Safety and Efficacy of Lenvatinib (E7080/MK-7902) With Pembrolizumab (MK-3475) in Combination With Transarterial Chemoembolization (TACE) in Participants With Incurable/Non-metastatic Hepatocellular Carcinoma (MK-7902-012/E7080-G000-318/LEAP-012)

Sponsor

Merck Sharp & Dohme LLC (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04246177

Collaborator

Eisai Inc. (Industry)

950

Enrollment

198

Locations

Arms

115.3

Anticipated Duration (Months)

4.8

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy and safety of lenvatinib and pembrolizumab in combination with TACE versus TACE plus oral and intravenous (IV) placebos in participants with incurable, non-metastatic hepatocellular carcinoma (HCC). The primary hypotheses are that pembrolizumab plus lenvatinib in combination with TACE is superior to placebo plus TACE with respect to progression-free survival (PFS) and overall survival (OS).

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Hepatocellular	Drug: Lenvatinib Biological: Pembrolizumab Drug: Oral Placebo Drug: IV Placebo Procedure: TACE	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

950 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

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

Primary Purpose:

Treatment

Official Title:

A Phase 3 Multicenter, Randomized, Double-blinded, Active-controlled, Clinical Study to Evaluate the Safety and Efficacy of Lenvatinib (E7080/MK-7902) With Pembrolizumab (MK-3475) in Combination With Transarterial Chemoembolization (TACE) Versus TACE in Participants With Incurable/Non-metastatic Hepatocellular Carcinoma (LEAP-012)

Actual Study Start Date :

May 22, 2020

Anticipated Primary Completion Date :

Apr 25, 2025

Anticipated Study Completion Date :

Dec 31, 2029

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lenvatinib plus Pembrolizumab plus TACE Participants will receive a combination of lenvatinib, pembrolizumab, and TACE. Lenvatinib will be administered at a dose of 12 mg (for participants with screening body weight ≥60 kg) or 8 mg (for participants with screening body weight <60 kg) orally once a day during each 21-day cycle until progressive disease or unacceptable toxicity (up to 2 years [~35 cycles] or longer with Sponsor approval). Pembrolizumab will be administered via IV infusion at a dose of 400 mg once every 6 weeks (Q6W) for up to 2 years (~17 doses). Participants will undergo TACE as a background procedure of chemotherapeutic and embolic agent(s).	Drug: Lenvatinib Administered at a dose of 12 mg (for participants with screening body weight ≥60 kg) or 8 mg (for participants with screening body weight <60 kg) via oral capsules once a day during each 21-day cycle. Other Names: MK-7902 E7080 LENVIMA® Biological: Pembrolizumab Administered via IV infusion at a dose of 400 mg once every 6 weeks (Q6W). Other Names: MK-3475 KEYTRUDA® Procedure: TACE Conducted as a background procedure of chemotherapeutic and embolic agent(s).
Active Comparator: Oral Placebo plus IV Placebo plus TACE Participants will receive a combination of lenvatinib-matching oral placebo, pembrolizumab-matching IV placebo, and TACE. Lenvatinib-matching oral placebo will be administered once a day during each 21-day cycle for up to 2 years (~35 cycles) or longer with Sponsor approval and pembrolizumab-matching IV placebo will be administered once every 6 weeks (Q6W) for up to 2 years (~17 doses). Participants will undergo TACE as a background procedure of chemotherapeutic and embolic agent(s).	Drug: Oral Placebo Lenvatinib-matching placebo administered via oral capsules once a day during each 21-day cycle. Drug: IV Placebo Pembrolizumab-matching placebo administered via IV infusion once every 6 weeks (Q6W). Procedure: TACE Conducted as a background procedure of chemotherapeutic and embolic agent(s).

Arm

Intervention/Treatment

Experimental: Lenvatinib plus Pembrolizumab plus TACE

Participants will receive a combination of lenvatinib, pembrolizumab, and TACE. Lenvatinib will be administered at a dose of 12 mg (for participants with screening body weight ≥60 kg) or 8 mg (for participants with screening body weight <60 kg) orally once a day during each 21-day cycle until progressive disease or unacceptable toxicity (up to 2 years [~35 cycles] or longer with Sponsor approval). Pembrolizumab will be administered via IV infusion at a dose of 400 mg once every 6 weeks (Q6W) for up to 2 years (~17 doses). Participants will undergo TACE as a background procedure of chemotherapeutic and embolic agent(s).

Drug: Lenvatinib

Administered at a dose of 12 mg (for participants with screening body weight ≥60 kg) or 8 mg (for participants with screening body weight <60 kg) via oral capsules once a day during each 21-day cycle.

Other Names:

MK-7902

E7080

LENVIMA®

Biological: Pembrolizumab

Administered via IV infusion at a dose of 400 mg once every 6 weeks (Q6W).

Other Names:

MK-3475

KEYTRUDA®

Procedure: TACE

Conducted as a background procedure of chemotherapeutic and embolic agent(s).

Active Comparator: Oral Placebo plus IV Placebo plus TACE

Participants will receive a combination of lenvatinib-matching oral placebo, pembrolizumab-matching IV placebo, and TACE. Lenvatinib-matching oral placebo will be administered once a day during each 21-day cycle for up to 2 years (~35 cycles) or longer with Sponsor approval and pembrolizumab-matching IV placebo will be administered once every 6 weeks (Q6W) for up to 2 years (~17 doses). Participants will undergo TACE as a background procedure of chemotherapeutic and embolic agent(s).

Drug: Oral Placebo

Lenvatinib-matching placebo administered via oral capsules once a day during each 21-day cycle.

Drug: IV Placebo

Pembrolizumab-matching placebo administered via IV infusion once every 6 weeks (Q6W).

Procedure: TACE

Conducted as a background procedure of chemotherapeutic and embolic agent(s).

Outcome Measures

Primary Outcome Measures

Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [Up to ~5 years]
PFS is defined as the time from randomization to the first documented progressive disease or death due to any cause, whichever occurs first. Responses are according to RECIST 1.1 as assessed by blinded independent central review (BICR).
Overall Survival (OS) [Up to ~5 years]
OS is defined as the time from randomization to death due to any cause.

Secondary Outcome Measures

PFS per Modified Response Evaluation Criteria in Solid Tumors (mRECIST) [Up to ~5 years]
PFS is defined as the time from randomization to the first documented progressive disease or death due to any cause, whichever occurs first. Responses are according to mRECIST as assessed by BICR.
Objective Response Rate (ORR) per mRECIST [Up to ~5 years]
ORR is defined as the percentage of participants who have a confirmed complete response (CR: disappearance of any intratumoral arterial enhancement in all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters of viable [enhancement in the arterial phase] target lesions, taking as reference the baseline sum of the diameters of target lesions). Responses are according to mRECIST as assessed by BICR.
Disease Control Rate (DCR) per mRECIST [Up to ~5 years]
DCR is defined as the percentage of participants who have a best overall response of CR (disappearance of any intratumoral arterial enhancement in all target lesions), PR (at least a 30% decrease in the sum of diameters of viable [enhancement in the arterial phase] target lesions, taking as reference the baseline sum of the diameters of target lesions), or stable disease (SD). Responses are according to mRECIST as assessed by BICR.
Duration of Response (DOR) per mRECIST [Up to ~5 years]
DOR is determined by disease assessment and is defined as the time from the first documented evidence of a response of CR (disappearance of any intratumoral arterial enhancement in all target lesions) or PR (at least a 30% decrease in the sum of diameters of viable [enhancement in the arterial phase] target lesions, taking as reference the baseline sum of the diameters of target lesions) until the first documented disease progression or death due to any cause, whichever occurs first. Responses are according to mRECIST as assessed by BICR.
Time to Progression (TTP) per mRECIST [Up to ~5 years]
TTP is defined as the time from randomization to the first documented disease progression. Responses are according to mRECIST as assessed by BICR.
Percentage of Participants Who Experience At Least One Adverse Event (AE) [Up to ~5 years]
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The percentage of participants who experience at least one AE will be reported.
Percentage of Participants Who Experience At Least One Serious Adverse Event (SAE) [Up to ~5 years]
An SAE is an AE that results in death, is life threatening, requires or prolongs a hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, is a cancer, is associated with an overdose, or is another important medical event. The percentage of participants who experience at least one SAE will be reported.
Percentage of Participants Who Experience At Least One Hepatic Event of Clinical Interest (ECI) [Up to ~5 years]
Percentage of participants with Hepatic ECIs not due to disease progression or TACE as assessed by the investigator will be reported.
Percentage of Participants Who Discontinue Study Drug Due to an AE [Up to ~5 years]
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The percentage of participants who discontinue study drug due to an AE will be reported.
ORR per RESCIST 1.1 [Up to ~5 years]
ORR is defined as the percentage of participants who have a confirmed complete response (CR: disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters). Responses are according to RECIST 1.1 as assessed by BICR.
DCR per RECIST 1.1 [Up to ~5 years]
DCR is defined as the percentage of participants who have a best overall response of CR (disappearance of all target lesions), PR (at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters), or SD. Responses are according to RECIST 1.1 as assessed by BICR.
DOR per RECIST 1.1 [Up to ~5 years]
DOR is determined by disease assessment and is defined as the time from the first documented evidence of a response of CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters) until the first documented disease progression or death due to any cause, whichever occurs first. Responses are according to RECIST 1.1 as assessed by BICR.
TTP per RECIST 1.1 [Up to ~5 years]
TTP is defined as the time from randomization to the first documented disease progression. Responses are according to RECIST 1.1 as assessed by BICR.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Has a diagnosis of HCC confirmed by radiology, histology, or cytology
Has HCC localized to the liver and not amenable to curative treatment
Participants with Hepatitis C virus (HCV) are eligible if treatment was completed at least 1 month prior to starting study intervention
Participants with Hepatitis B virus (HBV) are eligible
Has adequately controlled blood pressure with or without antihypertensive medications
Has adequate organ function

Exclusion Criteria:

Is currently a candidate for liver transplantation
Has had gastric bleeding within the last 6 months
Has ascites that is not controlled with medication
Has significant cardiovascular impairment within 12 months of the first dose of study intervention such as congestive heart failure
Has a serious nonhealing wound, ulcer, or bone fracture
Has received locoregional therapy to existing liver lesions

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arizona Oncology Associates PC- HOPE ( Site 0770)	Tucson	Arizona	United States	85711
2	Scripps Clinic Torrey Pines ( Site 0714)	La Jolla	California	United States	92037
3	USC Norris Comprehensive Cancer Center ( Site 0717)	Los Angeles	California	United States	90033
4	UCLA Hematology/Oncology - Santa Monica ( Site 0720)	Los Angeles	California	United States	90404
5	UC Irvine Health ( Site 0718)	Orange	California	United States	92868
6	Yale Cancer Center ( Site 0724)	New Haven	Connecticut	United States	06510
7	Tampa General Hospital ( Site 0764)	Tampa	Florida	United States	33606
8	Mountain States Tumor Institute ( Site 0773)	Boise	Idaho	United States	83712
9	University of Iowa Hospital and Clinics ( Site 0729)	Iowa City	Iowa	United States	52242
10	University of Kansas Cancer Center ( Site 0731)	Westwood	Kansas	United States	66205
11	University of Louisville ( Site 0757)	Louisville	Kentucky	United States	40202
12	Tulane Medical Center ( Site 0787)	New Orleans	Louisiana	United States	70112
13	University Medical Center New Orleans ( Site 0733)	New Orleans	Louisiana	United States	70112
14	Henry Ford Hospital-GI/Hepatology Research ( Site 0735)	Detroit	Michigan	United States	48202
15	Saint Louis University ( Site 0769)	Saint Louis	Missouri	United States	63110
16	Monter Cancer Center ( Site 0780)	Lake Success	New York	United States	11042
17	Icahn School of Medicine at Mount Sinai ( Site 0744)	New York	New York	United States	10029
18	Wake Forest Baptist Health ( Site 0741)	Winston-Salem	North Carolina	United States	27157
19	University of Cincinnati Medical Center ( Site 0791)	Cincinnati	Ohio	United States	45219
20	The Ohio State University Wexner Medical Center ( Site 0759)	Columbus	Ohio	United States	43210
21	ProMedica Flower Hospital ( Site 0796)	Sylvania	Ohio	United States	43560
22	Stephenson Cancer Center ( Site 0745)	Oklahoma City	Oklahoma	United States	73104
23	OHSU Center for Health & Healing ( Site 0746)	Portland	Oregon	United States	97239
24	Penn State Hershey Medical Center ( Site 0766)	Hershey	Pennsylvania	United States	17033-0850
25	Houston Methodist Research Institute ( Site 0784)	Houston	Texas	United States	77030
26	Edwards Comprehensive Cancer Center ( Site 0786)	Huntington	West Virginia	United States	25701
27	St George Hospital ( Site 0005)	Kogarah	New South Wales	Australia	2217
28	Westmead Hospital-Gastroenterology & Hepatology ( Site 0009)	Westmead	New South Wales	Australia	2145
29	Princess Alexandra Hospital ( Site 0006)	Brisbane	Queensland	Australia	4102
30	Austin Health ( Site 0008)	Heidelberg	Victoria	Australia	3084
31	Alfred Health ( Site 0004)	Melbourne	Victoria	Australia	3004
32	Royal Perth Hospital ( Site 0002)	Perth	Western Australia	Australia	6000
33	Hospital Nossa Senhora da Conceição-Centro Integrado de Pesquisa em Oncologia ( Site 0056)	Porto Alegre	Rio Grande Do Sul	Brazil	91350-200
34	Clinica de Oncologia Reichow ( Site 0052)	Blumenau	Santa Catarina	Brazil	89010-340
35	Fundacao Dr Amaral Carvalho ( Site 0050)	JAU	Sao Paulo	Brazil	17210-120
36	Hospital de Base de Sao Jose de Rio Preto ( Site 0043)	Sao Jose do Rio Preto	Sao Paulo	Brazil	15090-000
37	BP - A Beneficencia Portuguesa de São Paulo ( Site 0046)	São Paulo	Sao Paulo	Brazil	01321-001
38	A.C. Camargo Cancer Center ( Site 0054)	Sao Paulo		Brazil	01509-900
39	Centro Investigación del Cáncer James Lind ( Site 0064)	Temuco	Araucania	Chile	4780000
40	Centro de Cancer Nuestra Senora de la Esperanza ( Site 0065)	Santiago	Region M. De Santiago	Chile	8330024
41	Bradfordhill ( Site 0066)	Santiago	Region M. De Santiago	Chile	8420383
42	Anhui Provincial Hospital ( Site 0092)	Heifei	Anhui	China	230001
43	Beijing Cancer Hospital ( Site 0099)	Beijing	Beijing	China	100142
44	Beijing Cancer Hospital ( Site 0105)	Beijing	Beijing	China	100142
45	Peking Union Medical College Hospital ( Site 0087)	Beijing	Beijing	China	100730
46	Chinese People s Liberation Army Army Characteristic Medical Center ( Site 0117)	Chongqing	Chongqing	China	400042
47	Chongqing Three Gorges Central Hospital ( Site 0859)	Wanzhou	Chongqing	China	404199
48	Mengchao Hepatobiliary Hospital of Fujian Medical University ( Site 0121)	Fuzhou	Fujian	China	350001
49	Fujian Provincial Cancer Hospital ( Site 0085)	Fuzhou	Fujian	China	350014
50	The First Affiliated Hospital of Fujian Medical University ( Site 0089)	Fuzhou	Fujian	China	350014
51	Zhongshan Hospital Fudan University (Xiamen Branch) ( Site 0133)	Xiamen	Fujian	China	361015
52	Zhujiang Hospital of Southern Medical University ( Site 0115)	Guangzhou	Guangdong	China	510000
53	Guangdong Provincial People s Hospital ( Site 0100)	Guangzhou	Guangdong	China	510080
54	Nanfang Hospital of Southern Medical University ( Site 0088)	Guangzhou	Guangdong	China	510515
55	SUN YAT-SEN UNIVERSITY CANCER CENTRE-Department of Medical Imaging and Interventional Radiology ( Si	Guangzhou	Guangdong	China	510700
56	Guangxi Medical University Affiliated Tumor Hospital-Hepatological surgery ( Site 0862)	Nanning	Guangxi	China	530021
57	Hainan General Hospital ( Site 0112)	Haikou	Hainan	China	570311
58	Harbin Medical University Cancer Hospital ( Site 0090)	Harbin	Heilongjiang	China	150081
59	Henan Cancer Hospital ( Site 0114)	Zhengzhou	Henan	China	450008
60	Tongji Hospital Tongji Medical,Science & Technology ( Site 0126)	Wuhan	Hubei	China	430030
61	Hubei Cancer Hospital ( Site 0101)	Wuhan	Hubei	China	430079
62	Hunan Provincial People's Hospital ( Site 0113)	Changsha	Hunan	China	410005
63	Hunan Cancer Hospital ( Site 0096)	Changsha	Hunan	China	410013
64	The First Affiliated Hospital of Soochow University ( Site 0120)	Suzhou	Jiangsu	China	215006
65	Jiangxi Provincial Cancer Hospital-Cancer Hospital ( Site 0134)	Nanchang	Jiangxi	China	330029
66	Xi'an International Medical Center Hospital ( Site 0860)	Xi'an	Shaanxi	China	710126
67	The Third Affiliated Hospital of Naval Medical University ( Site 0123)	Shanghai	Shanghai	China	200028
68	Fudan University Shanghai Cancer Center ( Site 0106)	Shanghai	Shanghai	China	200032
69	Zhongshan Hospital Fudan University ( Site 0084)	Shanghai	Shanghai	China	200032
70	The First Affiliated Hospital of Xi an Jiaotong University ( Site 0108)	XI An	Shanxi	China	710048
71	West China Hospital of Sichuan University ( Site 0119)	Chengdu	Sichuan	China	610041
72	Suining Central Hospital ( Site 0857)	Suining	Sichuan	China	629000
73	Tianjin Medical University Cancer Institute & Hospital ( Site 0098)	Tianjin	Tianjin	China	300060
74	The First Hospital of Kunming ( Site 0124)	Kunming	Yunnan	China	650200
75	2nd Affil Hosp of Zhejiang University College of Medicine ( Site 0110)	Hangzhou	Zhejiang	China	310009
76	Sir Run Run Shaw Hospital ( Site 0094)	Hangzhou	Zhejiang	China	310018
77	Zhejiang Cancer Hospital ( Site 0103)	Hangzhou	Zhejiang	China	310022
78	Ningbo Medical Center ( Site 0132)	Ningbo	Zhejiang	China	315041
79	Hospital Pablo Tobon Uribe ( Site 0145)	Medellin	Antioquia	Colombia	050034
80	Administradora Country S.A. ( Site 0137)	Bogota	Distrito Capital De Bogota	Colombia	110221
81	Fundacion Cardiovascular de Colombia ( Site 0136)	Piedecuesta	Santander	Colombia	681017
82	Fundacion Valle del Lili ( Site 0140)	Cali	Valle Del Cauca	Colombia	760032
83	Herlev Hospital ( Site 0170)	Herlev	Hovedstaden	Denmark	2730
84	Aarhus Universitets hospital ( Site 0175)	Aarhus N	Midtjylland	Denmark	8200
85	Odense Universitetshospital ( Site 0160)	Odense	Syddanmark	Denmark	5000
86	Hopital de la Croix-Rousse ( Site 0193)	Lyon	Auvergne	France	69004
87	Hopital de la Timone ( Site 0188)	Marseille	Bouches-du-Rhone	France	13005
88	CHU Bordeaux Haut-Leveque ( Site 0185)	Pessac Cedex	Gironde	France	33604
89	C.H.U. de Nancy. Hopital de Brabois Adultes ( Site 0180)	Vandoeuvre les Nancy	Meurthe-et-Moselle	France	54500
90	A.P.H. Paris, Hopital Henri Mondor ( Site 0179)	Creteil	Val-de-Marne	France	94000
91	Hopital Paul Brousse ( Site 0182)	Villejuif	Val-de-Marne	France	94800
92	Universitaetsklinikum Freiburg ( Site 0199)	Freiburg	Baden-Wurttemberg	Germany	79106
93	Krankenhaus Nord-West GmbH ( Site 0208)	Frankfurt am Main	Hessen	Germany	60488
94	Medizinische Hochschule Hannover ( Site 0200)	Hannover	Niedersachsen	Germany	30625
95	Universitaetsklinikum Bonn ( Site 0203)	Bonn	Nordrhein-Westfalen	Germany	53127
96	Universitaetsklinikum Halle ( Site 0213)	Halle (Saale)	Sachsen-Anhalt	Germany	06120
97	Universitaetsklinikum Leipzig ( Site 0202)	Leipzig	Sachsen	Germany	04103
98	Universitaetsklinikum Schleswig-Holstein-Campus Lubeck ( Site 0215)	Luebeck	Schleswig-Holstein	Germany	23538
99	Charite - Universitaetsmedizin ( Site 0204)	Berlin		Germany	13353
100	Universitaetsklinikum Hamburg-Eppendorf ( Site 0207)	Hamburg		Germany	20246
101	Prince of Wales Hospital ( Site 0242)	Shatin		Hong Kong	000
102	Somogy Megyei Kaposi Mór Oktató Kórház-Oncology center ( Site 0267)	Kaposvár	Somogy	Hungary	7400
103	Zala Megyei Szent Rafael Korhaz ( Site 0265)	Zalaegerszeg	Zala	Hungary	8900
104	Semmelweis University ( Site 0264)	Budapest		Hungary	1085
105	St Vincents University Hospital ( Site 0690)	Dublin		Ireland	D04 YN63
106	Emek Medical Center ( Site 0307)	Afula		Israel	18341
107	Rambam Health Care Campus-Oncology Division ( Site 0305)	Haifa		Israel	3109601
108	Hadassah Ein Karem Jerusalem ( Site 0303)	Jerusaelm		Israel	9112001
109	Rabin Medical Center ( Site 0304)	Petah Tikva		Israel	4941492
110	Sourasky Medical Center ( Site 0306)	Tel Aviv		Israel	6423906
111	Ospedale del Mare ( Site 0327)	Napoli	Campania	Italy	80147
112	ASST Grande Ospedale Metropolitano Niguarda-Oncologia Falck ( Site 0331)	Milan	Milano	Italy	20162
113	AOU Policlinico G. Martino ( Site 0324)	Messina	Sicilia	Italy	98124
114	Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico ( Site 0325)	Milano		Italy	20122
115	Az Osp di Rilievo Nazionale A. Cardarelli ( Site 0329)	Napoli		Italy	80131
116	Azienda USL della Romagna-Dipartimento di Oncologia ed Ematologia ( Site 0332)	Ravenna		Italy	48121
117	Policlinico Universitario -Agostino Gemelli ( Site 0328)	Roma		Italy	00168
118	National Cancer Center Hospital East ( Site 0347)	Kashiwa	Chiba	Japan	2778577
119	Ehime University Hospital ( Site 0368)	Toon	Ehime	Japan	791-0295
120	Kurume University Hospital ( Site 0362)	Kurume	Fukuoka	Japan	830-0011
121	Hokkaido P.W.F.A.C Sapporo-Kosei General Hospital ( Site 0345)	Sapporo	Hokkaido	Japan	060-0033
122	Kanazawa University Hospital ( Site 0354)	Kanazawa	Ishikawa	Japan	920-8641
123	Kagawa Prefectural Central Hospital ( Site 0364)	Takamatsu	Kagawa	Japan	760-8557
124	Toranomon Hospital Kajigaya ( Site 0369)	Kawasaki	Kanagawa	Japan	213-8587
125	Yokohama City University Medical Center ( Site 0351)	Yokohama	Kanagawa	Japan	232-0024
126	Kanagawa Cancer Center ( Site 0352)	Yokohama	Kanagawa	Japan	241-8515
127	Nara Medical University Hospital ( Site 0359)	Kashihara	Nara	Japan	634-8522
128	Kindai University Hospital ( Site 0358)	Osakasayama	Osaka	Japan	5898511
129	Saitama Medical University Hospital ( Site 0370)	Iruma-gun	Saitama	Japan	350-0495
130	Shizuoka Cancer Center Hospital and Research Institute ( Site 0365)	Sunto-gun	Shizuoka	Japan	411-8777
131	Jichi Medical University Hospital ( Site 0353)	Shimotsuke	Tochigi	Japan	329-0498
132	Chiba University Hospital ( Site 0346)	Chiba		Japan	260-8677
133	National Hospital Organization Kyushu Medical Center ( Site 0361)	Fukuoka		Japan	810-8563
134	Hiroshima University Hospital ( Site 0360)	Hiroshima		Japan	7348551
135	Kumamoto University ( Site 0372)	Kumamoto		Japan	860-8556
136	University Hospital, Kyoto Prefectural University of Medicine ( Site 0367)	Kyoto		Japan	602-8566
137	Osaka International Cancer Institute ( Site 0357)	Osaka		Japan	5418567
138	Japanese Red Cross Osaka Hospital ( Site 0356)	Osaka		Japan	543-8555
139	Saga-Ken Medical Centre Koseikan ( Site 0363)	Saga		Japan	840-8571
140	Toranomon Hospital ( Site 0349)	Tokyo		Japan	105-8470
141	Juntendo University Hospital ( Site 0371)	Tokyo		Japan	113-0033
142	The University of Tokyo Hospital ( Site 0348)	Tokyo		Japan	113-8655
143	Chonnam National University Hwasun Hospital ( Site 0572)	Hwasun	Jeonranamdo	Korea, Republic of	58128
144	Seoul National University Bundang Hospital ( Site 0570)	Seongnam-si	Kyonggi-do	Korea, Republic of	13620
145	Pusan National University Hospital ( Site 0568)	Busan	Pusan-Kwangyokshi	Korea, Republic of	49241
146	Kyungpook National University Hospital ( Site 0569)	Daegu	Taegu-Kwangyokshi	Korea, Republic of	41944
147	Seoul National University Hospital ( Site 0567)	Seoul		Korea, Republic of	03080
148	Severance Hospital Yonsei University Health System ( Site 0564)	Seoul		Korea, Republic of	03722
149	Asan Medical Center ( Site 0565)	Seoul		Korea, Republic of	05505
150	Samsung Medical Center ( Site 0566)	Seoul		Korea, Republic of	06351
151	The Catholic University of Korea St. Mary s Hospital ( Site 0571)	Seoul		Korea, Republic of	06591
152	Korea University Guro Hospital ( Site 0573)	Seoul		Korea, Republic of	08308
153	Maastricht University Medical Centre ( Site 0440)	Maastricht	Limburg	Netherlands	6229 HX
154	AMC ( Site 0438)	Amsterdam	Noord-Holland	Netherlands	1105 AZ
155	Leids Universitair Medisch Centrum-Medical Oncology ( Site 0442)	Leiden	Zuid-Holland	Netherlands	2333 ZA
156	Erasmus University Medical Center ( Site 0439)	Rotterdam	Zuid-Holland	Netherlands	3015 GD
157	Universitair Medisch Centrum Utrecht-Medical Oncology ( Site 0441)	Utrecht		Netherlands	3584 CX
158	Auckland City Hospital ( Site 0459)	Auckland		New Zealand	1023
159	Oslo Universitetssykehus Ullevål ( Site 0500)	Oslo		Norway	0450
160	Centro Hospitalar e Universitario de Coimbra ( Site 0502)	Coimbra		Portugal	3000-075
161	Centro Hospitalar de Lisboa Central, EPE - Hosp St. Ant dos Capuchos ( Site 0505)	Lisboa		Portugal	1169-050
162	Centro Hospitalar do Porto, E.P.E. - Hospital Geral de Sto. Antonio ( Site 0504)	Porto		Portugal	4099-001
163	Inst. Portugues de Oncologia de Porto Francisco Gentil EPE ( Site 0503)	Porto		Portugal	4200-072
164	Centro Hospitalar de Sao Joao. EPE - Hospital de Sao Joao ( Site 0501)	Porto		Portugal	4200-319
165	Ad-Vance Medical Research LLC ( Site 0527)	Ponce		Puerto Rico	00717
166	Puerto Rico Medical Research Center LLC ( Site 0523)	San Juan		Puerto Rico	00918
167	VA Caribbean Healthcare System ( Site 0524)	San Juan		Puerto Rico	00921-3201
168	FDI Clinical Research ( Site 0522)	San Juan		Puerto Rico	00927
169	Hospital Universitario Puerta de Hierro ( Site 0596)	Majadahonda	Madrid	Spain	28222
170	Hospital General Universitario de Valencia ( Site 0595)	Valencia	Valenciana, Comunitat	Spain	46014
171	Hospital General Universitario Gregorio Maranon ( Site 0598)	Madrid		Spain	28007
172	Hospital Ramon y Cajal ( Site 0593)	Madrid		Spain	28034
173	Hospital Clinico San Carlos ( Site 0597)	Madrid		Spain	28040
174	Hospital Virgen del Rocio ( Site 0591)	Sevilla		Spain	41013
175	Chang Gung Medical Foundation. Kaohsiung Branch ( Site 0609)	Kaohsiung City	Kaohsiung	Taiwan	833
176	Kaohsiung Medical University Hospital ( Site 0611)	Kaohsiung		Taiwan
177	China Medical University Hospital-Surgical Department ( Site 0610)	Taichung		Taiwan	40447
178	Taichung Veterans General Hospital ( Site 0613)	Taichung		Taiwan	407
179	National Cheng Kung University Hospital ( Site 0608)	Tainan		Taiwan	70457
180	National Taiwan University Hospital ( Site 0606)	Taipei		Taiwan	10002
181	Taipei Veterans General Hospital-Division of Gastroenterology & Hepatology, Department of Medicine (	Taipei		Taiwan	112201
182	Chang Gung Medical Foundation. Linkou ( Site 0607)	Taoyuan		Taiwan	333
183	Chulalongkorn University ( Site 0627)	Bangkok	Krung Thep Maha Nakhon	Thailand	10330
184	Ramathibodi Hospital, Mahidol University ( Site 0628)	Bangkok	Krung Thep Maha Nakhon	Thailand	10400
185	Faculty of Medicine Siriraj Hospital ( Site 0629)	Bangkok	Krung Thep Maha Nakhon	Thailand	10700
186	Hacettepe University Medical Faculty ( Site 0653)	Ankara		Turkey	06230
187	Trakya University Medical Faculty Balkan Oncology Hospital ( Site 0648)	Edirne		Turkey	22030
188	Bezmialem Vakf Üniversitesi-Oncology ( Site 0660)	Istanbul		Turkey	34093
189	Ege University Medical Faculty Tulay Aktas Oncology Hospital ( Site 0654)	Izmir		Turkey	35100
190	Izmir Medical Park Hospital Department of Medical Oncology ( Site 0649)	Izmir		Turkey	35520
191	Konya Necmettin Erbakan University Medical Faculty ( Site 0652)	Konya		Turkey	42080
192	Inonu Universitesi Medical Fakultesi ( Site 0650)	Malatya		Turkey	44280
193	Grigoriev Institute for medical Radiology NAMS of Ukraine ( Site 0673)	Kharkiv	Kharkivska Oblast	Ukraine	61024
194	Communal non profit enterprise Regional Clinical Oncology Center ( Site 0669)	Kharkiv	Kharkivska Oblast	Ukraine	61070
195	Shalimov s NI of Surgery and Transplantation ( Site 0671)	Kyiv	Kyivska Oblast	Ukraine	03126
196	Barts Health NHS Trust ( Site 0692)	London	London, City Of	United Kingdom	EC1A 7BE
197	Royal Marsden NHS Foundation Trust ( Site 0694)	London	London, City Of	United Kingdom	SW3 6JJ
198	Royal Marsden NHS Trust ( Site 0693)	Sutton	Surrey	United Kingdom	SM25PT