201
21	Henry Ford Health System ( Site 1803)	Detroit	Michigan	United States	48202
22	Southdale Cancer Care, University of Minnesota Medical Center- Edina ( Site 2016)	Edina	Minnesota	United States	55435
23	Washington University School of Medicine ( Site 1800)	Saint Louis	Missouri	United States	63110
24	Mercy Clinic Cancer and Hematology - Chub O'Reilly Cancer Center ( Site 1897)	Springfield	Missouri	United States	65804
25	St. Vincent Healthcare Frontier Cancer Center ( Site 1818)	Billings	Montana	United States	59102
26	Memorial Sloan Kettering Cancer Center Basking Ridge ( Site 2036)	Basking Ridge	New Jersey	United States	07920
27	Memorial Sloan Kettering Cancer Center- Monmouth ( Site 2039)	Middletown	New Jersey	United States	07748
28	MSKCC-Bergen ( Site 2037)	Montvale	New Jersey	United States	07645
29	Rutgers New Jersey Medical School-department of Hematology oncology ( Site 2053)	Newark	New Jersey	United States	07103
30	The University of New Mexico Comprehensive Cancer Center ( Site 1882)	Albuquerque	New Mexico	United States	87131
31	Montefiore Einstein Center ( Site 2028)	Bronx	New York	United States	10467
32	Erie County Medical Center ( Site 2047)	Buffalo	New York	United States	14215
33	Memorial Sloan-Kettering Cancer Center at Commack ( Site 2038)	Commack	New York	United States	11725
34	Memorial Sloan-Kettering Cancer Center at West Harrison ( Site 2041)	Harrison	New York	United States	10604
35	Laura and Isaac Perlmutter Cancer Center at NYU Langone Health ( Site 2014)	New York	New York	United States	10016
36	Memorial Sloan Kettering Cancer Center ( Site 1857)	New York	New York	United States	10065
37	Weill Cornell Medical College ( Site 2050)	New York	New York	United States	10065
38	Northwell Health Cancer Institute ( Site 2030)	New York	New York	United States	10075
39	Memorial Sloan Kettering Cancer Center - Nassau ( Site 2040)	Uniondale	New York	United States	11553
40	Levine Cancer Institute ( Site 2003)	Charlotte	North Carolina	United States	28204
41	Wake Forest Compenhensive Cancer Center ( Site 2029)	Winston-Salem	North Carolina	United States	27357
42	Sanford Health Roger Maris Cancer Center ( Site 2034)	Fargo	North Dakota	United States	58102
43	University Hospitals ( Site 2032)	Cleveland	Ohio	United States	44106
44	The Ohio State University ( Site 2012)	Columbus	Ohio	United States	43210
45	Providence Portland Medical Center ( Site 1843)	Portland	Oregon	United States	97220
46	Kaiser Permanente Center for Health Research-Kaiser Permanente Medical Center ( Site 2022)	Portland	Oregon	United States	97227
47	Oregon Health Sciences University ( Site 1871)	Portland	Oregon	United States	97239
48	St. Luke's University Health Network ( Site 1801)	Bethlehem	Pennsylvania	United States	18015
49	Allegheny General Hospital ( Site 1833)	Pittsburgh	Pennsylvania	United States	15212
50	Sanford Cancer Center Oncology Clinic ( Site 1859)	Sioux Falls	South Dakota	United States	57104
51	Henry Joyce Cancer Clinic ( Site 1827)	Nashville	Tennessee	United States	37232
52	UT Southwestern Medical Center ( Site 1841)	Dallas	Texas	United States	75390
53	University of Utah, Huntsman Cancer Institute ( Site 1855)	Salt Lake City	Utah	United States	84112
54	University of Vermont Medical Center ( Site 2009)	Burlington	Vermont	United States	05401
55	UVA Health System - Emily Couric Cancer Center ( Site 1826)	Charlottesville	Virginia	United States	22908
56	Inova Schar Cancer Institute ( Site 2026)	Fairfax	Virginia	United States	22031
57	Seattle Cancer Care Alliance/Univ of Washington Medical Center ( Site 1865)	Seattle	Washington	United States	98109
58	Hospital Universitario Austral ( Site 0009)	Pilar	Buenos Aires	Argentina	B1629AHJ
59	Hospital Britanico de Buenos Aires ( Site 0012)	Ciudad de Buenos Aires	Caba	Argentina	C1280AEB
60	Fundacion Estudios Clinicos-Oncology ( Site 0017)	Rosario	Santa Fe	Argentina	2000
61	Sanatorio Britanico ( Site 0013)	Rosario	Santa Fe	Argentina	S2000CVB
62	Instituto de Oncologia de Rosario ( Site 0002)	Rosario	Santa Fe	Argentina	S2000KZE
63	Hospital Provincial del Centenario ( Site 0008)	Rosario	Santa Fe	Argentina	S2002KDS
64	IDIM - Instituto de Diagnóstico e Investigaciones Metabólicas ( Site 0016)	Buenos Aires		Argentina	C1012AAR
65	Hospital Aleman Buenos Aires Argentina ( Site 0004)	Buenos Aires		Argentina	C1118AAT
66	Instituto de Oncología Angel Roffo ( Site 0003)	Buenos Aires		Argentina	C1417DTB
67	CER San Juan Centro Polivalente de Asistencia e Investigacion Clinica ( Site 0010)	San Juan		Argentina	J5402DIL
68	The Crown Princess Mary Cancer Centre - Westmead Hospital ( Site 0051)	Westmead	New South Wales	Australia	2145
69	Royal Brisbane and Women s Hospital ( Site 0050)	Herston	Queensland	Australia	4029
70	Ordensklinikum Linz Gmbh - Barmherzige Schwestern ( Site 1901)	Linz	Oberosterreich	Austria	4010
71	Landeskrankenhaus - Universitatsklinikum Graz ( Site 1902)	Graz	Steiermark	Austria	8036
72	Landeskrankenhaus Salzburg - Universitatklinikum der PMU ( Site 1900)	Salzburg		Austria	5020
73	Medizinische Universität Wien ( Site 1903)	Wien		Austria	1090
74	Hopital de Jolimont ( Site 0103)	Haine Saint Paul	Hainaut	Belgium	7100
75	UZ Gent ( Site 0101)	Gent	Oost-Vlaanderen	Belgium	9000
76	AZ Nikolaas ( Site 0104)	Sint-Niklaas	Oost-Vlaanderen	Belgium	9100
77	Hospital Santa Izabel - Santa Casa de Misericordia da Bahia ( Site 0155)	Salvador	Bahia	Brazil	40050-410
78	Centro Regional Integrado de Oncologia ( Site 0160)	Fortaleza	Ceara	Brazil	60336-232
79	Hospital Marcio Cunha-Unidade de Pesquisa Clínica ( Site 0177)	Ipatinga	Minas Gerais	Brazil	35162-189
80	Liga Norte Riograndense Contra o Cancer ( Site 0171)	Natal	Rio Grande Do Norte	Brazil	59075-740
81	Hospital Nossa Senhora da Conceicao ( Site 0165)	Porto Alegre	Rio Grande Do Sul	Brazil	91359-200
82	Hospital de Base de Sao Jose de Rio Preto ( Site 0153)	Sao Jose do Rio Preto	Sao Paulo	Brazil	15090-000
83	Instituto Nacional do Cancer Jose Alencar Gomes da Silva INCA ( Site 0169)	Rio de Janeiro		Brazil	20231-050
84	Instituto do Cancer do Estado de Sao Paulo - ICESP ( Site 0167)	Sao Paulo		Brazil	01246-000
85	BP - A Beneficencia Portuguesa de São Paulo-Medical Oncology ( Site 0175)	Sao Paulo		Brazil	01321-001
86	Cross Cancer Institute ( Site 0201)	Edmonton	Alberta	Canada	T6G 1Z2
87	Princess Margaret Cancer Centre ( Site 0202)	Toronto	Ontario	Canada	M5G 2M9
88	McGill University Health Centre ( Site 0210)	Montreal	Quebec	Canada	H4A 3J1
89	CIUSSS de l'Estrie-CHUS ( Site 0209)	Sherbrooke	Quebec	Canada	J1H 5N4
90	Fundacion Arturo Lopez Perez FALP ( Site 0251)	Santiago	Region M. De Santiago	Chile	7500921
91	Clinica de la Costa Ltda. ( Site 0307)	Barranquilla	Atlantico	Colombia	080020
92	Centro de Investigacion Clinica del Country ( Site 0304)	Bogota	Distrito Capital De Bogota	Colombia	110221
93	Oncologos del Occidente S.A. ( Site 0310)	Pereira	Risaralda	Colombia	661002
94	Centro Medico Imbanaco de Cali S.A ( Site 0300)	Cali	Valle Del Cauca	Colombia	760042
95	Centre Antoine Lacassagne ( Site 0351)	Nice	Alpes-Maritimes	France	06189
96	Hopital de la Timone ( Site 0356)	Marseille	Bouches-du-Rhone	France	13005
97	Institut Claudius Regaud IUCT Oncopole ( Site 0355)	Toulouse	Haute-Garonne	France	31059
98	Institut Gustave Roussy ( Site 0353)	Villejuif	Val-de-Marne	France	94800
99	Institut Sainte Catherine ( Site 0352)	Avignon	Vaucluse	France	84918
100	Hopital Europeen Georges Pompidou ( Site 0358)	Paris		France	75015
101	Institut Curie ( Site 0350)	Paris		France	75248
102	Universitaetsklinikum Tuebingen - Medizinische Klinik ( Site 0401)	Tuebingen	Baden-Wurttemberg	Germany	72076
103	Universitaetsklinikum Ulm ( Site 0402)	Ulm	Baden-Wurttemberg	Germany	89075
104	Universitaetsklinikum Erlangen-Strahlenklinik ( Site 0412)	Erlangen	Bayern	Germany	91054
105	Klinikum rechts der Isar der Technischen Universitaet ( Site 0409)	Muenchen	Bayern	Germany	81675
106	Klinikum rechts der Isar der Technischen Universität München-HNO Klinik ( Site 0405)	München	Bayern	Germany	81675
107	Universitaetsklinikum Frankfurt ( Site 0403)	Frankfurt	Hessen	Germany	60590
108	Klinikum Kassel GmbH ( Site 0404)	Kassel	Hessen	Germany	34125
109	Universitätsklinikum Schleswig-Holstein ( Site 0411)	Luebeck	Schleswig-Holstein	Germany	23538
110	SRH Wald-Klinikum Gera GmbH ( Site 0406)	Gera	Thuringen	Germany	07548
111	Charite Universitätsmedizin Berlin Campus Benjamin Franklin ( Site 0414)	Berlin		Germany	12203
112	Universitaetsklinikum Hamburg Eppendorf ( Site 0407)	Hamburg		Germany	20246
113	Pecsi Tudomanyegyetem Onkoterapias Intezet ( Site 0452)	Pecs	Baranya	Hungary	7621
114	Jasz Nagykun Szolnok Megyei Hetenyi Geza Korhaz Rendelointezet ( Site 0450)	Szolnok	Jasz-Nagykun-Szolnok	Hungary	5000
115	Magyar Honvedseg Egeszsegugyi Kozpont ( Site 0453)	Budapest		Hungary	1062
116	Orszagos Onkologiai Intezet ( Site 0454)	Budapest		Hungary	1122
117	St. James s Hospital ( Site 0500)	Dublin		Ireland	8
118	Rambam Health Care Campus-Oncology Division ( Site 0550)	Haifa		Israel	3109601
119	Hadassah Medical Center. Ein Kerem ( Site 0554)	Jerusalem		Israel	9112001
120	Rabin Medical Center ( Site 0552)	Petah Tikva		Israel	49100
121	Chaim Sheba Medical Center. ( Site 0553)	Ramat Gan		Israel	5265601
122	Sourasky Medical Center ( Site 0551)	Tel Aviv		Israel	6423906
123	Aichi Cancer Center Hospital ( Site 0658)	Nagoya	Aichi	Japan	464-8681
124	National Cancer Center Hospital East ( Site 0661)	Kashiwa	Chiba	Japan	277-8577
125	Hyogo Cancer Center ( Site 0656)	Akashi	Hyogo	Japan	673-8558
126	Kagawa University Hospital ( Site 0651)	Kita-gun	Kagawa	Japan	761-0793
127	Yokohama City University Hospital ( Site 0657)	Yokohama	Kanagawa	Japan	2360064
128	Chiba Cancer Center ( Site 0652)	Chiba		Japan	260-8717
129	National Hospital Organization Kyushu Cancer Center ( Site 0660)	Fukuoka		Japan	811-1395
130	Hiroshima University Hospital ( Site 0655)	Hiroshima		Japan	734-8551
131	National Cancer Center Hospital ( Site 0650)	Tokyo		Japan	104-0045
132	Tokyo Medical University Hospital ( Site 0659)	Tokyo		Japan	160-0023
133	Tokyo Medical and Dental University Hospital ( Site 0654)	Tokyo		Japan
134	Chonnam National University Hwasun Hospital ( Site 0705)	Hwasun Gun	Jeonranamdo	Korea, Republic of	58128
135	National Cancer Center ( Site 0702)	Goyang-si	Kyonggi-do	Korea, Republic of	10408
136	The Catholic University of Korea St. Vincent s Hospital ( Site 0704)	Gyeonggi-do	Kyonggi-do	Korea, Republic of	16247
137	Seoul National University Bundang Hospital ( Site 0703)	Seongnam-si	Kyonggi-do	Korea, Republic of	13620
138	Severance Hospital, Yonsei University Health System ( Site 0701)	Seoul		Korea, Republic of	03722
139	Wojewodzki Szpital Specjalistyczny im. M. Kopernika w Lodzi ( Site 0920)	Lodz	Lodzkie	Poland	93-513
140	Szpital Specjalistyczny im. Ludwika Rydygiera w Krakowie ( Site 0905)	Krakow	Malopolskie	Poland	31-826
141	Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - Panstwowy Instytut Badawczy w Warszawie (	Warszawa	Mazowieckie	Poland	02-781
142	Szpitale Pomorskie Sp. z o.o. ( Site 0935)	Gdynia	Pomorskie	Poland	81-159
143	Narodowy Instytut Onkologii - Oddzial w Gliwicach ( Site 0901)	Gliwice	Slaskie	Poland	44-101
144	Hospital de Braga ( Site 0951)	Braga		Portugal	4710-243
145	CHLN Hospital Santa Maria ( Site 0952)	Lisboa		Portugal	1649-035
146	Hospital CUF Descobertas ( Site 0953)	Lisboa		Portugal	1998-018
147	Inst. Portugues de Oncologia de Porto Francisco Gentil EPE ( Site 0950)	Porto		Portugal	4200-072
148	N.N. Blokhin NMRCO ( Site 1005)	Moscow	Moskva	Russian Federation	115478
149	Republican Clinical Oncology Dispensary of Tatarstan MoH ( Site 1000)	Kazan	Tatarstan, Respublika	Russian Federation	420029
150	Yaroslavl Regional SBIH Clinical Oncology Hospital ( Site 1001)	Yaroslavl	Yaroslavskaya Oblast	Russian Federation	150054
151	Hospital Germans Trias i Pujol. ICO de Badalona ( Site 1204)	Badalona	Barcelona	Spain	08916
152	ICO L Hospitalet ( Site 1208)	Hospitalet de Llobregat	Barcelona	Spain	08908
153	Hospital Clinico Universitario de Santiago ( Site 1207)	Santiago de Compostela	La Coruna	Spain	15706
154	Hospital Vall D Hebron ( Site 1200)	Barcelona		Spain	08035
155	Hospital Universitario La Paz ( Site 1201)	Madrid		Spain	28046
156	Hospital Universitario Virgen del Rocio ( Site 1206)	Sevilla		Spain	41013
157	Universitaetsspital Zurich ( Site 1923)	Zuerich	Aargau	Switzerland	8091
158	Istituto Oncologica della Svizzera Italiana (IOSI) ( Site 1921)	Bellinzona	Ticino	Switzerland	6500
159	Hopitaux Universitaires de Geneve HUG ( Site 1920)	Geneve		Switzerland	1211
160	Chang Gung Medical Foundation. Kaohsiung Branch ( Site 1303)	Kaohsiung		Taiwan	833
161	Taichung Veterans General Hospital ( Site 1301)	Taichung		Taiwan	40705
162	National Cheng Kung University Hospital ( Site 1302)	Tainan		Taiwan	704
163	National Taiwan University Hospital ( Site 1300)	Taipei		Taiwan	10002
164	Dnipropetrovsk Regional Hospital n.a. I.I. Mechnikov ( Site 1709)	Dnipropetrovsk	Dnipropetrovska Oblast	Ukraine	49005
165	Clinical oncology dispensary of Dnipro ( Site 1706)	Dnipro	Dnipropetrovska Oblast	Ukraine	49055
166	Municipal Non-Profit Enterprise City Clinical Hospital 4 of Dnipro City Council ( Site 1705)	Dnipro	Dnipropetrovska Oblast	Ukraine	49102
167	Ukrainian Center of Tomotherapy ( Site 1708)	Kropyvnitskiy	Kirovohradska Oblast	Ukraine	25011
168	PP PPC Acinus Medical and Diagnostic Centre ( Site 1704)	Kropyvnytskyi	Kirovohradska Oblast	Ukraine	25006
169	Medical Center of Yuriy Spizhenko LLC.-Clinical Trial ( Site 1703)	Kapitanivka Village	Kyivska Oblast	Ukraine	08111
170	National Cancer Institute of the MoH of Ukraine ( Site 1702)	Kyiv	Kyivska Oblast	Ukraine	03022
171	LISOD. Hospital ( Site 1707)	Pliuty	Kyiv	Ukraine	08720
172	Kyiv City Clinical Oncology Centre ( Site 1701)	Kyiv		Ukraine	03115
173	Castle Hill Hospital ( Site 1601)	Cottingham-Hull	Kingston Upon Hull	United Kingdom	HU16 5JQ
174	Guy s & St Thomas NHS Foundation Trust ( Site 1604)	London	London, City Of	United Kingdom	SE1 9RT
175	Royal Marsden Hospital - Fulham Road London ( Site 1609)	London	London, City Of	United Kingdom	SW3 6JJ
176	Imperial Healthcare NHS Trust Charing Cross Hospital ( Site 1603)	London	London, City Of	United Kingdom	W6 8RF
177	Weston Park Hospital ( Site 1607)	Sheffield		United Kingdom	S10 2SJ