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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT02702414
Registration number
NCT02702414
Ethics application status
Date submitted
3/03/2016
Date registered
8/03/2016
Date last updated
18/10/2023
Titles & IDs
Public title
Study of Pembrolizumab (MK-3475) as Monotherapy in Participants With Advanced Hepatocellular Carcinoma (MK-3475-224/KEYNOTE-224)
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Scientific title
A Phase 2 Study of Pembrolizumab (MK-3475) as Monotherapy in Subjects With Advanced Hepatocellular Carcinoma (KEYNOTE-224)
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Secondary ID [1]
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MK-3475-224
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Secondary ID [2]
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3475-224
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Hepatocellular Carcinoma
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Condition category
Condition code
Cancer
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Non melanoma skin cancer
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Cancer
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Kidney
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Cancer
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Liver
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Other interventions - Pembrolizumab
Experimental: Cohort 1: Hepatocellular Carcinoma (HCC)-Prior Systemic Therapy with Sorafenib - Participants with previously systemically treated HCC received a pembrolizumab 200 mg intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 administrations. Participants who stopped pembrolizumab as a result of obtaining a confirmed complete response (CR) or those who stopped after receiving 35 trial treatments were eligible for an additional 17 trial treatments (approximately an additional 1 year of treatment) after progressive disease if they met the criteria for re-treatment.
Experimental: Cohort 2: HCC-Systemic Therapy Naïve - Participants with HCC who had not received treatment for systemic disease received a pembrolizumab 200 mg IV infusion on Day 1 of each 3-week cycle for up to 35 administrations. Participants who stopped pembrolizumab as a result of obtaining a confirmed complete response (CR) or those who stopped after receiving 35 trial treatments were eligible for an additional 17 trial treatments (approximately an additional 1 year of treatment) after progressive disease if they met the criteria for re-treatment.
Other interventions: Pembrolizumab
Intravenous (IV) infusion
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Intervention code [1]
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Other interventions
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Objective Response Rate (ORR)
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Assessment method [1]
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ORR was defined as the percentage of participants who had a confirmed Complete Response (CR: Disappearance of all target and non-target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target and non-target lesions) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by blinded central imaging vendor. Participants with missing data were considered non-responders. The percentage of participants who experienced a CR or PR per RECIST 1.1 is presented.
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Timepoint [1]
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Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2
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Secondary outcome [1]
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Duration of Response (DOR)
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Assessment method [1]
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DOR was determined in participants who demonstrated a confirmed Complete Response (CR: disappearance of all target and non-target lesions) or Partial Response (PR: =30% decrease in the sum of diameters of target and non-target lesions) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by blinded central imaging vendor. DOR was defined as the time from first documented evidence of a CR or PR until progressive disease (PD) or death. Participants who had not progressed, started a new anti-cancer therapy, been lost to follow-up, or died at the time of analysis were censored at the date of their last tumor assessment. Per RECIST 1.1, PD was at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm, OR unequivocal progression for non-target lesions, OR appearance of one or more new lesions. The DOR per RECIST 1.1 for all participants who had a confirmed CR or PR is presented.
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Timepoint [1]
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Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2
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Secondary outcome [2]
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Disease Control Rate (DCR)
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Assessment method [2]
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DCR was defined as the percentage of participants who had a CR (disappearance of all target and non-target lesions), PR (at least a 30% decrease in the sum of diameters of target and non-target lesions), or Stable Disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease [PD was at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm, OR unequivocal progression for non-target lesions, OR appearance of one or more new lesions.]). CR, PR, and SD were evaluated per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by blinded central imaging vendor. Participants with missing data were considered as participants whose disease was not under control. The percentage of participants who experienced a confirmed CR, PR, or SD is reported.
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Timepoint [2]
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Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2
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Secondary outcome [3]
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Time to Progression (TTP)
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Assessment method [3]
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TTP was defined as the time from the first dose to the first documented disease progression per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by blinded central imaging vendor. PD was at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm, OR unequivocal progression for non-target lesions, OR appearance of one or more new lesions. If there was no documented disease progression, TTP was censored at last tumor assessment date. The TTP was analyzed using the product-limit (Kaplan-Meier) method for censored data. TTP per RECIST 1.1 is presented.
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Timepoint [3]
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Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2
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Secondary outcome [4]
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Progression-Free Survival (PFS)
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Assessment method [4]
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PFS was defined as the time from the first dose to the first documented progressive disease (PD) or death due to any cause, whichever occurred first, per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as assessed by blinded central imaging vendor. PD was at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm, OR unequivocal progression for non-target lesions, OR appearance of one or more new lesions. If there was no disease progression or death, participants were censored at the date of their last disease assessment. The PFS was analyzed using the product-limit (Kaplan-Meier) method for censored data. PFS is presented.
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Timepoint [4]
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Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2
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Secondary outcome [5]
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Overall Survival (OS)
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Assessment method [5]
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OS was determined for all participants and was defined as the time from the first dose to death due to any cause. Participants were censored at the last known alive date. The OS was analyzed using the product-limit (Kaplan-Meier) method for censored data. The OS is presented.
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Timepoint [5]
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Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2
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Secondary outcome [6]
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Number of Participants Who Experienced At Least One Adverse Event (AE)
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Assessment method [6]
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An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event. The number of participants who experienced at least one AE is presented. Per protocol, final analysis for this outcome measure was planned to be performed during the first course of therapy only.
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Timepoint [6]
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Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2
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Secondary outcome [7]
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Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE)
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Assessment method [7]
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An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event. The number of participants who discontinued study treatment due to an AE is presented. Per protocol, final analysis for this outcome measure was planned to be performed during the first course of therapy only.
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Timepoint [7]
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Up to approximately 34 months for Cohort 1 and up to approximately 28 months for Cohort 2
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Eligibility
Key inclusion criteria
- For Cohort 1: has histologically or cytologically confirmed diagnosis of HCC
(fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes are not eligible)
based on pathology report
- For Cohort 2: has an HCC diagnosis confirmed by radiology, histology, or cytology
(fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes are not eligible)
- Has Barcelona Clinic Liver Cancer (BCLC) Stage C disease or BCLC Stage B disease not
amenable to locoregional therapy or refractory to locoregional therapy, and not
amenable to a curative treatment approach
- Has a Child-Pugh Class A liver score within 7 days of first dose of study drug
- Has a predicted life expectancy >3 months
- Has measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST)
1.1 as confirmed by the blinded central imaging vendor
- Has a performance status of 0 or 1 using the Eastern Cooperative Oncology Group (ECOG)
Performance Scale within 7 days of first dose of study drug
- For Cohort 1: has documented objective radiographic progression after stopping
treatment with sorafenib or else intolerance to sorafenib
- Is willing to use an adequate method of contraception for the course of the study
through 120 days after the last dose of study drug (male and female participants of
childbearing potential)
- Demonstrates adequate organ function
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
- Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy, herbal/complementary oral or
IV medicine, or used an investigational device within 4 weeks of the first dose of
study drug. Participant must also have recovered from associated therapy (i.e., to
Grade =1 or baseline) and from adverse events due to any prior therapy
- For Cohort 1: has received sorafenib within 14 days of first dose of study drug
- Has had esophageal or gastric variceal bleeding within the last 6 months
- Has clinically apparent ascites on physical examination
- Has portal vein invasion at the main portal (Vp4), inferior vena cava, or cardiac
involvement of HCC based on imaging
- Has had encephalopathy in the last 6 months. Participants on rifaximin or lactulose to
control their encephalopathy are not allowed
- Had a solid organ or hematologic transplant
- For Cohort 1: had prior systemic therapy for HCC other than sorafenib, or intercurrent
local therapy to the liver tumor between sorafenib and study drug
- For Cohort 2: had prior systemic therapy in the advanced disease setting
- Has active autoimmune disease that has required systemic treatment in past 2 years
(i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive
drugs)
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of study
drug
- Has a diagnosed additional malignancy within 5 years for Cohort 1 and 3 years for
Cohort 2 prior to first dose of study treatment with the exception of curatively
treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin and/or
curatively resected in situ cervical and/or breast cancers
- Has radiographically detectable central nervous system (CNS) metastases and/or
carcinomatous meningitis
- Has evidence or history of interstitial lung disease or active noninfectious
pneumonitis
- Has an active infection requiring systemic therapy
- Has a known severe hypersensitivity to pembrolizumab, its active substance and/or any
of its excipients
- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the study
- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the screening visit through 120 days
after the last dose of trial treatment
- Has received prior immunotherapy including anti-programmed death-1 (anti-PD-1),
anti-PD-ligand-1 (anti-PD-L1), or anti-PD-L2 agents, or if the participant has
previously participated in clinical studies with pembrolizumab (MK-3475)
- Has a known history of human immunodeficiency virus (HIV)
- Has untreated active Hepatitis B virus (HBV)
- For Cohort 1: has dual infection with HBV/Hepatitis C virus (HCV) or other hepatitis
combinations at study entry
- For Cohort 2: has dual active HBV infection (Hepatitis B surface antigen positive
and/or detectable HBV deoxyribonucleic acid [DNA]) and HCV infection (detectable HCV
ribonucleic acid [RNA]) at study entry
- Has received a live vaccine within 30 days of planned start of study drug (Cycle 1,
Day 1)
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Non-randomised trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 2
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
31/05/2016
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
29/09/2023
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Sample size
Target
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Accrual to date
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Final
156
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Recruitment in Australia
Recruitment state(s)
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Merck Sharp & Dohme LLC
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Address
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Country
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Ethics approval
Ethics application status
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Summary
Brief summary
This is a efficacy and safety study of pembrolizumab (MK-3475, KEYTRUDA®) as monotherapy in
participants with hepatocellular carcinoma (HCC) in two cohorts: participants with advanced
HCC and with no curative option after disease progression on sorafenib or intolerance of
sorafenib (Cohort 1) or who had not received treatment for systemic disease (Cohort 2). Study
participants may receive pembrolizumab once every 3 weeks for up to 35 initial cycles (up to
approximately 2 years) and a potential additional 17 cycles in a re-treatment phase
(approximately an additional 1 year of treatment) .
The primary objective of this study is to determine the Objective Response Rate (ORR) of
pembrolizumab given as monotherapy in participants with HCC.
Effective with Amendment 7: Upon study completion, participants are discontinued and may be
enrolled in a pembrolizumab extension study, if available.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT02702414
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Trial related presentations / publications
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Public notes
This record is viewable in the ANZCTR as it had previously listed Australia and/or New Zealand as a recruitment site, however these sites have since been removed
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Contacts
Principal investigator
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Medical Director
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Address
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Merck Sharp & Dohme LLC
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Phone
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Fax
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Email
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Contact person for public queries
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Address
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Fax
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Email
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT02702414
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