Clinical Trials List
Protocol NumberMK3475-240
NCT Number(ClinicalTrials.gov Identfier)NCT02702401
2016-05-01 - 2020-04-30
Phase III
Terminated6
ICD-10C22.0
Liver cell carcinoma
ICD-10C22
Malignant neoplasm of liver and intrahepatic bile ducts
ICD-9155.0
Malignant neoplasm of liver, primary
A Phase III Study of Pembrolizumab (MK-3475) vs. Best Supportive Care as Second-Line Therapy in Subjects with Previously Systemically Treated Advanced Hepatocellular Carcinoma (KEYNOTE-240)
-
Trial Applicant
Merck Sharp & Dohme (I.A.) LLC
-
Sponsor
Merck Sharp & Dohme Corp.
-
Trial scale
Multi-Regional Multi-Center
-
Update
2025/08/20
Investigators and Locations
Co-Principal Investigator
- Yi-Ping Hung Division of Hematology & Oncology
- Yi-Hsiang Huang Digestive System Department
- Chung-Pin Li Digestive System Department
- Rheun-Chuan Lee Division of Radiology
The Actual Total Number of Participants Enrolled
0 Terminated
Audit
None
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- 陳昇弘 Digestive System Department
- Po-Heng Chuang Digestive System Department
- Cheng-Yuan Peng Digestive System Department
- Hung-Wei Wang Digestive System Department
- 蘇文邦 Digestive System Department
- Hung-Yao Chen Digestive System Department
- Hsueh-Chou Lai Digestive System Department
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
- 魯維丞 Division of Hematology & Oncology
- Shih-Jer Hsu Digestive System Department
- FU-JEN HSUEH Division of Hematology & Oncology
- JO-PAI CHEN Division of Hematology & Oncology
- 吳旭 Division of Hematology & Oncology
- WEI-LI MA Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
Audit
None
Linkou Chang Gung Medical Foundation
Taiwan National PI
林錫銘
Co-Principal Investigator
- Ming-Mo Hou Division of Hematology & Oncology
- Wei-Chen Lee Division of Gastroenterological Surgery
- 呂嘉偉 Division of Radiology
- Ming-Chin Yu Division of General Surgery
- Jen-Shi Chen Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
2 Terminated
Audit
CRO
Co-Principal Investigator
- Chih-Hung Hsu Division of Hematology & Oncology
- 呂理駿 Division of Hematology & Oncology
- 林宗哲 Division of Hematology & Oncology
- Chien-Hung Chen Division of General Internal Medicine
- Ying-Chun Shen Division of Hematology & Oncology
- Ming-Chih Ho Division of General Surgery
- Chiun Hsu Division of Hematology & Oncology
- YU-YUN SHAO Division of Hematology & Oncology
- - - Division of Radiology
The Actual Total Number of Participants Enrolled
0 Terminated
Audit
None
Condition/Disease
Advanced Hepatocellular Carcinoma
Objectives
This is a study of pembrolizumab (MK-3475) in participants with previously systemically treated advanced hepatocellular carcinoma (HCC).
The primary objectives of this study are to determine 1) Progression-Free Survival (PFS) and 2) Overall Survival (OS) of pembrolizumab plus best supportive care (BSC) compared with placebo plus BSC. The primary hypotheses of this study are: 1) pembrolizumab plus BSC prolongs PFS per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, assessed by Blinded Independent Central Review compared to placebo plus BSC, and 2) pembrolizumab plus BSC improves OS compared with placebo plus BSC.
Effective with Amendment 4: Upon study completion, participants are discontinued and may be enrolled in a pembrolizumab extension study, if available.
Test Drug
Pembrolizumab (MK-3475) /KEYTRUDA
Active Ingredient
Humanized anti-PD-1 mAb
Dosage Form
Injection
Dosage
100
Endpoints
Primary Efficacy Endpoints
The primary efficacy objective of this study is to evaluate the anti -tumor activity
of pembrolizumab in subjects with HCC who were previously treated with
sorafenib. PFS per RECIST 1.1 criteria as assessed by the blinded central imaging
vendor and OS will be used as the primary endpoints. The endpoint of OS is the
standard for demonstrating superiority of antineoplastic therapy in clinical studies
in the area of oncology. PFS is being included as a second primary endpoint in
case of unplanned treatment switching.
Secondary Efficacy Endpoints
The secondary efficacy objectives of this study are to:
(1) Compare ORR per RECIST 1.1 assessed by a blinded central imaging vendor.
(2) Evaluate DOR, DCR and TTP per RECIST 1.1 assessed by a blinded central
imaging vendor.
Measurable disease will be confirmed centrally at enrollment, prior to subject
randomization, to ensure that the assessment of measurable disease is accurate.
These endpoints have been chosen as ancillary markers of efficacy in a population
with few treatment options.
The primary efficacy objective of this study is to evaluate the anti -tumor activity
of pembrolizumab in subjects with HCC who were previously treated with
sorafenib. PFS per RECIST 1.1 criteria as assessed by the blinded central imaging
vendor and OS will be used as the primary endpoints. The endpoint of OS is the
standard for demonstrating superiority of antineoplastic therapy in clinical studies
in the area of oncology. PFS is being included as a second primary endpoint in
case of unplanned treatment switching.
Secondary Efficacy Endpoints
The secondary efficacy objectives of this study are to:
(1) Compare ORR per RECIST 1.1 assessed by a blinded central imaging vendor.
(2) Evaluate DOR, DCR and TTP per RECIST 1.1 assessed by a blinded central
imaging vendor.
Measurable disease will be confirmed centrally at enrollment, prior to subject
randomization, to ensure that the assessment of measurable disease is accurate.
These endpoints have been chosen as ancillary markers of efficacy in a population
with few treatment options.
Inclution Criteria
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written informed consent for the trial. The
subject may also provide consent for Future Biomedical Research (FBR).
However, the subject may participate in the main trial without participating in
FBR.
2. Be ≥ 18 years of age on day of signing informed consent.
3. Have histologically or cytologically confirmed diagnosis of HCC
(fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes are not
eligible) based on pathology report.
4. Have 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.
5. Have a Child-Pugh class A liver score within 7 days of first dose of study
drug.
6. Have a predicted life expectancy of greater than 3 months.
7. Have measurable disease based on RECIST 1.1 as confirmed by the blinded
central imaging vendor.
Note: the same image acquisition and processing parameters should be used
throughout the study for a given subject.
8. Have 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.
9. Have documented objective radiographic progression after stopping treatment
with sorafenib or else intolerance to sorafenib.
The definition of sorafenib intolerance will be:
Any Grade ≥2 drug-related AE which, despite supportive therapy,
recurred after sorafenib treatment interruption of at least 7 days and dose
reduction resulting in the subject requesting, or the physician
recommending discontinuation due to toxicity.
10. Subjects with chronic infection by HCV who are untreated are allowed on
study. In addition, subjects with successful HCV treatment (defined as
sustained virologic response [SVR] 12 or SVR 24) are allowed as long as 4
weeks have passed between completion of HCV therapy and start of study
drug.
11. Have a negative urine or serum pregnancy test within 72 hours prior to
receiving the first dose of study medication (Cycle 1, Day 1) (female subjects
of childbearing potential). If the urine test is positive or cannot be confirmed
as negative, a serum pregnancy test will be required.
12. Be willing to use an adequate method of contraception for the course of the
study through 120 days after the last dose of study medication (male and
female subjects of childbearing potential).
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.
13. Demonstrate adequate organ function as defined in Table 1.
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written informed consent for the trial. The
subject may also provide consent for Future Biomedical Research (FBR).
However, the subject may participate in the main trial without participating in
FBR.
2. Be ≥ 18 years of age on day of signing informed consent.
3. Have histologically or cytologically confirmed diagnosis of HCC
(fibrolamellar and mixed hepatocellular/cholangiocarcinoma subtypes are not
eligible) based on pathology report.
4. Have 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.
5. Have a Child-Pugh class A liver score within 7 days of first dose of study
drug.
6. Have a predicted life expectancy of greater than 3 months.
7. Have measurable disease based on RECIST 1.1 as confirmed by the blinded
central imaging vendor.
Note: the same image acquisition and processing parameters should be used
throughout the study for a given subject.
8. Have 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.
9. Have documented objective radiographic progression after stopping treatment
with sorafenib or else intolerance to sorafenib.
The definition of sorafenib intolerance will be:
Any Grade ≥2 drug-related AE which, despite supportive therapy,
recurred after sorafenib treatment interruption of at least 7 days and dose
reduction resulting in the subject requesting, or the physician
recommending discontinuation due to toxicity.
10. Subjects with chronic infection by HCV who are untreated are allowed on
study. In addition, subjects with successful HCV treatment (defined as
sustained virologic response [SVR] 12 or SVR 24) are allowed as long as 4
weeks have passed between completion of HCV therapy and start of study
drug.
11. Have a negative urine or serum pregnancy test within 72 hours prior to
receiving the first dose of study medication (Cycle 1, Day 1) (female subjects
of childbearing potential). If the urine test is positive or cannot be confirmed
as negative, a serum pregnancy test will be required.
12. Be willing to use an adequate method of contraception for the course of the
study through 120 days after the last dose of study medication (male and
female subjects of childbearing potential).
Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the subject.
13. Demonstrate adequate organ function as defined in Table 1.
Exclusion Criteria
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. 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 investigation device
within 4 weeks of the first dose of treatment. Subjects must also have
recovered from associated therapy (i.e., to Grade ≤ 1 or baseline) and from
adverse events due to any prior therapy.
2. Has received sorafenib within 14 days of first dose of study medication.
3. Has had esophageal or gastric variceal bleeding within the last 6 months. All
subjects will be screened for esophageal varices, unless such screening has
been performed in the past 12 months before first dose of treatment. If varices
are present, they should be treated according to institutional standards before
starting study treatment.
4. Has clinically apparent ascites on physical examination.
Note: ascites detectable on imaging studies only IS allowed.
5. Portal vein invasion at the main portal branch (Vp4), inferior vena cava, or
cardiac involvement of HCC based on imaging.
6. Has had encephalopathy in the last 6 months. Subjects on rifaximin or
lactulose to control their encephalopathy are not allowed.
7. Had a solid organ or hematologic transplant.
8. Had prior systemic therapy for HCC other than sorafenib, or intercurrent local
therapy to the liver tumor between sorafenib and study drug.
9. 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). Replacement therapy (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency, etc.) is not considered a form of systemic treatment.
10. 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 trial treatment. The use of physiologic doses of corticosteroids
may be approved after consultation with the Sponsor.
11. Has received locoregional therapy to liver (transcatheter chemoembolization
[TACE], transcatheter embolization [TAE], radiation, radioembolization, or
ablation) or major surgery to liver or other site within 6 weeks prior to the first
dose of study drug. Minor surgery (e.g., simple excision, tooth extraction)
must have occurred at least 7 days prior to the first dose of study treatment
(Cycle 1, Day 1). Subjects must have recovered adequately (i.e., Grade ≤ 1 or
baseline) from the toxicity and/or complications from any intervention prior to
starting therapy.
12. Has a diagnosed additional malignancy within 5 years 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.
13. Has radiographically detectable (even if asymptomatic and/or previously
treated) central nervous system (CNS) metastases and/or carcinomatous
meningitis as assessed by local site investigator.
14. Has a known history of, or any evidence of, interstitial lung disease or active
noninfectious pneumonitis.
15. Has an active infection requiring systemic therapy.
16. Has a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the trial, interfere with the
subject’s participation for the full duration of the trial, or is not in the best
interest of the subject to participate, in the opinion of the treating investigator,
including dialysis.
17. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
18. 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.
19. Has received prior immunotherapy including anti–PD-1, anti–PD-L1, or
anti–PD-L2 agents, or if the subject has previously participated in Merck
pembrolizumab clinical trials.
20. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2
antibodies).
21. Has untreated active Hepatitis B.
Note: To qualify for enrollment, antiviral therapy for HBV must be given for
at least 3 months, and HBV viral load must be less than 100 IU/mL prior to
first dose of study drug. Those on active HBV therapy with viral loads under
100 IU/ml should stay on the same therapy throughout study treatment. Those
subjects who are anti-HBc (+) and negative for HBsAg and negative for
anti-HBs, and have an HBV viral load under 100 IU/mL do not require HBV
anti-viral prophylaxis, but need close monitoring.
22. Has dual infection with HBV/HCV or other hepatitis combinations at study
entry.
23. Has received a live vaccine within 30 days of planned start of study t herapy
(Cycle 1, Day 1).
Note: The killed virus vaccines used for seasonal influenza vaccines for
injection are allowed; however intranasal influenza vaccines (e.g., FluMist®)
are live attenuated vaccines and are not allowed.
The subject must be excluded from participating in the trial if the subject:
1. 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 investigation device
within 4 weeks of the first dose of treatment. Subjects must also have
recovered from associated therapy (i.e., to Grade ≤ 1 or baseline) and from
adverse events due to any prior therapy.
2. Has received sorafenib within 14 days of first dose of study medication.
3. Has had esophageal or gastric variceal bleeding within the last 6 months. All
subjects will be screened for esophageal varices, unless such screening has
been performed in the past 12 months before first dose of treatment. If varices
are present, they should be treated according to institutional standards before
starting study treatment.
4. Has clinically apparent ascites on physical examination.
Note: ascites detectable on imaging studies only IS allowed.
5. Portal vein invasion at the main portal branch (Vp4), inferior vena cava, or
cardiac involvement of HCC based on imaging.
6. Has had encephalopathy in the last 6 months. Subjects on rifaximin or
lactulose to control their encephalopathy are not allowed.
7. Had a solid organ or hematologic transplant.
8. Had prior systemic therapy for HCC other than sorafenib, or intercurrent local
therapy to the liver tumor between sorafenib and study drug.
9. 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). Replacement therapy (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency, etc.) is not considered a form of systemic treatment.
10. 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 trial treatment. The use of physiologic doses of corticosteroids
may be approved after consultation with the Sponsor.
11. Has received locoregional therapy to liver (transcatheter chemoembolization
[TACE], transcatheter embolization [TAE], radiation, radioembolization, or
ablation) or major surgery to liver or other site within 6 weeks prior to the first
dose of study drug. Minor surgery (e.g., simple excision, tooth extraction)
must have occurred at least 7 days prior to the first dose of study treatment
(Cycle 1, Day 1). Subjects must have recovered adequately (i.e., Grade ≤ 1 or
baseline) from the toxicity and/or complications from any intervention prior to
starting therapy.
12. Has a diagnosed additional malignancy within 5 years 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.
13. Has radiographically detectable (even if asymptomatic and/or previously
treated) central nervous system (CNS) metastases and/or carcinomatous
meningitis as assessed by local site investigator.
14. Has a known history of, or any evidence of, interstitial lung disease or active
noninfectious pneumonitis.
15. Has an active infection requiring systemic therapy.
16. Has a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the trial, interfere with the
subject’s participation for the full duration of the trial, or is not in the best
interest of the subject to participate, in the opinion of the treating investigator,
including dialysis.
17. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
18. 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.
19. Has received prior immunotherapy including anti–PD-1, anti–PD-L1, or
anti–PD-L2 agents, or if the subject has previously participated in Merck
pembrolizumab clinical trials.
20. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2
antibodies).
21. Has untreated active Hepatitis B.
Note: To qualify for enrollment, antiviral therapy for HBV must be given for
at least 3 months, and HBV viral load must be less than 100 IU/mL prior to
first dose of study drug. Those on active HBV therapy with viral loads under
100 IU/ml should stay on the same therapy throughout study treatment. Those
subjects who are anti-HBc (+) and negative for HBsAg and negative for
anti-HBs, and have an HBV viral load under 100 IU/mL do not require HBV
anti-viral prophylaxis, but need close monitoring.
22. Has dual infection with HBV/HCV or other hepatitis combinations at study
entry.
23. Has received a live vaccine within 30 days of planned start of study t herapy
(Cycle 1, Day 1).
Note: The killed virus vaccines used for seasonal influenza vaccines for
injection are allowed; however intranasal influenza vaccines (e.g., FluMist®)
are live attenuated vaccines and are not allowed.
The Estimated Number of Participants
-
Taiwan
36 participants
-
Global
408 participants
