A Multiple-dose Study of ASP8374, an Immune Checkpoint Inhibitor, as a Single Agent and in Combination With Pembrolizumab in Subjects With Advanced Solid Tumors

Sponsor

Astellas Pharma Global Development, Inc. (Industry)

Overall Status

Completed

CT.gov ID

NCT03260322

Collaborator

Merck Sharp & Dohme LLC (Industry)

169

Enrollment

Locations

Arms

55.4

Actual Duration (Months)

3.1

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary purpose of this study is to evaluate the tolerability and safety profile of ASP8374 when administered as a single agent and in combination with pembrolizumab in participants with locally advanced (unresectable) or metastatic solid tumor malignancies. Also primary purpose is to characterize the pharmacokinetic profile of ASP8374 when administered as a single agent and in combination with pembrolizumab. Last primary purpose of this study is to determine the recommended Phase 2 dose (RP2D) of ASP8374 when administered as a single agent and in combination with pembrolizumab.

The secondary purpose of this study is to evaluate the anti-tumor effect (objective response rate [ORR], duration of response [DOR], persistence of response after discontinuation, and disease control rate [DCR]) of ASP8374 when administered as a single agent and in combination with pembrolizumab.

Condition or Disease	Intervention/Treatment	Phase
Advanced Solid Tumors	Drug: ASP8374 Drug: Pembrolizumab	Phase 1

Detailed Description

This is a multi-center, multiple-dose, dose-escalation and expansion study of ASP8374 as a single agent and in combination with pembrolizumab. After discontinuation of study drug treatment (initial treatment and re-treatment), all participants will complete an end of treatment visit along with 30-day and 90-day safety follow-up visits from the last dose of ASP8374. Participants will be enrolled in respectively escalation cohorts or expansion cohorts. The 90-day safety follow-up visit is optional for participants who discontinue due to progressive disease or initiate new anticancer treatment after the last dose of study drug.

Escalation cohorts: Approximately 60 participants may be enrolled in the escalation cohorts (approximately 30 participants for monotherapy and 30 participants for combination therapy).

Expansion cohorts: The total number of subjects in the expansion cohorts will depend on the observed pharmacokinetic and antitumor activity. It is estimated that approximately 240 participants may be enrolled in the monotherapy and combination therapy expansion cohorts.

As the number of participants in the escalation cohorts and the expansion cohorts will depend on the observed Dose Limiting Toxicity (DLT), pharmacokinetics and antitumor activity, approximately 300 participants are expected to be enrolled.

Study Design

Study Type:

Interventional

Actual Enrollment :

169 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1b Study of ASP8374, an Immune Checkpoint Inhibitor, as a Single Agent and in Combination With Pembrolizumab in Subjects With Advanced Solid Tumors

Actual Study Start Date :

Sep 8, 2017

Actual Primary Completion Date :

Apr 20, 2022

Actual Study Completion Date :

Apr 20, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ASP8374 Participants will be enrolled in the escalation cohorts or expansion cohorts and receive ASP8374 (monotherapy) intravenously on Day 1 of every 3-week cycle (up to a maximum of 8 dose strengths).	Drug: ASP8374 intravenous
Experimental: ASP8374 and pembrolizumab Participants will be enrolled in the escalation cohorts or expansion cohorts and receive ASP8374 and pembrolizumab (combination therapy) intravenously on Day 1 of every 3-week cycle (up to a maximum of 5 dose strengths of ASP8374 and one fixed dose strength of pembrolizumab).	Drug: ASP8374 intravenous Drug: Pembrolizumab intravenous Other Names: Keytruda

Arm

Intervention/Treatment

Experimental: ASP8374

Participants will be enrolled in the escalation cohorts or expansion cohorts and receive ASP8374 (monotherapy) intravenously on Day 1 of every 3-week cycle (up to a maximum of 8 dose strengths).

Drug: ASP8374

intravenous

Experimental: ASP8374 and pembrolizumab

Participants will be enrolled in the escalation cohorts or expansion cohorts and receive ASP8374 and pembrolizumab (combination therapy) intravenously on Day 1 of every 3-week cycle (up to a maximum of 5 dose strengths of ASP8374 and one fixed dose strength of pembrolizumab).

Drug: ASP8374

intravenous

Drug: Pembrolizumab

intravenous

Other Names:

Keytruda

Outcome Measures

Primary Outcome Measures

Safety and tolerability assessed by Dose Limiting Toxicity (DLT) [Up to 21 days]
DLT as graded using National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE] Version 4.03. The DLT observation period may be increased if deemed appropriate by the Dose Escalation and Safety Committee
Safety and tolerability assessed by adverse events (AEs) [Up to 30 days following the last dose of study drug or until initiation of a new anti-cancer treatment, whichever comes first of each treatment period (Up to a maximum of 52 weeks)]
Initial and re-treatment. An AE is any untoward medical occurrence in a subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product
Safety and tolerability assessed by immune-related AEs (irAEs) [Up to 30 days following the last dose of study drug or until initiation of a new anti-cancer treatment, whichever comes first of each treatment period (Up to a maximum of 52 weeks)]
Initial and re-treatment. Most frequent immune-related AEs include rash, oral mucositis, dry mouth, colitis/diarrhea, hepatitis, pneumonitis, and endocrinopathies
Safety and tolerability assessed by serious adverse events (SAEs) [Up to 90 days following the last dose of study drug or until initiation of a new anti-cancer treatment, whichever comes first of each treatment period (Up to a maximum of 60 weeks)]
Initial and re-treatment. Adverse event (AE) is considered "serious" if the investigator or sponsor view any of the following outcomes: Death, life-threatening, persistent or significant disability/incapacity, congenital anomaly or birth defect, hospitalization, or medically important event
Number of participants with laboratory value abnormalities and/or adverse events related to treatment [Up to 30 days from last dose in safety follow up period for each treatment period (Up to a maximum of 52 weeks)]
Initial and re-treatment. Number of participants with potentially clinically significant laboratory values. The laboratory tests include hematology, biochemistry, urine dipstick, pregnancy test, thyroid stimulating hormone (TSH) and free T4; Hepatitis B and C; Testosterone and prostate-specific antigen (PSA) (metastatic castration resistant prostate cancer (mCRPC) only)
Safety and tolerability assessed by 12-lead electrocardiogram (ECG) [Up to end of treatment (up to 48 weeks for each treatment period)]
Initial and re-treatment. ECGs should be obtained after the participant has rested quietly and is awake in a fully supine position (or semi-recumbent, if supine is not tolerated) for 10 minutes before the first ECG from a triplicate or single ECG. Any clinically significant adverse changes on the ECG will be reported as (serious) Adverse Event
Number of participants with vital signs abnormalities and/or adverse events related to treatment [Up to 90 days from last dose in safety follow up period for each treatment period (Up to a maximum of 60 weeks)]
Initial and re-treatment. Number of participants with potentially clinically significant vital sign values. Vital signs will include systolic and diastolic blood pressure, radial pulse and temperature. All vital signs will be measured with the subject in the sitting or supine position
Number of participants with Physical Exam abnormalities and/or adverse events related to treatment [Up to end of treatment (up to 48 weeks for each treatment period)]
Initial and re-treatment. Standard, full physical examinations will be performed at screening to assess general appearance, skin, eyes, ears, nose, throat, neck, cardiovascular system, chest and lungs, abdomen, musculoskeletal system, neurologic status, mental status, and lymphatic system
Safety and tolerability assessed by ECOG performance status [Up to 30 days from last dose in safety follow up period of each treatment period (Up to a maximum of 52 weeks)]
Initial and re-treatment. The eastern cooperative oncology group (ECOG) Scale [Oken, 1982] will be used to assess performance status.0 = Fully active, able to carry on all predisease performance without restriction; 1=Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature; 2= Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours; 3= Capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4= Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
Pharmacokinetics (PK) of ASP8374 in serum: AUClast (Initial treatment, escalation cohorts in monotherapy only) [Cycle 1 and 7: day 1: predose 0 hr, end of dosing, 4 hr postdose; day 2: 24 hr postdose; day 3: 48 hr postdose; day 8: 168 hr postdose; day 15: 336 hr postdose; day 22: 504 hr postdose (for cycle 1 only)]
AUClast: area under the concentration-time curve from the time of dosing to the last measurable concentration. AUClast will be derived from the PK serum samples collected.
Pharmacokinetics (PK) of ASP8374 in serum: AUCinf (Initial treatment, escalation cohorts in monotherapy only) [Cycle 1: day 1: predose 0 hr, end of dosing, 4 hr postdose; day 2: 24 hr postdose; day 3: 48 hr postdose; day 8: 168 hr postdose; day 15: 336 hr postdose; day 22: 504 hr postdose (for cycle 1 only)]
AUCinf: area under the concentration-time curve from the time of dosing extrapolated to time infinity. AUCinf will be derived from the PK serum samples collected.
Pharmacokinetics (PK) of ASP8374 in serum: AUCtau (Initial treatment, escalation cohorts in monotherapy only) [Cycle 1 and 7: day 1: predose 0 hr, end of dosing, 4 hr postdose; day 2: 24 hr postdose; day 3: 48 hr postdose; day 8: 168 hr postdose; day 15: 336 hr postdose; day 22: 504 hr postdose (for cycle 1 only)]
AUCtau: Area under the concentration-time curve from the time of dosing to the start of the next dosing interval. AUCtau will be derived from the PK serum samples collected.
Pharmacokinetics (PK) of ASP8374 in serum: Cmax (Initial treatment, escalation cohorts in monotherapy only) [Cycle 1 and 7: day 1: predose 0 hr, end of dosing, 4 hr postdose; day 2: 24 hr postdose; day 3: 48 hr postdose; day 8: 168 hr postdose; day 15: 336 hr postdose; day 22: 504 hr postdose (cycle 1 only)]
Cmax: maximum concentration. Cmax will be derived from the PK serum samples collected.
Pharmacokinetics (PK) of ASP8374 in serum: Ctrough (Initial treatment, escalation and expansion cohorts in both monotherapy and combination therapy) [Cycle 2, 4, 7, 10 and 15: day 1: predose 0 hr]
Ctrough: Trough concentration. Ctrough will be derived from the PK serum samples collected.
Pharmacokinetics (PK) of pembrolizumab in serum: Ctrough (Initial treatment, escalation cohorts in combination therapy) [Cycle 2, 4, 7, 10 and 15: day 1: predose 0 hr]
Ctrough: Trough concentration. Ctrough will be derived from the PK serum samples collected.
Pharmacokinetics (PK) of ASP8374 in serum: Ctrough (Re-treatment, escalation and expansion cohorts in both monotherapy and combination therapy) [Cycle 5, 10 and 15: day 1: predose 0 hr]
Ctrough: Trough concentration. Ctrough will be derived from the PK serum samples collected.
Pharmacokinetics (PK) of ASP8374 in serum: tmax (Initial treatment, escalation cohorts in monotherapy only) [Cycle 1 and 7: day 1: predose 0 hr, end of dosing, 4 hr postdose; day 2: 24 hr postdose; day 3: 48 hr postdose; day 8: 168 hr postdose; day 15: 336 hr postdose; day 22: 504 hr postdose (cycle 1 only)]
tmax: time of maximum concentration. tmax will be derived from the PK serum samples collected.
Pharmacokinetics (PK) of ASP8374 in serum: t1/2 (Initial treatment, escalation cohorts in monotherapy only) [Cycle 1: day 1: predose 0 hr, end of dosing, 4 hr postdose; day 2: 24 hr postdose; day 3: 48 hr postdose; day 8: 168 hr postdose; day 15: 336 hr postdose; day 22: 504 hr postdose]
t1/2: terminal elimination half-life. t1/2 will be derived from the PK serum samples collected.
Pharmacokinetics (PK) of ASP8374 in serum: CL (Initial treatment, escalation cohorts in monotherapy only) [Cycle 1 and 7: day 1: predose 0 hr, end of dosing, 4 hr postdose; day 2: 24 hr postdose; day 3: 48 hr postdose; day 8: 168 hr postdose; day 15: 336 hr postdose; day 22: 504 hr postdose (cycle 1 only)]
CL: Clearance. CL will be derived from the PK serum samples collected.
Pharmacokinetics (PK) of ASP8374 in serum: Vz (Initial treatment, escalation cohorts in monotherapy only) [Cycle 1: day 1: predose 0 hr, end of dosing, 4 hr postdose; day 2: 24 hr postdose; day 3: 48 hr postdose; day 8: 168 hr postdose; day 15: 336 hr postdose; day 22: 504 hr postdose]
Vz: Volume of distribution after intravenous dosing during the terminal elimination phase. Vz will be derived from the PK serum samples collected.
Pharmacokinetics (PK) of ASP8374 in serum: Vss (Initial treatment, escalation cohorts in monotherapy only) [Cycle 7: day 1: predose 0 hr, end of dosing, 4 hr postdose; day 2: 24 hr postdose; day 3: 48 hr postdose; day 8: 168 hr postdose; day 15: 336 hr postdose]
Vss: Volume of distribution at steady state after intravenous dosing. Vss will be derived from the PK serum samples collected.

Secondary Outcome Measures

Objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and iRECIST [Up to end of follow up period (up to 105 weeks) of each treatment period]
Initial and re-treatment. 'Immune' Response Evaluation Criteria in Solid Tumors (iRECIST). ORR is defined as the proportion of participants for each dose level whose best overall response is rated as confirmed CR or PR
Duration of response (DOR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and iRECIST [Up to end of follow up period (up to 105 weeks) of each treatment period]
Initial and re-treatment. DOR will be calculated only for the subgroup of participants with confirmed response CR/PR
Persistence of response after discontinuation by iRECIST [Up to end of follow up period (up to 105 weeks) of each treatment period]
Initial and re-treatment. Persistence of response after discontinuation is defined for participants who discontinued the treatment and responded to the treatment per iRECIST only
Disease control rate (DCR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and iRECIST [Up to End of follow up period (up to 105 weeks) of each treatment period]
Initial and re-treatment. DCR is defined as the proportion of participants for each dose level whose best overall response is rated as confirmed CR, PR or Stable Disease (SD)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Subject has locally-advanced (unresectable) or metastatic solid tumor malignancy (no limit to the number of prior treatment regimens) that is confirmed by available pathology records or current biopsy as well as:
Subject in the escalation cohort has received all standard therapies (unless the therapy is contraindicated or intolerable) felt to provide clinical benefit for the subject's specific tumor type. OR
Subject in an expansion cohort has received at least one standard therapy for the subject's specific tumor type.
For Korea, Italy and Portugal only: Subject has locally-advanced (unresectable) or metastatic solid tumor malignancy (no limit to the number of prior treatment regimens) that is confirmed by available pathology records or current biopsy and has received all standard therapies (unless the therapy is contraindicated or intolerable) felt to provide clinical benefit for the subject's specific tumor type.
Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 or

Subject's last dose of prior antineoplastic therapy, including any immunotherapy, was 21 days or 5 half-lives, whichever is shorter, prior to initiation of study drug administration. A subject with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutation-positive NSCLC is allowed to remain on EGFR tyrosine kinase inhibitor (TKI) therapy or ALK inhibitor until 4 days prior to the start of study drug administration.
For Korea only: Subject's last dose of prior antineoplastic therapy, including any immunotherapy, was at least 21 days or 5 half-lives, whichever is shorter, prior to initiation of study drug administration. For drugs with a half-life greater than or equal to 21 days, the investigator should consider if this washout is sufficient. A subject with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) is allowed to remain on EGFR tyrosine kinase inhibitor (TKI) therapy until 7 days prior to the start of study drug administration.
Subject has completed any radiotherapy (including stereotactic radiosurgery) at least 2 weeks prior to study drug administration.
Subject's adverse events (excluding alopecia) from prior therapy have improved to grade 1 or baseline within 14 days prior to start of study treatment.
Subject with metastatic castration resistant prostate cancer (mCRPC) (positive bone scan and/or soft tissue disease documented by computed tomography (CT) / magnetic resonance imaging (MRI)) meets both of the following:
Subject has serum testosterone ≤ 50 ng/dL at screening.
Subject has had an orchiectomy or plans to continue androgen deprivation therapy (ADT) for the duration of study treatment.
Subject has adequate organ function prior to start of study treatment as indicated by the following laboratory values. If a subject has received a recent blood transfusion, the laboratory tests must be obtained ≥ 4 weeks after any blood transfusion.
Female subject is eligible to participate if she is not pregnant and at least 1 of the following conditions applies:
Not a woman of childbearing potential (WOCBP)
WOCBP who agrees to follow the contraceptive guidance throughout the treatment period and for at least 6 months after the final study drug administration.
Female subject must agree not to breastfeed starting at screening and throughout the study treatment, and for 6 months after the final study drug administration.
Female subject must not donate ova starting at screening and throughout the study treatment, and for 6 months after the final study drug administration.
A male subject with female partner(s) of childbearing potential must agree to use contraception as detailed during the treatment period and for at least 6 months after the final study drug administration.
Male subject must not donate sperm starting at screening and throughout the study treatment, and for 6 months after the final study drug administration.
Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy or time partner is breastfeeding throughout the study treatment and for 6 months after the final study drug administration.
Subject agrees not to participate in another interventional study while receiving study drug (subjects who are currently in the follow-up period of an interventional clinical trial are allowed).

Additional Inclusion Criteria for Subjects in the Expansion Cohorts:

Subject meets one of the following:
Subject has the tumor type for which a confirmed response was observed in a monotherapy or combination therapy dose escalation cohort; or
For an expansion cohort opened due to achieving predicted efficacious exposure, subject has squamous cell carcinoma of the head and neck (SCCHN); or
For tumor specific expansion cohorts of ASP8374 with pembrolizumab, subject has the applicable tumor type (e.g., non-small cell lung cancer (NSCLC), bladder cancer, gastric cancer, metastatic castration resistant prostate cancer (MCRPC) or colorectal cancer (CRC)).
Subject has at least 1 measureable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. Subjects with mCRPC who do not have measurable lesions must have at least one of the following:
Progression with 2 or more new bone lesions; or
Prostate-specific antigen (PSA) progression (defined as a minimum of three rising PSA levels with an interval of ≥ 1 week between each determination) within 6 weeks prior to study drug administration and a PSA value at the screening visit ≥ 2 ng/mL.
Subject consents to provide an available tumor specimen in a tissue block or unstained serial slides obtained within 56 days prior to first dose of study treatment, or subject is an appropriate candidate for tumor biopsy and is amenable to undergoing a tumor biopsy (core needle biopsy or excision) during the screening period.This does not apply to subjects with mCRPC without measurable disease.
Subject in any expansion cohort, is an appropriate candidate for tumor biopsy and consents to undergoing a tumor biopsy (core needle biopsy or excision) during the treatment period as indicated in the Schedule of Assessments.

Exclusion:

Subject weighs < 45 kg at screening.
Subject has received investigational therapy (other than an investigational epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) in a subject with EGFR activating mutations or ALK inhibitor in a subject with an ALK mutation) within 21 days or 5 half-lives, whichever is shorter, prior to start of study drug.
Subject requires or has received systemic steroid therapy or any other immunosuppressive therapy within 14 days prior to study drug administration. Subjects using a physiologic replacement dose of hydrocortisone or its equivalent (defined as up to 30 mg per day of hydrocortisone up to 10 mg per day of prednisone) are allowed.
Subject has symptomatic central nervous system (CNS) metastases or subject has evidence of unstable CNS metastases even if asymptomatic (e.g., progression on scans). Subjects with previously treated CNS metastases are eligible, if subject is clinically stable and have no evidence of CNS progression by imaging for at least 4 weeks prior to start of study treatment and are not requiring immunosuppressive doses of systemic steroids (> 30 mg per day of hydrocortisone or > 10 mg per day of prednisone or equivalent) for longer than 2 weeks.
Subject has an active autoimmune disease. Subjects with type 1 diabetes mellitus, endocrinopathies stably maintained on appropriate replacement therapy, or skin disorders (e.g., vitiligo, psoriasis, or alopecia) not requiring systemic treatment are allowed.
Subject was discontinued from prior immunomodulatory therapy due to a grade ≥ 3 toxicity that was mechanistically related (e.g., immune related) to the agent.
Subject has known history of serious hypersensitivity reaction to a known ingredient of ASP8374 or pembrolizumab or severe hypersensitivity reaction to treatment with another monoclonal antibody.
Subject has a known history of Human Immunodeficiency Virus.
Subject with positive for Hepatitis B virus (HBV) antibodies and surface antigen (including acute HBV or chronic HBV) or Hepatitis C ([HCV]; ribonucleic acid [RNA] detected by qualitative assay). Hepatitis C RNA testing is not required in subjects with negative Hepatitis C antibody testing.
Subject has received a live vaccine against infectious diseases within 28 days prior to initiation of study treatment.
Subject has a history of drug-induced pneumonitis (interstitial lung disease), a history of (non-infectious) pneumonitis that required steroids, radiation pneumonitis or currently has pneumonitis.
Subject has an infection requiring systemic therapy within 14 days prior to study drug treatment.
Subject has received a prior allogeneic bone marrow or solid organ transplant.
Subject is expected to require another form of antineoplastic therapy while on study treatment.
Subject has had a myocardial infarction or unstable angina within 6 months prior to the start of study treatment or currently has an uncontrolled illness including, but not limited to symptomatic congestive heart failure, clinically significant cardiac disease, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
Any condition that makes the subject unsuitable for study participation.
Subject has had a major surgical procedure and has not completely recovered within 28 days prior to the start of study treatment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Honor Health Research Institute	Scottsdale	Arizona	United States	85258
2	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
3	University of California Los Angeles	Los Angeles	California	United States	90095
4	University of California, Davis	Sacramento	California	United States	95817
5	University of California, San Francisco	San Francisco	California	United States	94115
6	Mount Sinai Comprehensive Cancer Center	Miami Beach	Florida	United States	33140
7	University of Iowa Hospitals and Clinics	Iowa City	Iowa	United States	52242
8	University of Kansas Cancer Center	Fairway	Kansas	United States	66205
9	Karmanos Cancer Institute	Detroit	Michigan	United States	48201
10	Henry Ford Health System	Detroit	Michigan	United States	48202
11	Columbia University Medical Center	New York	New York	United States	10032
12	University Hospital of Cleveland	Cleveland	Ohio	United States	44106
13	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111
14	University of Pittsburgh Cancer Institute	Pittsburgh	Pennsylvania	United States	15232
15	Sarah Cannon Research Institute	Nashville	Tennessee	United States	37203
16	Mary Crowley Research Center	Dallas	Texas	United States	75251
17	Huntsman Cancer Institute	Salt Lake City	Utah	United States	84112
18	Virginia Cancer Specialists	Fairfax	Virginia	United States	22031
19	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226-3522
20	Site CA15004	Edmonton	Alberta	Canada	T6G 1Z2
21	Site CA15003	Toronto	Ontario	Canada	M4N 3M5
22	Site CA15001	Toronto	Ontario	Canada	M5G 2M9
23	Site CA15002	Montreal	Quebec	Canada	H3T 1E2
24	Site IT39004	Ancona		Italy
25	Site IT39002	Milano		Italy
26	Site IT39003	Milano		Italy
27	Site IT39008	Milano		Italy
28	Site IT39009	Milano		Italy
29	Site IT39010	Modena		Italy
30	Site IT39005	Monza		Italy
31	Site IT39011	Negrar		Italy
32	Site JP81001	Chuo-ku		Japan
33	Site KR82004	Goyang-si	Gyeonggi-do	Korea, Republic of	410-769
34	Site KR82005	Seongnam-Si	Gyeonggi-do	Korea, Republic of	013620
35	Site KR82001	Seoul		Korea, Republic of	03080
36	SIte KR82002	Seoul		Korea, Republic of	120-752
37	Site KR82006	Seoul		Korea, Republic of
38	Site PT35101	Lisboa		Portugal
39	Site PT35106	Porto		Portugal
40	Site ES34002	Barcelona		Spain
41	Site ES34003	Barcelona		Spain
42	Site ES34009	Barcelona		Spain
43	Site ES34010	Barcelona		Spain
44	Site ES34001	Madrid		Spain
45	Site ES34006	Madrid		Spain
46	Site ES34013	Madrid		Spain
47	Site ES34014	Valencia		Spain
48	Site TW88602	Taichung		Taiwan	00404
49	Site TW88601	Tainan		Taiwan
50	Site TW88603	Taipei City		Taiwan
51	Site GB44003	London		United Kingdom
52	Site GB44006	London		United Kingdom
53	Site GB44004	Newcastle upon Tyne		United Kingdom
54	Site GB44005	Sutton Surry		United Kingdom