Study of Pemetrexed + Platinum Chemotherapy With or Without Pembrolizumab (MK-3475) in Adults With Tyrosine Kinase Inhibitor- (TKI)-Resistant Epidermal Growth Factor Receptor- (EGFR)-Mutated Metastatic Non-squamous Non-small Cell Lung Cancer (NSCLC) (MK-3475-789/KEYNOTE-789)

Sponsor

Merck Sharp & Dohme LLC (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03515837

Collaborator

(none)

492

Enrollment

158

Locations

Arms

59.5

Anticipated Duration (Months)

3.1

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 pemetrexed plus platinum chemotherapy (carboplatin or cisplatin) with or without pembrolizumab (MK-3475; KEYTRUDA®) in the treatment of adults with the following types of tyrosine kinase inhibitor (TKI)-resistant, epidermal growth factor receptor (EGFR)-mutated, metastatic non-squamous non-small cell lung cancer (NSCLC) tumors: 1) TKI-failures (including osimertinib [TAGRISSO®] failure) with T790M-negative mutation tumors, 2) T790M-positive mutation tumors with prior exposure to osimertinib, and 3) first-line osimertinib failure regardless of T790M mutation status.

The primary study hypotheses are that the combination of pembrolizumab plus chemotherapy has superior efficacy compared to saline placebo plus chemotherapy in terms of: 1) Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) based on blinded independent central review, and 2) Overall Survival (OS). This study will be considered to have met its success criteria if the combination of pembrolizumab plus chemotherapy is superior to saline placebo plus chemotherapy in terms of PFS or OS.

Condition or Disease	Intervention/Treatment	Phase
Non-small Cell Lung Cancer	Biological: pembrolizumab Drug: pemetrexed Drug: carboplatin Drug: cisplatin Drug: saline solution	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

492 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

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

Primary Purpose:

Treatment

Official Title:

A Randomized, Double-Blind, Phase 3 Study of Pemetrexed + Platinum Chemotherapy With or Without Pembrolizumab (MK-3475) in TKI-resistant EGFR-mutated Tumors in Metastatic Non-squamous Non-small Cell Lung Cancer (NSCLC) Participants (KEYNOTE-789)

Actual Study Start Date :

Jun 29, 2018

Anticipated Primary Completion Date :

Jun 15, 2023

Anticipated Study Completion Date :

Jun 15, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pembro+Pemetrexed+Chemo Participants receive pembrolizumab (pembro) 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles PLUS pemetrexed 500 mg/m^2 via IV infusion Q3W with no restrictions on the number of cycles PLUS platinum chemotherapy (chemo) (either carboplatin Area Under the Curve [AUC] 5 via IV infusion Q3W for 4 cycles [Cycles 1-4] or cisplatin 75 mg/m^2 via IV infusion Q3W for 4 cycles [Cycles 1-4]).	Biological: pembrolizumab IV infusion Other Names: MK-3475 Drug: pemetrexed IV infusion Drug: carboplatin IV infusion Drug: cisplatin IV infusion
Active Comparator: Placebo+Pemetrexed+Chemo Participants receive normal saline solution via IV infusion on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles PLUS pemetrexed 500 mg/m^2 via IV infusion Q3W with no restrictions on the number of cycles PLUS platinum chemotherapy (chemo)(either carboplatin AUC 5 via IV infusion Q3W for 4 cycles [Cycles 1-4] or cisplatin 75 mg/m^2 via IV infusion Q3W for 4 cycles [Cycles 1-4]).	Drug: pemetrexed IV infusion Drug: carboplatin IV infusion Drug: cisplatin IV infusion Drug: saline solution IV infusion Other Names: Normal saline solution

Arm

Intervention/Treatment

Experimental: Pembro+Pemetrexed+Chemo

Participants receive pembrolizumab (pembro) 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles PLUS pemetrexed 500 mg/m^2 via IV infusion Q3W with no restrictions on the number of cycles PLUS platinum chemotherapy (chemo) (either carboplatin Area Under the Curve [AUC] 5 via IV infusion Q3W for 4 cycles [Cycles 1-4] or cisplatin 75 mg/m^2 via IV infusion Q3W for 4 cycles [Cycles 1-4]).

Biological: pembrolizumab

IV infusion

Other Names:

MK-3475

Drug: pemetrexed

IV infusion

Drug: carboplatin

IV infusion

Drug: cisplatin

IV infusion

Active Comparator: Placebo+Pemetrexed+Chemo

Participants receive normal saline solution via IV infusion on Day 1 of each 3-week cycle (Q3W) for up to 35 cycles PLUS pemetrexed 500 mg/m^2 via IV infusion Q3W with no restrictions on the number of cycles PLUS platinum chemotherapy (chemo)(either carboplatin AUC 5 via IV infusion Q3W for 4 cycles [Cycles 1-4] or cisplatin 75 mg/m^2 via IV infusion Q3W for 4 cycles [Cycles 1-4]).

Drug: pemetrexed

IV infusion

Drug: carboplatin

IV infusion

Drug: cisplatin

IV infusion

Drug: saline solution

IV infusion

Other Names:

Normal saline solution

Outcome Measures

Primary Outcome Measures

Progression-free Survival (PFS) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [Up to approximately 40 months]
PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. PFS will be assessed by blinded independent central review (BICR) using RECIST 1.1. Per RECIST 1.1, PD is defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions is also considered PD. The PFS for participants will be presented.
Overall Survival (OS) [Up to approximately 66 months]
OS is defined as the time from randomization to death due to any cause. Participants without documented death at the time of the final analysis will be censored at the date of the last follow-up. The OS of participants will be presented.

Secondary Outcome Measures

Objective Response Rate (ORR) Per RECIST 1.1 [Up to approximately 32 months]
ORR is defined as the percentage of participants in the analysis population who experience a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters) per RECIST 1.1. The ORR for participants will be presented.
Duration of Response (DOR) Per RECIST 1.1 [Up to approximately 32 months]
For participants who experience a response of CR or PR, DOR is defined as the time from the earliest date of qualifying response until earliest date of PD or death from any cause, whichever comes first. DOR will be assessed per RECIST 1.1 based on BICR. The DOR of participants who experience a CR or PR will be presented.
Change from Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 Item (QLQ-C30) Global Health Status (Item 29) Scale Score [Baseline and Week 12, Week 27]
The EORTC QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. For Global Health Status, participants are asked "How would you rate your overall health during the past week?" Individual responses are given on a 7-point scale (1=Very poor; 7=Excellent), with a higher score indicating a better outcome. The change from baseline in EORTC-QLQ-C30 score for Global Health Status will be presented.
Time to True Deterioration (TTD) in the EORTC Questionnaire Composite Endpoint of Cough, Chest Pain or Dyspnea [Up to approximately 32 months]
TTD is the time from baseline to first onset of 10 points or more deterioration from baseline with confirmation by the subsequent visit of 10 points or more deterioration from baseline in the composite endpoint of cough [EORTC QLQ-Lung Cancer Module 13 (LC13) Item 1; How much did you cough?], chest pain [EORTC QLQ-LC13 Item 10; Have you had pain in your chest?], or dyspnea [EORTC QLQ-C30 Item 8; Were you short of breath?]. Individual responses are given on a 4-point scale (1=Not at all; 4=Very much), with a lower score indicating a better outcome. The time to true deterioration in the composite endpoint of cough, chest pain or dyspnea will be presented.
Adverse Events (AEs) [Up to 90 days after last dose of study treatment (Up to approximately 42 months)]
An AE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of study treatment. The number of participants who experience an AE will be presented.
Study Treatment Discontinuations Due to AEs [Up to approximately 39 months]
The number of participants who discontinue study treatment due to an AE will be presented.
Change from Baseline in EORTC-QLQ-C30 Quality of Life (Item 30) Scale Score [Baseline and Week 12, Week 27]
The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. For Quality of Life, participants are asked "How would you rate your overall quality of life during the past week?" Individual responses are given on a 7-point scale (1=Very poor; 7=Excellent), with a higher score indicating a better outcome. The change from baseline in EORTC-QLQ-C30 score for Quality of Life will be presented.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Histologically or cytologically confirmed diagnosis of Stage IV non-squamous NSCLC.
Documentation of tumor activating EGFR mutation, specifically either DEL19 or L858R.
Investigator-determined radiographic disease progression per RECIST 1.1 after treatment with an EGFR TKI therapy: a) Participants previously treated with 1st or 2nd generation EGFR TKI (e.g. erlotinib/afatinib/gefitinib) are required to have confirmed documented absence of EGFR T790M mutation; b) Participants with confirmed acquired T790M mutation after 1st or 2nd generation EGFR TKI (e.g. erlotinib/afatinib/gefitinib) are required to have osimertinib TKI treatment failure prior to enrollment; c) Participants previously failed osimertinib TKI treatment as 1st line therapy are eligible regardless of their EGFR T790M mutation status. Note: TKI washout period for all participants is 1 week or 2 half-lives after last treatment dose, whichever is longer. TKI washout should be completed prior to first dose of study treatment.
Measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology.
Provided archival tumor tissue sample or newly obtained (no anti-neoplastic therapy since biopsy) core or excisional biopsy of a tumor lesion not previously irradiated.
Life expectancy of at least 3 months.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 7 days prior to the first dose of study treatment but before randomization.
Male participants must agree to use contraception during the treatment period and for at least 120 days after the last dose of pembrolizumab and up to 180 days after last dose of chemotherapeutic agents.
Female participants must not be pregnant, not breastfeeding, and must agree to use contraception during the treatment period and for at least 120 days after the last dose of pembrolizumab and up to 180 days after the last dose of chemotherapeutic agents.
Adequate organ function.

Exclusion Criteria:

Predominantly squamous cell histology NSCLC. Mixed tumors will be categorized by the predominant cell type; if small cell elements are present, the participant is ineligible.
Symptomatic ascites or pleural effusion. A participant who is clinically stable following treatment for these conditions (including therapeutic thoraco- or paracentesis) is eligible.
Received prior therapy with an anti-programmed cell death protein-1 (anti-PD-1), anti-programmed cell death-ligand 1 (anti-PD-L1), or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g. cytotoxic T-lymphocyte-associated protein-4 [CTLA-4], OX-40, CD137).
Received prior systemic cytotoxic chemotherapy or investigational agent(s), excluding EGFR TKIs, for metastatic NSCLC. [Notes: 1) Prior treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant therapy is allowed as long as therapy was completed at least 6 months prior to the diagnosis of metastatic NSCLC. 2) If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment.

Prior exposure to traditional medicine(s) is allowed as long as therapy was discontinued at least 4 weeks prior to the first dose of study treatment.]

Received prior radiotherapy within 2 weeks of start of study treatment or has received lung radiation therapy of >30 Gray (Gy) within 6 months before the first dose of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system (CNS) disease.
Received a live vaccine within 30 days prior to the first dose of study treatment.
Currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study treatment.
Known additional malignancy that is progressing or has required active treatment within the past 5 years. (Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.)
Known active untreated CNS metastases and/or carcinomatous meningitis.
Severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients.
Known sensitivity to any component of cisplatin, carboplatin, or pemetrexed.
Active autoimmune disease that has required systemic treatment in past 2 years.
History of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
Active infection requiring systemic therapy.
Known history of human immunodeficiency virus (HIV) infection.
Known history of Hepatitis B or known active Hepatitis C virus.
Known history of active tuberculosis (TB; Bacillus tuberculosis)
Pregnant, breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of pembrolizumab and up to 180 days after the last dose of chemotherapeutic agents.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cedars-Sinai Medical Center ( Site 0070)	Los Angeles	California	United States	90048
2	Pacific Cancer Care ( Site 0058)	Monterey	California	United States	93940
3	UC Irvine Medical Center/Chao Family Comprehensive Cancer Center ( Site 0092)	Orange	California	United States	92868
4	St. Joseph Heritage Healthcare ( Site 0003)	Santa Rosa	California	United States	95403
5	North Shore University Health System ( Site 0030)	Evanston	Illinois	United States	60201
6	Siouxland Regioinal Cancer Center dba June E. Nylen Cancer Center ( Site 0065)	Sioux City	Iowa	United States	51101
7	Southdale Cancer Care, University of Minnesota Medical Center- Edina ( Site 0048)	Edina	Minnesota	United States	55435
8	Saint Lukes Hospital of Kansas City ( Site 0060)	Kansas City	Missouri	United States	64111
9	New York Oncology Hematology P.C ( Site 8000)	Albany	New York	United States	12208
10	Monter Cancer Center ( Site 0054)	Lake Success	New York	United States	11042
11	Memorial Sloan Kettering Cancer Center-Rockerfeller Patient Pavilion ( Site 0049)	New York	New York	United States	10022
12	White Plains Hospital Center for Cancer Care ( Site 0014)	White Plains	New York	United States	10601
13	Providence Portland Medical Center ( Site 0097)	Portland	Oregon	United States	97213
14	Kaiser Permanente Northwest ( Site 0037)	Portland	Oregon	United States	97227
15	Parkland Health & Hospital System ( Site 2102)	Dallas	Texas	United States	75235
16	University of Texas Southwestern Medical Center at Dallas ( Site 0035)	Dallas	Texas	United States	75390
17	Utah Cancer Specialists ( Site 0001)	Salt Lake City	Utah	United States	84106
18	Emily Couric Clinical Cancer Center ( Site 0020)	Charlottesville	Virginia	United States	22903
19	Froedtert Hospital & the Medical College of Wisconsin ( Site 0041)	Milwaukee	Wisconsin	United States	53226
20	Chris OBrien Lifehouse ( Site 0200)	Camperdown	New South Wales	Australia	2050
21	Westmead Hospital ( Site 0201)	Westmead	New South Wales	Australia	2145
22	Eastern Health ( Site 0202)	Box Hill	Victoria	Australia	3128
23	Austin Health ( Site 0203)	Heidelberg	Victoria	Australia	3084
24	Liga Norte Riograndense Contra o Cancer ( Site 1909)	Natal	Rio Grande Do Norte	Brazil	59075-740
25	Hospital de Caridade de Ijui ( Site 1907)	Ijui	Rio Grande Do Sul	Brazil	98700-000
26	Hospital Bruno Born ( Site 1913)	Lajeado	Rio Grande Do Sul	Brazil	95900-010
27	Hospital de Clinicas de Porto Alegre ( Site 1905)	Porto Alegre	Rio Grande Do Sul	Brazil	90035-903
28	Uniao Brasileira de Educacao e Assistencia Hospital Sao Lucas da Pucrs ( Site 1904)	Porto Alegre	Rio Grande Do Sul	Brazil	90610-000
29	Fundacao Pio XII - Hospital de Cancer de Barretos ( Site 1911)	Barretos	Sao Paulo	Brazil	14784-400
30	Hosp. Clinicas da Fac. de Medicina de Ribeirao Preto - USP ( Site 1912)	Ribeirao Preto	Sao Paulo	Brazil	14048-900
31	Instituto do Cancer do Estado de Sao Paulo - ICESP ( Site 1903)	Sao Paulo		Brazil	01246-000
32	William Osler Health System ( Site 0100)	Brampton	Ontario	Canada	L6R 3J7
33	Sunnybrook Health Sciences, Odette Cancer Centre ( Site 0102)	Toronto	Ontario	Canada	M4N 3M5
34	Princess Margaret Cancer Centre ( Site 0104)	Toronto	Ontario	Canada	M5G 2M9
35	Jewish General Hospital ( Site 0105)	Montreal	Quebec	Canada	H3T 1E2
36	The First Affiliated Hospital of Anhui Medical University ( Site 0721)	Hefei	Anhui	China	230088
37	Cancer Hospital Chinese Academy of Medical Sciences ( Site 0717)	Beijing	Beijing	China	100021
38	Peking Union Medical College Hospital ( Site 0703)	Beijing	Beijing	China	100032
39	Beijing Cancer Hospital ( Site 0718)	Beijing	Beijing	China	100036
40	Southwest Hospital, The Third Military Medical University ( Site 0725)	Chongqing	Chongqing	China	400038
41	Fujian Cancer Hospital ( Site 0723)	Fuzhou	Fujian	China	350014
42	The Affiliated Tumour Hospital of Harbin Medical University ( Site 0706)	Harbin	Heilongjiang	China	150081
43	Henan Cancer Hospital ( Site 0711)	Zhengzhou	Henan	China	450008
44	Xiangya Hospital of Central South University ( Site 0710)	Changsha	Hunan	China	410008
45	Hunan Cancer Hospital ( Site 0722)	Changsha	Hunan	China	410013
46	Jiangsu Cancer Hospital ( Site 0719)	Nanjing	Jiangsu	China	210000
47	The First Hospital of Jilin University ( Site 0702)	Chang chun	Jilin	China	130021
48	Jilin Cancer Hospital ( Site 0705)	Changchun	Jilin	China	130103
49	Shanghai Chest Hospital ( Site 0700)	Shanghai	Shanghai	China	200030
50	Zhongshan Hospital Fudan University ( Site 0712)	Shanghai	Shanghai	China	200433
51	Tangdu Hospital ( Site 0708)	XI An	Shanxi	China	710038
52	The First Affiliated Hospital of Xi an Jiaotong University ( Site 0709)	XI An	Shanxi	China	710061
53	Affiliated Tumor Hospital of Xinjiang Medical University ( Site 0701)	Urumqi	Xinjiang	China	830000
54	The First Affiliated Hospital.Zhejiang University ( Site 0713)	Hangzhou	Zhejiang	China	310003
55	Sir Run Run Shaw Hospital School of Medicine, Zhejiang University ( Site 0715)	Hangzhou	Zhejiang	China	310016
56	Zhejiang Cancer Hospital ( Site 0716)	Hangzhou	Zhejiang	China	310022
57	Centre Leon Berard ( Site 0801)	Lyon	Auvergne	France	69008
58	CHU Caen Service de Pneumologie ( Site 0804)	Caen	Calvados	France	14033
59	Centre Georges Francois Leclerc ( Site 0809)	Dijon	Cote-d'Or	France	21000
60	Hopital Jean Minjoz Besancon ( Site 0805)	Besancon	Doubs	France	25030
61	Hopital Prive d'Antony ( Site 0811)	Antony	Hauts-de-Seine	France	92160
62	C.H.U. de Tours - Hopital Bretonneau ( Site 0806)	Tours	Indre-et-Loire	France	37044
63	Centre D Oncologie de Gentilly ( Site 0810)	Nancy	Meurthe-et-Moselle	France	54100
64	Clinique Victor Hugo ( Site 0802)	Le Mans	Sarthe	France	72000
65	CHU Poitiers ( Site 0803)	Poitiers	Vienne	France	86021
66	Robert Bosch Krankenhaus Klinik Schillerhoehe ( Site 0904)	Gerlingen	Baden-Wurttemberg	Germany	70839
67	Universitaetsklinikum Mannheim ( Site 0911)	Mannheim	Baden-Wurttemberg	Germany	68167
68	Klinikum Wuerzburg Mitte gGmbH ( Site 0901)	Wuerzburg	Bayern	Germany	97074
69	Pius Hospital Oldenburg ( Site 0905)	Oldenburg	Niedersachsen	Germany	26121
70	Florence Nightingale Krankenhaus ( Site 0912)	Duesseldorf	Nordrhein-Westfalen	Germany	40489
71	Kliniken Essen-Mitte ( Site 0900)	Essen	Nordrhein-Westfalen	Germany	45136
72	Universitaetsklinikum Muenster ( Site 0906)	Muenster	Nordrhein-Westfalen	Germany	48149
73	Medizinische Fakultaet Carl Gustav Carus der TU Dresden ( Site 0907)	Dresden	Sachsen	Germany	01307
74	Asklepios Klinikum Hamburg ( Site 0908)	Hamburg		Germany	21075
75	Hong Kong Integrated Oncology Centre ( Site 0304)	Hong Kong		Hong Kong
76	Queen Mary Hospital ( Site 0301)	Hong Kong		Hong Kong
77	Queen Mary Hospital ( Site 0303)	Hong Kong		Hong Kong
78	Hong Kong United Oncology Centre ( Site 0306)	Kowloon		Hong Kong
79	Tuen Mun Hospital ( Site 0305)	Tuen Mun		Hong Kong
80	Barzilai Medical Center ( Site 1706)	Ashkelon	HaDarom	Israel	7830604
81	Soroka Medical Center ( Site 1702)	Beer-Sheva	HaDarom	Israel	8457108
82	Meir Medical Center ( Site 1701)	Kfar-Saba	HaMerkaz	Israel	4428164
83	Rabin Medical Center ( Site 1704)	Petah Tikva	HaMerkaz	Israel	4941492
84	Ha Emek Medical Center ( Site 1707)	Afula	HaTsafon	Israel	1834111
85	Rambam Medical Center ( Site 1703)	Haifa	Heifa	Israel	3109601
86	Chaim Sheba Medical Center. ( Site 1700)	Ramat Gan	Tell Abib	Israel	5265601
87	Sourasky Medical Center ( Site 1705)	Tel Aviv	Tell Abib	Israel	6423906
88	Istituto Europeo di Oncologia ( Site 1303)	Milano	Lombardia	Italy	20141
89	Ospedale San Vincenzo di Taormina ( Site 1302)	Taormina	Messina	Italy	98039
90	AOU San Luigi Gonzaga di Orbassano ( Site 1300)	Orbassano	Torino	Italy	10043
91	IRCCS Giovanni Paolo II. Ospedale Oncologico ( Site 1305)	Bari		Italy	70124
92	Azienda Ospedaliero Universitaria Careggi ( Site 1301)	Firenze		Italy	50134
93	Azienda Ospedaliera dei Colli V. Monaldi ( Site 1306)	Napoli		Italy	80131
94	Universita Campus Bio-Medico di Roma ( Site 1304)	Roma		Italy	00128
95	National Hospital Organization Nagoya Medical Center ( Site 0608)	Nagoya	Aichi	Japan	460-0001
96	Aichi Cancer Center Hospital ( Site 0612)	Nagoya	Aichi	Japan	464-8681
97	Fujita Health University Hospital ( Site 0619)	Toyoake	Aichi	Japan	470-1192
98	National Cancer Center Hospital East ( Site 0601)	Kashiwa	Chiba	Japan	277-8577
99	National Hospital Organization Shikoku Cancer Center ( Site 0616)	Matsuyama	Ehime	Japan	791-0280
100	Hyogo Cancer Center ( Site 0604)	Akashi	Hyogo	Japan	673-8558
101	Kanazawa University Hospital ( Site 0617)	Kanazawa	Ishikawa	Japan	920-8641
102	Kanagawa Cancer Center ( Site 0609)	Yokohama	Kanagawa	Japan	241-8515
103	Kansai Medical University Hospital ( Site 0606)	Hirakata	Osaka	Japan	573-1191
104	Shizuoka Cancer Center Hospital and Research Institute ( Site 0602)	Sunto-gun	Shizuoka	Japan	411-8777
105	National Hospital Organization Kyushu Medical Center ( Site 0621)	Fukuoka		Japan	810-8563
106	Kyushu University Hospital ( Site 0605)	Fukuoka		Japan	812-8582
107	Niigata Cancer Center Hospital ( Site 0610)	Niigata		Japan	951-8566
108	Okayama University Hospital ( Site 0614)	Okayama		Japan	700-8558
109	Osaka International Cancer Institute ( Site 0611)	Osaka		Japan	541-8567
110	National Cancer Center Hospital ( Site 0603)	Tokyo		Japan	104-0045
111	Toranomon Hospital ( Site 0615)	Tokyo		Japan	105-8470
112	Tokyo Metropolitan Komagome Hospital ( Site 0618)	Tokyo		Japan	113-8677
113	Wakayama Medical University Hospital ( Site 0613)	Wakayama		Japan	641-8510
114	Chungbuk National University Hospital ( Site 0404)	Cheongju si	Chungcheongbuk-do [Chungbuk]	Korea, Republic of	28644
115	Gachon University Gil Medical Center ( Site 0408)	Incheon	Incheon-gwangyeoksi [Incheon]	Korea, Republic of	21565
116	National Cancer Center ( Site 0400)	Gyeonggi-do	Kyonggi-do	Korea, Republic of	10408
117	Seoul National University Bundang Hospital ( Site 0405)	Seongnam-si	Kyonggi-do	Korea, Republic of	13620
118	Seoul National University Hospital ( Site 0402)	Seoul	Seoul-teukbyeolsi [Seoul]	Korea, Republic of	03080
119	Asan Medical Center ( Site 0407)	Seoul	Seoul-teukbyeolsi [Seoul]	Korea, Republic of	05505
120	Samsung Medical Center ( Site 0403)	Seoul	Seoul-teukbyeolsi [Seoul]	Korea, Republic of	06351
121	The Catholic University of Korea. Seoul St. Mary s Hospital ( Site 0406)	Seoul	Seoul-teukbyeolsi [Seoul]	Korea, Republic of	06591
122	Ulsan University Hospital ( Site 0401)	Ulsan	Ulsan-Kwangyokshi	Korea, Republic of	44033
123	Instituto Jaliscience de Cancerologia ( Site 2000)	Guadalajara	Jalisco	Mexico	44280
124	Medica Sur S.A.B de C.V. ( Site 2003)	Mexico City		Mexico	14050
125	Oaxaca Site Management Organization SC ( Site 2001)	Oaxaca		Mexico	68000
126	Instituto Nacional de Cancerologia. ( Site 2007)	Tlalpan		Mexico	14080
127	Hospitalo Univ. Germans Trias i Pujol ( Site 1100)	Badalona	Barcelona [Barcelona]	Spain	08916
128	Hospital de la Santa Creu i Sant Pau ( Site 1102)	Barcelona	Barcelona [Barcelona]	Spain	08025
129	Hospital Universitari Vall d Hebron ( Site 1106)	Barcelona	Barcelona [Barcelona]	Spain	08035
130	Hospital Ramon y Cajal ( Site 1101)	Madrid		Spain	28034
131	Hospital Universitario 12 de Octubre ( Site 1103)	Madrid		Spain	28041
132	Complejo Hospitalario Carlos Haya de Malaga ( Site 1107)	Malaga		Spain	29010
133	Hospital Universitario Virgen Macarena ( Site 1104)	Sevilla		Spain	41009
134	Linkopings Universitetssjukhus ( Site 1504)	Linkoping	Ostergotlands Lan [se-05]	Sweden	581 85
135	Skanes Universitetssjukhus Lund ( Site 1503)	Lund	Skane Lan [se-12]	Sweden	221 85
136	Karolinska Universitetssjukhuset Solna ( Site 1500)	Solna	Stockholms Lan [se-01]	Sweden	171 64
137	Sahlgrenska Universitetssjukhuset ( Site 1502)	Goteborg	Vastra Gotalands Lan [se-14]	Sweden	413 45
138	Taipei Tzu Chi Hospital ( Site 0512)	New Taipei City	New Taipei	Taiwan	231
139	Changhua Christian Hospital ( Site 0509)	Changhua		Taiwan	50006
140	National Taiwan University Hospital Hsin-Chu Branch ( Site 0511)	Hsinchu		Taiwan	300
141	Hualien Tzu Chi Medical Center-Hospital ( Site 0510)	Hualien		Taiwan	970
142	Kaohsiung Chang Gung Memorial Hospital ( Site 0507)	Kaohsiung		Taiwan	833
143	Taipei Medical University Shuang Ho Hospital ( Site 0508)	New Taipei		Taiwan	235
144	China Medical University Hospital ( Site 0505)	Taichung		Taiwan	40447
145	Taichung Veterans General Hospital ( Site 0504)	Taichung		Taiwan	40705
146	National Cheng Kung University Hospital ( Site 0506)	Tainan		Taiwan	704
147	National Taiwan University Hospital ( Site 0500)	Taipei		Taiwan	100
148	Mackay Memorial Hospital ( Site 0503)	Taipei		Taiwan	104
149	Taipei Veterans General Hospital ( Site 0501)	Taipei		Taiwan	11217
150	Chang Gung Medical Foundation. Linkou ( Site 0502)	Taoyuan		Taiwan	333
151	Sussex University Hospitals ( Site 1003)	Brighton	Brighton And Hove	United Kingdom	BN2 5BE
152	Western General Hospital ( Site 1009)	Edinburgh	Edinburgh, City Of	United Kingdom	EH4 2XU
153	Leicester Royal Infirmary ( Site 1000)	Leicester	Leicestershire	United Kingdom	LE1 5WW
154	University College London Hospitals NHS Foundation Trust ( Site 1006)	London	London, City Of	United Kingdom	NW1 2PG
155	Chelsea & Westminster Hospital ( Site 1001)	London	London, City Of	United Kingdom	SW10 9NH
156	Birmingham Heartlands Hospital ( Site 1002)	Birmingham		United Kingdom	B9 5SS
157	St James s University Hospital ( Site 1008)	Leeds		United Kingdom	LS9 7TF
158	Barking Havering and Redbridge University Hospitals NHS Trust Queen s Hospital ( Site 1004)	Romford		United Kingdom	RM7 0AG