Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Chemoradiotherapy (CRT) Versus CRT Alone in Muscle-invasive Bladder Cancer (MIBC) (MK-3475-992/KEYNOTE-992)

Sponsor

Merck Sharp & Dohme LLC (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04241185

Collaborator

(none)

636

Enrollment

112

Locations

Arms

83.7

Anticipated Duration (Months)

5.7

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study is designed to assess the antitumor efficacy and safety of pembrolizumab in combination with chemoradiotherapy (CRT) versus CRT alone in participants with muscle-invasive bladder cancer (MIBC). The primary hypothesis is that pembrolizumab + chemoradiotherapy is superior to placebo + chemoradiotherapy with respect to bladder intact event-free survival.

Condition or Disease	Intervention/Treatment	Phase
Urinary Bladder Neoplasms	Drug: Pembrolizumab Radiation: Conventional Radiotherapy (Bladder only) Radiation: Conventional Radiotherapy (Bladder and pelvic nodes) Radiation: Hypofractionated Radiotherapy (Bladder only) Drug: Cisplatin Drug: Fluorouracil (5-FU) Drug: Mitomycin C (MMC) Drug: Gemcitabine Drug: Placebo to Pembrolizumab	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

636 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

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

Masking Description:

All Sponsor personnel will be blinded to treatment assignments, with the exception of designated unblinded team members. Chemoradiotherapy will be administered to all participants and will be open-label.

Primary Purpose:

Treatment

Official Title:

A Phase 3, Randomized, Double-blind, Placebo-controlled Clinical Trial to Study the Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Chemoradiotherapy (CRT) Versus CRT Alone in Participants With Muscle-invasive Bladder Cancer (MIBC) (KEYNOTE-992)

Actual Study Start Date :

May 19, 2020

Anticipated Primary Completion Date :

Oct 10, 2026

Anticipated Study Completion Date :

May 10, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pembrolizumab + Chemotherapy + Radiotherapy Participants receive pembrolizumab plus one of three chemotherapy regimens chosen by investigator, plus one of three radiotherapy regimens chosen by investigator.	Drug: Pembrolizumab 400 mg of IV (intravenous) pembrolizumab once every 6 weeks. Other Names: MK-3475 KEYTRUDA® Radiation: Conventional Radiotherapy (Bladder only) 64 Gy of radiation administered to participant's bladder only. Thirty-two fractions will be administered over 6.5 weeks. Radiation: Conventional Radiotherapy (Bladder and pelvic nodes) 64 Gy of radiation administered to participant's bladder and pelvic nodes. Thirty-two fractions will be administered over 6.5 weeks. Radiation: Hypofractionated Radiotherapy (Bladder only) 55 Gy of radiation administered to participant's bladder only. Twenty fractions will be administered over 4 weeks. Drug: Cisplatin 35 mg of cisplatin per cubic meter of body volume, administered once weekly via IV infusion. Drug: Fluorouracil (5-FU) 5-FU administered via IV infusion at a dose of 500 mg per cubic meter of body volume on Days 1-5 and 22-26. Drug: Mitomycin C (MMC) MMC administered via IV infusion at a dose of 12 mg per cubic meter of body volume on Day 1. Drug: Gemcitabine Gemcitabine administered via IV infusion at a dose of 27 mg per cubic meter of body volume twice weekly.
Placebo Comparator: Placebo + Chemotherapy + Radiotherapy Participants receive placebo to pembrolizumab plus one of three chemotherapy regimens chosen by investigator, plus one of three radiotherapy regimens chosen by investigator.	Radiation: Conventional Radiotherapy (Bladder only) 64 Gy of radiation administered to participant's bladder only. Thirty-two fractions will be administered over 6.5 weeks. Radiation: Conventional Radiotherapy (Bladder and pelvic nodes) 64 Gy of radiation administered to participant's bladder and pelvic nodes. Thirty-two fractions will be administered over 6.5 weeks. Radiation: Hypofractionated Radiotherapy (Bladder only) 55 Gy of radiation administered to participant's bladder only. Twenty fractions will be administered over 4 weeks. Drug: Cisplatin 35 mg of cisplatin per cubic meter of body volume, administered once weekly via IV infusion. Drug: Fluorouracil (5-FU) 5-FU administered via IV infusion at a dose of 500 mg per cubic meter of body volume on Days 1-5 and 22-26. Drug: Mitomycin C (MMC) MMC administered via IV infusion at a dose of 12 mg per cubic meter of body volume on Day 1. Drug: Gemcitabine Gemcitabine administered via IV infusion at a dose of 27 mg per cubic meter of body volume twice weekly. Drug: Placebo to Pembrolizumab Placebo to intravenous (IV) pembrolizumab administered once every 6 weeks.

Arm

Intervention/Treatment

Experimental: Pembrolizumab + Chemotherapy + Radiotherapy

Participants receive pembrolizumab plus one of three chemotherapy regimens chosen by investigator, plus one of three radiotherapy regimens chosen by investigator.

Drug: Pembrolizumab

400 mg of IV (intravenous) pembrolizumab once every 6 weeks.

Other Names:

MK-3475

KEYTRUDA®

Radiation: Conventional Radiotherapy (Bladder only)

64 Gy of radiation administered to participant's bladder only. Thirty-two fractions will be administered over 6.5 weeks.

Radiation: Conventional Radiotherapy (Bladder and pelvic nodes)

64 Gy of radiation administered to participant's bladder and pelvic nodes. Thirty-two fractions will be administered over 6.5 weeks.

Radiation: Hypofractionated Radiotherapy (Bladder only)

55 Gy of radiation administered to participant's bladder only. Twenty fractions will be administered over 4 weeks.

Drug: Cisplatin

35 mg of cisplatin per cubic meter of body volume, administered once weekly via IV infusion.

Drug: Fluorouracil (5-FU)

5-FU administered via IV infusion at a dose of 500 mg per cubic meter of body volume on Days 1-5 and 22-26.

Drug: Mitomycin C (MMC)

MMC administered via IV infusion at a dose of 12 mg per cubic meter of body volume on Day 1.

Drug: Gemcitabine

Gemcitabine administered via IV infusion at a dose of 27 mg per cubic meter of body volume twice weekly.

Placebo Comparator: Placebo + Chemotherapy + Radiotherapy

Participants receive placebo to pembrolizumab plus one of three chemotherapy regimens chosen by investigator, plus one of three radiotherapy regimens chosen by investigator.

Radiation: Conventional Radiotherapy (Bladder only)

64 Gy of radiation administered to participant's bladder only. Thirty-two fractions will be administered over 6.5 weeks.

Radiation: Conventional Radiotherapy (Bladder and pelvic nodes)

64 Gy of radiation administered to participant's bladder and pelvic nodes. Thirty-two fractions will be administered over 6.5 weeks.

Radiation: Hypofractionated Radiotherapy (Bladder only)

55 Gy of radiation administered to participant's bladder only. Twenty fractions will be administered over 4 weeks.

Drug: Cisplatin

35 mg of cisplatin per cubic meter of body volume, administered once weekly via IV infusion.

Drug: Fluorouracil (5-FU)

5-FU administered via IV infusion at a dose of 500 mg per cubic meter of body volume on Days 1-5 and 22-26.

Drug: Mitomycin C (MMC)

MMC administered via IV infusion at a dose of 12 mg per cubic meter of body volume on Day 1.

Drug: Gemcitabine

Gemcitabine administered via IV infusion at a dose of 27 mg per cubic meter of body volume twice weekly.

Drug: Placebo to Pembrolizumab

Placebo to intravenous (IV) pembrolizumab administered once every 6 weeks.

Outcome Measures

Primary Outcome Measures

Bladder Intact Event-Free Survival (BI-EFS) [Up to approximately 71 months]
BI-EFS is defined as the time from randomization to any of the following events: residual/recurrent MIBC post-chemoradiotherapy (CRT), nodal or distant metastases as assessed by computerized tomography (CT) and CT urography (CTU) or magnetic resonance urography (MRU) per blinded independent central review (BICR) and/or biopsy results assessed by central pathology review, radical cystectomy, or death due to any cause. If biopsy is not feasible due to participant safety, the imaging alone will be sufficient. The BI-EFS for all participants will be presented.

Secondary Outcome Measures

Overall Survival (OS) [Up to approximately 83 months]
Time from randomization to death due to any cause.
Metastasis-Free Survival (MFS) [Up to approximately 83 months]
MFS is defined as the time from randomization to the first documented occurrence of nodal or distant metastases as assessed by CT and CTU or MRU per BICR and/or biopsy results assessed by central pathology review If biopsy is not feasible due to participant safety, the imaging alone will be sufficient.
Time to Occurrence of Non-Muscle-Invasive Bladder Cancer (NMIBC) [Up to approximately 83 months]
Time to occurrence of low-grade disease, defined as the time from randomization until the development of NMIBC, will be presented.
Number of Participants Who Experienced an Adverse Event (AE) [Up to approximately 83 months]
An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who experience an AE will be presented.
Number of Participants Who Discontinued Study Intervention Due to an AE [Up to approximately 1 year]
An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who discontinue study treatment due to an AE will be presented.
Change from Baseline in the Global Health Status/Quality of Life (Items 29 and 30) Combined Score on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) [Baseline and up to approximately 83 months]
The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to the questions "How would you rate your overall health during the past week?" and "How would you rate your overall quality of life during the past week?" are scored on a 7-point scale (1=Very Poor to 7=Excellent). A higher score indicates a better overall outcome. The change from baseline in Global Health Status/Quality of Life (EORTC QLQ-C30 Items 29 and 30) combined score will be presented.
Change from Baseline in Physical Functioning (Items 1-5) Combined Score on the EORTC QLQ-C30 [Baseline and up to approximately 83 months]
EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=Not at All to 4=Very Much). A higher score indicates a better quality of life. The change from baseline in Physical Functioning (EORTC QLQ-C30 Items 1-5) combined score will be presented.
Change from Baseline in Urinary, Bowel, and Sexual Domains of the Bladder Cancer Index (BCI) [Baseline and up to approximately 83 months]
The BCI is a validated, condition-specific health questionnaire assessing quality of life among participants with bladder cancer. The BCI contains 36 items which assess 3 domains (urinary, bowel, and sexual) with function and bother subdomains. Scores range from 0 to 100 with higher scores corresponding to better functioning and health-related quality of life. The change from baseline in the combined scores of the urinary, bowel, and sexual domains of the BCI will be presented.
Change from Baseline in the Visual Analog Score (VAS) of the European Quality of Life (EuroQoL)-5 Dimensions, 5-level Questionnaire (EQ-5D-5L) [Baseline and up to approximately 83 months]
The EQ-5D-5L VAS records the respondent's self-rated health on a 10 cm vertical, visual analogue scale. It is rated by the respondent on a scale 0 to 100, with 0 being "the worst health you can imagine" and 100 being "the best health you can imagine". The change from baseline in EQ-5D-5L VAS will be presented.
Time to Deterioration (TTD) in the Global Health Status/Quality of Life (Items 29 and 30) Combined Score on the EORTC QLQ-C30 [Up to approximately 83 months]
The EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to the questions "How would you rate your overall health during the past week?" and "How would you rate your overall quality of life during the past week?" are scored on a 7-point scale (1=Very Poor to 7=Excellent). A higher score indicates a better overall outcome. TTD in Global Health Status/Quality of Life is defined as the time from baseline to the first onset of a 10 point or greater decrease from baseline in the Global Health Status/Quality of Life (EORTC QLQ-C30 Items 29 and 30) combined score, with or without subsequent confirmation.
TTD in Physical Functioning (Items 1-5) Combined Score on the EORTC QLQ-C30 [Up to approximately 83 months]
EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Participant responses to 5 questions about their physical functioning are scored on a 4-point scale (1=Not at All to 4=Very Much). A higher score indicates a better quality of life. TTD in Physical Functioning (EORTC QLQ-C30 Items 1-5) combined score is defined as the time from baseline (at randomization) to the first onset of a ≥10-point decrease with confirmation by the subsequent visit of a ≥10-point decrease in physical functioning Items 1 to 5 scale scores.
TTD in Urinary, Bowel, and Sexual Domains of the BCI [Up to approximately 83 months]
The BCI is a validated, condition-specific health questionnaire assessing quality of life among participants with bladder cancer. The BCI contains 36 items which assess 3 domains (urinary, bowel, and sexual) with function and bother subdomains. Scores range from 0 to 100 with higher scores corresponding to better functioning and health-related quality of life. TTD in BCI is defined as a 6, 7, and 7 points or greater worsening from baseline for urinary, bowel, and sexual domains, respectively, with or without subsequent confirmation, under a right-censoring rule.
TTD in the VAS of the EQ-5D-5L [Up to approximately 83 months]
The EQ-5D-5L VAS records the respondent's self-rated health on a 10 cm vertical, visual analogue scale. It is rated by the respondent on a scale 0 to 100, with 0 being "the worst health you can imagine" and 100 being "the best health you can imagine". TTD in EQ-5D-5L VAS is defined as the time from baseline to the first onset of a 7 point or greater decrease from baseline in EQ-5D-5L VAS, with or without subsequent confirmation, under a right-censoring rule.
Time to Cystectomy [Up to approximately 83 months]
Time to cystectomy is defined as time from a participant's randomization to date of cystectomy.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Has a histologically confirmed initial diagnosis of muscle-invasive bladder cancer (MIBC) with predominant urothelial histology
Has clinically non-metastatic bladder cancer (N0M0)
Has planned and is eligible to receive chemoradiotherapy (CRT) and one of the protocol-specified radiosensitizing chemotherapy regimens
Has Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
Demonstrates adequate organ function
Male participants are eligible to participate if they agree to the following during the intervention period and for at least 90 days after the last dose of CRT treatment:
Refrain from donating sperm
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent; or must agree to use contraception unless confirmed to be azoospermic
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
Is not a woman of childbearing potential (WOCBP)
Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), during the intervention period and for at least 180 days the time needed to eliminate each study intervention after the last dose of study intervention; and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. The length of time required to continue contraception for each study intervention is as follows: MK-3475 - 120 days and CRT - 180 days

Exclusion Criteria:

Has the presence of diffuse carcinoma in situ (CIS) (multiple foci of CIS) throughout the bladder
Has the presence of urothelial carcinoma (UC) at any site outside of the urinary bladder in the previous 2 years except for Ta stage/T1 stage/CIS of the upper tract if the participant has undergone a complete nephroureterectomy
Has a known additional malignancy that is progressing or has required active therapy within the past 3 years, except basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer or other carcinoma in situ that has undergone potentially curative therapy
Has the presence of bilateral hydronephrosis
Has limited bladder function with frequency of small amounts of urine (< 30 mL), urinary incontinence, or requires self-catheterization or a permanent indwelling catheter
Has received prior pelvic/local radiation therapy or any antineoplastic treatment for muscle-invasive bladder cancer (MIBC). Treatment for non-muscle invasive bladder cancer (NMIBC) with intravesical instillation therapy that was completed ≥28 days prior to randomization is allowed. Prior systemic treatment of NMIBC is not permitted.
Received prior therapy with an anti-PD-1 (programmed cell death protein 1), anti-PD-L1 (programmed death-ligand 1), or anti-PD-L2 (programmed cell death 1 ligand 2), or with an agent directed to another stimulatory or coinhibitory T-cell receptor (e.g., CTLA-4 [cytotoxic T-lymphocyte-associated protein 4], OX 40, or CD137 [cluster of differentiation 137])
Has received a live vaccine within 30 days before the first dose of study medication
Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study medication
Has known severe hypersensitivity (≥Grade 3) to the selected chemotherapy regimen, and/or any of their excipients and excipients of pembrolizumab
Has a 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 before the first dose of study medication
Has an active autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed
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 Hepatitis B or known active Hepatitis C virus infection
Has a known history of active tuberculosis (TB; Bacillus tuberculosis)
Has a known psychiatric or substance abuse disorder that would interfere with the participant's ability to cooperate with the requirements of the study
Has had an allogenic tissue/solid organ transplant

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Washington Cancer Institute at MedStar Washington Hospital Center ( Site 0041)	Washington	District of Columbia	United States	20010
2	Bay Pines VA Medical Center ( Site 0055)	Bay Pines	Florida	United States	33744
3	AdventHealth Orlando-AdventHealth Medical Group Hematology & Oncology at Orlando ( Site 0004)	Orlando	Florida	United States	32804
4	Norton Cancer Institute ( Site 0044)	Louisville	Kentucky	United States	40207
5	Pikeville Medical Center ( Site 0009)	Pikeville	Kentucky	United States	41501
6	Baltimore VA Medical Center ( Site 0054)	Baltimore	Maryland	United States	21201
7	Washington University ( Site 0003)	Saint Louis	Missouri	United States	63110
8	John Theurer Cancer Center at Hackensack University Medical Center ( Site 0005)	Hackensack	New Jersey	United States	07601
9	New York Oncology Hematology P.C ( Site 0024)	Albany	New York	United States	12206
10	Winthrop University Hospital ( Site 0069)	Mineola	New York	United States	11501
11	New York University Perlmutter Cancer Center ( Site 0001)	New York	New York	United States	10016
12	Cleveland Clinic ( Site 0062)	Cleveland	Ohio	United States	44195
13	MidLantic urology ( Site 0070)	Bala-Cynwyd	Pennsylvania	United States	19004
14	Saint Francis Cancer Center ( Site 0026)	Greenville	South Carolina	United States	29607
15	Carolina Urologic Research Center ( Site 0002)	Myrtle Beach	South Carolina	United States	29572
16	West Virginia University - Charleston Area Medical Center ( Site 6003)	Charleston	West Virginia	United States	25304
17	Froedtert and Medical College of Wisconsin ( Site 0022)	Milwaukee	Wisconsin	United States	53226
18	Liverpool Hospital ( Site 0220)	Liverpool	New South Wales	Australia	2170
19	Northern Cancer Institute ( Site 0217)	St Leonards	New South Wales	Australia	2065
20	Monash Health-Monash Medical Centre ( Site 0216)	Clayton	Victoria	Australia	3168
21	Austin Health ( Site 0218)	Heidelberg	Victoria	Australia	3084
22	Sir Charles Gairdner Hospital ( Site 0223)	Nedlands	Western Australia	Australia	6009
23	Fakultni nemocnice Olomouc ( Site 0559)	Olomouc		Czechia	775 20
24	2. LF UK a FN Motol ( Site 0555)	Praha 5		Czechia	150 06
25	Nemocnice Na Bulovce ( Site 0556)	Praha 8		Czechia	180 81
26	Herlev og Gentofte Hospital. ( Site 0401)	Herlev	Hovedstaden	Denmark	2730
27	Odense Universitetshospital ( Site 0403)	Odense	Syddanmark	Denmark	5000
28	North Estonia Medical Centre Foundation ( Site 0081)	Tallin	Harjumaa	Estonia	13419
29	Tartu University Hospital ( Site 0079)	Tartu	Tartumaa	Estonia	51014
30	Institut Sainte Catherine ( Site 0121)	Avignon	Provence-Alpes-Cote-d Azur	France	84918
31	CHU Amiens Picardie Site Sud Amiens ( Site 0123)	Amiens	Somme	France	80000
32	Institut Curie ( Site 0112)	Paris		France	75005
33	A.P.H. Paris. Hopital Bichat Claude Bernard ( Site 0115)	Paris		France	75018
34	Centro de Investigaciones Clinicas de Latinoamerica S.A. - CELAN ( Site 0146)	Guatemala		Guatemala	01010
35	Oncomedica ( Site 0145)	Guatemala		Guatemala	01010
36	Grupo Medico Angeles ( Site 0143)	Guatemala		Guatemala	01015
37	Medi-K Cayala ( Site 0142)	Guatemala		Guatemala	01016
38	Centro Medico Integral De Cancerología (CEMIC) ( Site 0144)	Quetzaltenango		Guatemala	09002
39	Bacs-Kiskun Megyei Korhaz-Onkoradiologiai Kozpont ( Site 0095)	Kecskemét	Bacs-Kiskun	Hungary	6000
40	BAZ Megyei Korhaz. Klinikai Onkologia es Sugarterapias Centrum ( Site 0092)	Miskolc	Borsod-Abauj-Zemplen	Hungary	3526
41	Petz Aladar Megyei Oktato Korhaz ( Site 0099)	Gyor	Gyor-Moson-Sopron	Hungary	9024
42	Debreceni Egyetem Klinikai Kozpont ( Site 0097)	Debrecen		Hungary	4032
43	Somogy Megyei Kaposi Mor Oktato Korhaz ( Site 0091)	Kaposvar		Hungary	7400
44	Soroka Medical Center-Oncology ( Site 7031)	Be'er Sheva		Israel	8400000
45	Rambam Health Care Campus-Oncology Division ( Site 0088)	Haifa		Israel	3109601
46	Hadassah Medical Center. Ein Kerem ( Site 0086)	Jerusalem		Israel	9112001
47	Chaim Sheba Medical Center ( Site 0087)	Ramat Gan		Israel	5265601
48	Sourasky Medical Center ( Site 0089)	Tel Aviv		Israel	6423906
49	IRCCS Giovanni Paolo II. Ospedale Oncologico ( Site 0193)	Bari	Puglia	Italy	70124
50	AOU Careggi ( Site 0191)	Firenze		Italy	50134
51	Ospedale Civile di Macerata ( Site 0190)	Macerata		Italy	62100
52	Ospedale San Raffaele ( Site 0194)	Milano		Italy	20132
53	Fondazione IRCCS Istituto Nazionale dei Tumori di Milano ( Site 0186)	Milano		Italy	20133
54	Azienda Ospedaliero - Universitaria Policlinico di Modena ( Site 0188)	Modena		Italy	41124
55	Istituto Nazionale Tumori IRCCS Fondazione Pascale ( Site 0192)	Napoli		Italy	80131
56	Hirosaki University Hospital ( Site 0602)	Hirosaki	Aomori	Japan	036-8563
57	University of Tsukuba Hospital ( Site 0605)	Tsukuba	Ibaraki	Japan	305-8576
58	Osaka Medical and Pharmaceutical University Hospital ( Site 0604)	Takatsuki	Osaka	Japan	569-8686
59	Nagasaki University Hospital ( Site 0600)	Nagasaki		Japan	852-8510
60	Tokyo Metropolitan Komagome Hospital ( Site 0606)	Tokyo		Japan	113-8677
61	Tokyo Medical and Dental University Hospital ( Site 0601)	Tokyo		Japan
62	National Cancer Center ( Site 0202)	Gyeonggi-do	Kyonggi-do	Korea, Republic of	10408
63	Seoul National University Bundang Hospital ( Site 0204)	Seongnam-si	Kyonggi-do	Korea, Republic of	13620
64	Asan Medical Center ( Site 0200)	Songpagu	Seoul	Korea, Republic of	05505
65	Chungnam National University Hospital ( Site 0203)	Daejeon	Taejon-Kwangyokshi	Korea, Republic of	35015
66	Korea University Anam Hospital ( Site 0205)	Seoul		Korea, Republic of	02841
67	Severance Hospital Yonsei University Health System ( Site 0201)	Seoul		Korea, Republic of	03722
68	Pauls Stradins Clinical University Hospital ( Site 0073)	Riga		Latvia	LV-1002
69	Hospital Universiti Sains Malaysia ( Site 0237)	Kubang Kerian	Kelantan	Malaysia	16150
70	Hospital Pulau Pinang ( Site 0239)	Penang	Pulau Pinang	Malaysia	10990
71	Hospital Kuala Lumpur ( Site 0238)	Kuala Lumpur		Malaysia	50586
72	University Malaya Medical Centre ( Site 0236)	Kuala Lumpur		Malaysia	59100
73	Netherlands Cancer Institute (NKI) ( Site 0183)	Amsterdam	Noord-Holland	Netherlands	1066 CX
74	Erasmus MC ( Site 0182)	Rotterdam	Zuid-Holland	Netherlands	3015 GD
75	Szpital Specjalistyczny im. Ludwika Rydygiera w Krakowie ( Site 0153)	Krakow	Malopolskie	Poland	31-826
76	Szpital Wojewodzki im. Mikolaja Kopernika ( Site 0152)	Koszalin	Zachodniopomorskie	Poland	75-581
77	Centro Hospitalar e Universitario de Coimbra ( Site 0306)	Coimbra		Portugal	3000-075
78	CHLO, EPE - Hospital de Sao Francisco Xavier ( Site 0302)	Lisboa		Portugal	1449-005
79	Centro Hospitalar Lisboa Norte EPE - Hospital de Santa Maria ( Site 0305)	Lisboa		Portugal	1649-035
80	Advance Urology and Laparoscopic Center ( Site 0281)	Ponce		Puerto Rico	00716
81	PAN American Center Oncologic ( Site 0280)	San Juan, Rio Piedras		Puerto Rico	00935
82	Institutul Oncologic Prof.Dr. Ion Chiricuta Cluj-Napoca ( Site 0249)	Cluj Napoca	Cluj	Romania	400015
83	S.C. Radiotherapy Center Cluj S.R.L ( Site 0252)	Cluj-Napoca	Cluj	Romania	407280
84	S.C. Centrul de Oncologie Sf. Nectarie SRL ( Site 0248)	Craiova	Dolj	Romania	200347
85	Policlinica Oncomed SRL ( Site 0254)	Timisoara	Timis	Romania	300239
86	Institutul Regional de Oncologie Iasi ( Site 0255)	Iasi		Romania	700483
87	Instituto Catalan de Oncologia - ICO ( Site 0103)	L Hospitalet De Llobregat	Barcelona	Spain	08908
88	Hospital La Fe de Valencia ( Site 0105)	Valencia	Valenciana, Comunitat	Spain	46026
89	Chi Mei Medical Center ( Site 0215)	Tainan City	Tainan	Taiwan	71004
90	Kaohsiung Chang Gung Memorial Hospital ( Site 0209)	Kaohsiung		Taiwan	83301
91	Taichung Veterans General Hospital ( Site 0213)	Taichung		Taiwan	407
92	National Cheng Kung University Hospital ( Site 0208)	Tainan		Taiwan	704
93	National Taiwan University Hospital ( Site 0210)	Taipei		Taiwan	10002
94	Taipei Veterans General Hospital ( Site 0211)	Taipei		Taiwan	11217
95	Chang Gung Medical Foundation.Linkou Branch ( Site 0212)	Taoyuan		Taiwan	333
96	Ankara Universitesi Tip Fakultesi. ( Site 0502)	Ankara		Turkey	06100
97	Istanbul Uni. Cerrahpasa Tip Fakultesi ( Site 0501)	Istanbul		Turkey	34098
98	Göztepe Prof. Dr. Süleyman Yalçın Şehir Hastanesi-oncology ( Site 0504)	Istanbul		Turkey	34722
99	Ege University Medical Faculty ( Site 0508)	Izmir		Turkey	35100
100	Karadeniz Teknik Universitesi Tip Fakultesi ( Site 0503)	Trabzon		Turkey	61080
101	Clinical oncology dispensary of Dnipro ( Site 0133)	Dnipro	Dnipropetrovska Oblast	Ukraine	49055
102	Grigoriev Institute for medical Radiology NAMS of Ukraine ( Site 0139)	Kharkiv	Kharkivska Oblast	Ukraine	61024
103	CNPE "Regional Center of Oncology" ( Site 0134)	Kharkiv	Kharkivska Oblast	Ukraine	61070
104	Ukranian Center of TomoTherapy ( Site 0140)	Kropyvnytskiy	Kirovohradska Oblast	Ukraine	25011
105	National Cancer Institute of the MoH of Ukraine ( Site 0136)	Kyiv	Kyivska Oblast	Ukraine	03022
106	Kyiv City Clinical Oncology Center ( Site 0135)	Kyiv		Ukraine	03115
107	Betsi Cadwaladr University Health Board ( Site 0447)	Rhyl	Denbighshire	United Kingdom	LL18 5UJ
108	South Devon Healthcare Foundation Trust. Torbay Hospital ( Site 0444)	Torquay	Devon	United Kingdom	TQ2 7AA
109	University College London Hospitals NHS Foundation Trust ( Site 0445)	London	London, City Of	United Kingdom	NW1 2PG
110	The Royal Marsden NHS Foundation Trust. ( Site 0442)	London	London, City Of	United Kingdom	SW3 6JJ
111	Nottingham University Hospital NHS Trust ( Site 0250)	Nottingham	Nottinghamshire	United Kingdom	NG5 1PB
112	Darlington Memorial Hospital NHS Trust ( Site 0446)	Darlington		United Kingdom	DL3 6HX