A Study of Gebasaxturev (V937) in Combination With Pembrolizumab (MK-3475) in Participants With Advanced/Metastatic Solid Tumors (V937-013)

Phase 1

Terminated

Conditions: Neoplasm Metastasis

Interventions: Biological: Gebasaxturev
Drug: Pembrolizumab

Registration Number: NCT04521621

Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary: The purpose of this study is to evaluate the safety, tolerability, and efficacy in participants with advanced/metastatic or recurrent malignancies who receive gebasaxturev (V937) in combination with pembrolizumab (MK-3475). The primary objective for Part 1 is to evaluate the objective response rate, and the primary objective for Part 2 is to determine the safety and tolerability of gebasaxturev administered in combination with pembrolizumab. With Amendment 4, this study will be terminated once all participants who have completed or discontinued gebasaxturev treatment and are only receiving pembrolizumab may be enrolled in a pembrolizumab extension study, if available, to continue pembrolizumab monotherapy for up to 35 cycles from first pembrolizumab dose on V937-013.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 76

Inclusion Criteria

Locally-advanced disease that is not amenable to surgery or radiation, or Stage IV advanced/metastatic solid tumor malignancies
Histologically- or cytologically-confirmed diagnosis of an advanced/metastatic solid tumor.
Measurable disease by RECIST 1.1 criteria as assessed by investigator. Target lesions in a previously irradiated area will be considered measurable if progression has been demonstrated in such lesions
Submitted a baseline tumor sample for analysis. Participants enrolling in Part 2 Cohorts D-F may enroll without submitting a tumor sample if all other enrollment criteria are met.
Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale obtained within 72 hours prior to the first dose of study intervention
If participant has known human immunodeficiency virus (HIV)-positive disease, participant must have well-controlled HIV on antiretroviral therapy (ART), per study criteria.
Adequate organ function
Male participants are eligible to participate if they agree to the following during the intervention period and for at least 120 days: Be abstinent from heterosexual intercourse as their preferred and usual lifestyle and agree to remain abstinent, OR must agree to use contraception unless confirmed to be azoospermic.
Female participants are eligible to participate if 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, 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 120 days after the last dose of study intervention.
Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
Part 1, All Cohorts: participants must have at least one injectable lesion amenable to injection and/or biopsy.
Part 1, Cohort A:
- Locally recurrent, inoperable OR metastatic breast cancer treated with at least 1 prior line of therapy in the metastatic setting with skin involvement and/or subcutaneous lesions or accessible lymph nodes amenable to local injection. An exception would be allowed for participants who are not eligible to receive chemotherapy.
- Diagnosis of triple-negative breast cancer (estrogen receptor, progesterone receptor, and HER2-receptor negative status)
Part 1, Cohort B:
- Histologically confirmed advanced or metastatic head and neck squamous cell carcinoma (HNSCC) of the oral cavity, oropharynx, hypopharynx, and/or larynx considered incurable and/or treated with no more than 1 previous line of therapy
- Tumors must be PD-L1+
- Documentation of HPV status for oropharyngeal cancers. Other HNSCC subtypes may submit HPV testing, but is not required.
Part 1, Cohort C:
- Histologically confirmed cutaneous squamous cell carcinoma (cSCC) as the primary site of malignancy
- Recurrent/metastatic disease only: Has metastatic disease defined as disseminated disease distant from the initial/primary site of diagnosis and/or with a history of locally-recurrent disease previously treated with surgery and/or radiotherapy, which is now incurable
- Locally-advanced disease only: Must be ineligible for surgical resection per study criteria, and must have received prior radiation therapy to the index site or deemed ineligible for radiation therapy
Part 2, Solid Tumors+Liver Metastases Dose Level 1-3 arms:
- Histologically-confirmed advanced/metastatic solid tumor that has progressed on all treatment known to confer clinical benefit
- Metastatic liver lesion(s) not exceeding one-third of the total liver volume AND a minimum of one injectable liver lesion
Part 2, Cohort D:
- Advanced hepatocellular carcinoma (HCC) following progression on, or intolerance to, sorafenib or lenvatinib with no curative options
- Diagnosis of HCC confirmed by radiology, histology, or cytology
- Child-Pugh Class A score
- If a participant has a history of hepatitis C virus (HCV) infection, then the participant must have been successfully treated for this condition
- Controlled (treated) hepatitis B participants will be allowed if they meet protocol-specified criteria
- Participants who are anti-hepatitis B core (HBc) positive, negative for hepatitis B surface antigen (HBsAg), negative or positive for anti-hepatitis B surface (HBs), and who have an HBV viral load under 100 IU/mL, do not require HBV anti-viral prophylaxis
Part 2, Cohort E:
- Histologically- or cytologically-confirmed diagnosis of locally advanced, unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma
- Received at least one prior line of therapy that includes a platinum/fluoropyrimidine doublet or triplet regimen
- Had proven clinical progression 6 months following (or during) last dose of adjuvant or neo-adjuvant therapy
- Human epidermal growth factor receptor 2 (HER2) negative status; or, those with HER2 positive status AND documented disease progression on a prior regimen containing trastuzumab

Exclusion Criteria

Chemotherapy, definitive radiation, or biological cancer therapy within 4 weeks (2 weeks for palliative radiation) prior to first dose of study intervention, or has not recovered to Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 or better
If major or minor surgery was performed at/near the area being considered for injection, participant must be recovered from toxicity and/or complications of intervention
If participant has had injection or radiation therapy, participant must be recovered from toxicity and/or complications of intervention
History of second malignancy, unless potentially curative treatment has been completed with no further evidence of disease for ≥5 years.
Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with treated brain metastases may participate if lesions are radiologically stable.
Active infection requiring therapy, except HIV criteria as stated above, and HBV and HCV criteria for HCC cohort as stated above
History of interstitial lung disease
History of noninfectious pneumonitis requiring active steroid therapy or ongoing pneumonitis
Active autoimmune disease that required systemic treatment in the past 2 years except vitiligo or resolved childhood asthma/atopy
Known Hepatitis B or C infections or known to be positive for HBsAg/HBV deoxyribonucleic acid (DNA) or Hepatitis C Antibody or ribonucleic acid (RNA)
History of Kaposi's sarcoma and/or Multicentric Castleman's Disease
Known hypersensitivity to gebasaxturev and/or pembrolizumab or any of their excipients
Received prior therapy with anti-programmed cell death protein-1 (anti-PD-1), anti-programmed cell death-ligand 1 (anti-PD-L1) agents, Talimogene Laherparepvec (T-VEC), or any other oncolytic virus therapies
Received a live or live-attenuated vaccine within 30 days prior to first dose of study intervention. Administration of killed vaccines is allowed.
Pregnant or 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 study intervention
Part 2, Cohort D:
- Has had esophageal or gastric variceal bleeding within the last 6 months
- Has had clinically diagnosed hepatic encephalopathy in the 6 months prior to initiation of study intervention
Part 2, Cohort E:
- Squamous cell or undifferentiated gastric cancer

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Part 1, Cohort C: Cutaneous Squamous Cell Carcinoma	Pembrolizumab	This arm will enroll participants with cutaneous squamous cell carcinoma (cSCC) solid tumors. Participants receive 3 X 10\^8 TCID50 of gebasaxturev intratumorally for 8 cycles, and pembrolizumab intravenously for a maximum of 35 cycles. Cycle 1 is 28 days, and cycles 2-35 are 21 days.
Part 1, Cohort A: Triple-Negative Breast Cancer	Gebasaxturev	This arm will enroll participants with triple-negative breast cancer (TNBC) solid tumors. Participants receive 3 X 10\^8 50% tissue culture infectious dose (TCID50) of gebasaxturev intratumorally for 8 cycles, and pembrolizumab intravenously for a maximum of 35 cycles. Cycle 1 is 28 days, and cycles 2-35 are 21 days.
Part 2 Dose Level 1, Solid Tumors + Liver Metastases	Pembrolizumab	This arm will enroll participants with solid tumors with liver metastases. Participants receive 3 X 10\^7 TCID50 of gebasaxturev intratumorally for 8 cycles, and pembrolizumab intravenously for a maximum of 35 cycles. Cycle 1 is 28 days, and cycles 2-35 are 21 days.
Part 1, Cohort B: Head and Neck Squamous Cell Carcinoma	Pembrolizumab	This arm will enroll participants with head and neck squamous cell carcinoma (HNSCC) solid tumors. Participants receive 3 X 10\^8 TCID50 of gebasaxturev intratumorally for 8 cycles, and pembrolizumab intravenously for a maximum of 35 cycles. Cycle 1 is 28 days, and cycles 2-35 are 21 days.
Part 1, Cohort A: Triple-Negative Breast Cancer	Pembrolizumab	This arm will enroll participants with triple-negative breast cancer (TNBC) solid tumors. Participants receive 3 X 10\^8 50% tissue culture infectious dose (TCID50) of gebasaxturev intratumorally for 8 cycles, and pembrolizumab intravenously for a maximum of 35 cycles. Cycle 1 is 28 days, and cycles 2-35 are 21 days.
Part 1, Cohort B: Head and Neck Squamous Cell Carcinoma	Gebasaxturev	This arm will enroll participants with head and neck squamous cell carcinoma (HNSCC) solid tumors. Participants receive 3 X 10\^8 TCID50 of gebasaxturev intratumorally for 8 cycles, and pembrolizumab intravenously for a maximum of 35 cycles. Cycle 1 is 28 days, and cycles 2-35 are 21 days.
Part 1, Cohort C: Cutaneous Squamous Cell Carcinoma	Gebasaxturev	This arm will enroll participants with cutaneous squamous cell carcinoma (cSCC) solid tumors. Participants receive 3 X 10\^8 TCID50 of gebasaxturev intratumorally for 8 cycles, and pembrolizumab intravenously for a maximum of 35 cycles. Cycle 1 is 28 days, and cycles 2-35 are 21 days.
Part 2 Dose Level 2, Solid Tumors + Liver Metastases	Gebasaxturev	This arm will enroll participants with solid tumors with liver metastases. Participants receive 1 X 10\^8 TCID50 of gebasaxturev intratumorally for 8 cycles, and pembrolizumab intravenously for a maximum of 35 cycles. Cycle 1 is 28 days, and cycles 2-35 are 21 days.
Part 2 Dose Level 1, Solid Tumors + Liver Metastases	Gebasaxturev	This arm will enroll participants with solid tumors with liver metastases. Participants receive 3 X 10\^7 TCID50 of gebasaxturev intratumorally for 8 cycles, and pembrolizumab intravenously for a maximum of 35 cycles. Cycle 1 is 28 days, and cycles 2-35 are 21 days.
Part 2 Dose Level 2, Solid Tumors + Liver Metastases	Pembrolizumab	This arm will enroll participants with solid tumors with liver metastases. Participants receive 1 X 10\^8 TCID50 of gebasaxturev intratumorally for 8 cycles, and pembrolizumab intravenously for a maximum of 35 cycles. Cycle 1 is 28 days, and cycles 2-35 are 21 days.
Part 2 Dose Level 3, Solid Tumors + Liver Metastases	Gebasaxturev	This arm will enroll participants with solid tumors with liver metastases. Participants receive 3 X 10\^8 TCID50 of gebasaxturev intratumorally for 8 cycles, and pembrolizumab intravenously for a maximum of 35 cycles. Cycle 1 is 28 days, and cycles 2-35 are 21 days.
Part 2 Dose Level 3, Solid Tumors + Liver Metastases	Pembrolizumab	This arm will enroll participants with solid tumors with liver metastases. Participants receive 3 X 10\^8 TCID50 of gebasaxturev intratumorally for 8 cycles, and pembrolizumab intravenously for a maximum of 35 cycles. Cycle 1 is 28 days, and cycles 2-35 are 21 days.
Part 2, Cohort D: Hepatocellular Carcinoma (HCC)	Gebasaxturev	This arm will enroll participants with hepatocellular carcinoma (HCC) solid tumors. Participants receive the gebasaxturev recommended phase 2 dose (RP2D) intratumorally for 8 cycles, and pembrolizumab intravenously for a maximum of 35 cycles. Cycle 1 is 28 days, and cycles 2-35 are 21 days.
Part 2, Cohort D: Hepatocellular Carcinoma (HCC)	Pembrolizumab	This arm will enroll participants with hepatocellular carcinoma (HCC) solid tumors. Participants receive the gebasaxturev recommended phase 2 dose (RP2D) intratumorally for 8 cycles, and pembrolizumab intravenously for a maximum of 35 cycles. Cycle 1 is 28 days, and cycles 2-35 are 21 days.
Part 2, Cohort E: Gastric Carcinoma	Pembrolizumab	This arm will enroll participants with gastric carcinoma solid tumors. Participants receive the gebasaxturev recommended phase 2 dose (RP2D) intratumorally for 8 cycles, and pembrolizumab intravenously for a maximum of 35 cycles. Cycle 1 is 28 days, and cycles 2-35 are 21 days.
Part 2, Cohort E: Gastric Carcinoma	Gebasaxturev	This arm will enroll participants with gastric carcinoma solid tumors. Participants receive the gebasaxturev recommended phase 2 dose (RP2D) intratumorally for 8 cycles, and pembrolizumab intravenously for a maximum of 35 cycles. Cycle 1 is 28 days, and cycles 2-35 are 21 days.

Primary Outcome Measures

Name	Time	Method
Part 2: Number of Participants Who Discontinued Study Intervention Due to an AE	Up to approximately 10 months	An AE was defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment. Per protocol, only participants in Part 2 were analyzed in this outcome measure.
Part 1: Objective Response Rate (ORR) Per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 as Assessed by Investigator	Up to approximately 30 months	ORR was defined as the percentage of participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions and no new lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by investigator. For this study, RECIST 1.1 has been modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and to specify that intratumoral injection does not render a lesion non-evaluable. Per protocol, only participants in Part 1 were analyzed in this outcome measure.
Number of Participants Who Experienced a Dose-Limiting Toxicity (DLT)	Cycle 1 (28-day cycle)	The following toxicities during DLT evaluation period were considered a DLT, if assessed by investigator to be possibly, probably, or definitely related to treatment: Grade (Gr) 4 nonhematologic toxicity; Gr 4 hematologic toxicity lasting ≥7 days, except Gr 3 thrombocytopenia (if associated with clinically significant bleeding) or any grade febrile neutropenia; nonhematologic adverse event (AE) ≥ Gr 3 (with exceptions); Gr 3 or 4 nonhematologic lab abnormality (if medical intervention is required, leads to hospitalization, or persists for \>1 week); drug-related toxicity that causes a \>2 week delay in Cycle 2 initiation; drug-related toxicity that causes treatment discontinuation or missed dosage of gebasaxturev; or Gr 5 toxicity. Per protocol, only the participants in Part 2 were analyzed in this outcome measure.
Part 2: Number of Participants Who Experienced One or More Adverse Events (AEs)	Up to approximately 29 months	An AE is defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment. Per protocol, only participants in Part 2 were analyzed in this outcome measure.

Secondary Outcome Measures

Name	Time	Method
ORR Per iRECIST as Assessed by Investigator	Up to approximately 30 months	ORR was defined as the percentage of participants who had confirmed responses assessed using RECIST 1.1 before PD or an immune-based Complete Response (iCR: Disappearance of all target lesions) or an immune-based Partial Response (iPR: ≥30% decrease in the sum of diameters of target lesions) after a single PD per iRECIST as assessed by investigator.
Duration of Response (DOR) Per RECIST 1.1 as Assessed by Investigator	Up to approximately 30 months	For participants who demonstrated a confirmed Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by investigator, DOR was defined as the time from first documented evidence of CR or PR until disease progression or death, whichever occurs first. For this study, RECIST 1.1 was modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and to specify that intratumoral injection did not render a lesion non-evaluable. Per protocol, only participants in Part 1 were analyzed in this outcome measure.
PFS Per Response Evaluation Criteria in Solid Tumors 1.1 for Immune-Based Therapeutics (iRECIST) as Assessed by Investigator	Up to approximately 30 months	PFS was defined as the time from first dose of study treatment to the first documented immune-based confirmed progressive disease (iCPD) or death due to any cause, whichever occurs first as assessed by investigator. Per iRECIST, iCPD was defined as worsening of any existing cause of progression, or the appearance of any other cause of progression, relative to the initial appearance of progressive disease by RECIST 1.1. Per protocol, only participants in Part 1 were analyzed in this outcome measure.
Part 2: ORR Per RECIST 1.1 as Assessed by Investigator	Up to approximately 29 months	ORR was defined as the percentage of participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions and no new lesions) or a Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1 as assessed by investigator. For this study, RECIST 1.1 was modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and to specify that intratumoral injection does not render a lesion non-evaluable. Per protocol, only participants in Part 2 were analyzed for this outcome measure.
Progression-Free Survival (PFS) Per RECIST 1.1 as Assessed by Investigator	Up to approximately 30 months	PFS was defined as the time from first dose of study treatment to the first documented progressive disease (PD) or death due to any cause, whichever occurs first as assessed by investigator. Per RECIST 1.1, PD is defined as ≥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 ≥5 mm. The appearance of one or more new lesions is also considered PD. For this study, RECIST 1.1 has been modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and to specify that intratumoral injection does not render a lesion non-evaluable. Per protocol, only participants in Part 1 were analyzed in this outcome measure.
DOR Per iRECIST as Assessed by Investigator	Up to approximately 30 months	For participants who demonstrated confirmed CR (disappearance of all target lesions and non-target lesions) or PR (≥30% decrease in the sum of diameters of target lesions) per RECIST 1.1 or immune-based Complete Response (iCR: Disappearance of all target lesions) or immune-based Partial Response (iPR: ≥30% decrease in the sum of diameters of target lesions) after a single PD per iRECIST, DOR was defined as the time from the first documented CR or PR, or iCR or an iPR, as assessed by investigator, until progressive disease or death, whichever occurs first. For this study, RECIST 1.1 was modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, and to specify that intratumoral injection did not render a lesion non-evaluable. Per protocol, only participants in Part 1 were analyzed in this outcome measure.
Overall Survival (OS)	Up to approximately 30 months	OS was defined as the time from first dose of study intervention to death due to any cause. Per protocol, only participants in Part 1 were analyzed in this outcome measure.
Part 1: Number of Participants Who Experienced One or More AEs	Up to approximately 30 months	An AE was defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment. Per protocol, only participants in Part 1 were analyzed in this outcome measure.
Part 1: Number of Participants Who Discontinued Study Intervention Due to an AE	Up to approximately 23 months	An AE was defined as any unfavorable and unintended sign, symptom, disease, or worsening of preexisting condition temporally associated with study treatment and irrespective of causality to study treatment. Per protocol, only participants in Part 1 were analyzed in this outcome measure.

Trial Locations

Locations (29): Hopital La Timone ( Site 0051)
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Marseille, Bouches-du-Rhone, France
Centre Hospitalier de l Universite de Montreal - CHUM ( Site 0032)
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Montreal, Quebec, Canada
Universitaetsklinikum Tuebingen ( Site 0171)
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Tuebingen, Baden-Wurttemberg, Germany
Sourasky Medical Center ( Site 0073)
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Tel Aviv, Israel
Clinica San Gabriel ( Site 0097)
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Lima, Peru
Clinica Universitaria de Navarra ( Site 0122)
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Madrid, Spain
Centre Hospitalier Lyon-Sud ( Site 0055)
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Pierre Benite, Rhone-Alpes, France
Hospital Universitari Vall d Hebron ( Site 0121)
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Barcelona, Spain
Gustave Roussy ( Site 0053)
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Villejuif, Val-de-Marne, France
National Cheng Kung University Hospital ( Site 0142)
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Tainan, Taiwan
Orszagos Onkologiai Intezet ( Site 0070)
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Budapest, Hungary
National Taiwan University Hospital ( Site 0141)
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Taipei, Taiwan
John Theurer Cancer Center ( Site 0004)
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Hackensack, New Jersey, United States
Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - P-Oddzial Badan Wczesnych Faz ( Site 0181
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Warszawa, Mazowieckie, Poland
Instituto Português de Oncologia do Porto Francisco Gentil, EPE ( Site 0191)
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Porto, Portugal
Hadassah Medical Center. Ein Kerem ( Site 0072)
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Jerusalem, Israel
Helse Bergen HF - Haukeland Universitetssykehus ( Site 0162)
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Bergen, Hordaland, Norway
Centro Hospitalar Universitário Lisboa Norte, E.P.E. - Hospital de Santa Maria ( Site 0192)
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Lisbon, Lisboa, Portugal
Providence Portland Medical Center ( Site 0001)
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Portland, Oregon, United States
Mackay Memorial Hospital ( Site 0143)
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Taipei, Taiwan
Universitaetsklinikum Heidelberg-Nationales Centrum für Tumorerkrankungen ( Site 0172)
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Heidelberg, Baden-Wurttemberg, Germany
HaEmek Medical Center ( Site 0071)
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Afula, Israel
National Cancer Center Hospital East ( Site 0166)
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Kashiwa, Chiba, Japan
Oslo Universitetssykehus Radiumhospitalet ( Site 0161)
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Oslo, Norway
Chang Gung Medical Foundation - Kaohsiung ( Site 0145)
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Kaohsiung, Taiwan
China Medical University Hospital ( Site 0144)
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Taichung, Taiwan
Princess Margaret Cancer Centre ( Site 0031)
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Toronto, Ontario, Canada
Istituto Europeo di Oncologia IRCCS-Divisione di Sviluppo di Nuovi Farmaci per Terapie Innovative (
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Milano, Italy
Chang Gung Memorial Hospital - Linkou Branch ( Site 0146)
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Taoyuan, Taiwan