Clinical Trials List
Protocol NumberMK3475-394
2017-05-10 - 2025-12-31
Phase III
Terminated2
Study ended1
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 Randomized Double-blind Study of Pembrolizumab plus Best Supportive Care vs. Placebo plus Best Supportive Care as Second-Line Therapy in Asian Subjects with Previously Systemically Treated Advanced Hepatocellular Carcinoma (KEYNOTE-394)
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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
- 吳毅晉 Digestive System Department
- Liu Yi-Sheng Division of Radiology
- 姜乃榕 Division of Hematology & Oncology
- 邱彥程 Digestive System Department
- Nai-Jung Chiang Division of Hematology & Oncology
- Pin-Nan Cheng Digestive System Department
- 簡世杰 Digestive System Department
- Yih-Jyh Lin Division of General Surgery
- Chiu Hung Chiu Digestive System Department
The Actual Total Number of Participants Enrolled
0 Terminated
Audit
None
The Actual Total Number of Participants Enrolled
0 Terminated
Co-Principal Investigator
Audit
None
Co-Principal Investigator
- Hung-Yao Chen Digestive System Department
- 蘇文邦 Digestive System Department
- Wei-Fan Hsu Digestive System Department
- Hsueh-Chou Lai Digestive System Department
- Hung-Wei Wang Digestive System Department
- Cheng-Yuan Peng Digestive System Department
- Po-Heng Chuang Digestive System Department
- 陳昇弘 Digestive System Department
The Actual Total Number of Participants Enrolled
2 Study ended
Condition/Disease
Advanced Hepatocellular Carcinoma
Objectives
The primary objective of this trial is to compare the overall survival (OS) in subjects who
receive pembrolizumab plus BSC and those who receive placebo plus BSC. On-study
imaging assessments will be performed Q6W calculated from the date of randomization and
independent of treatment delays. RECIST 1.1 will be used by the site for treatment decisions
until the first radiologic evidence of progressive disease (PD).
Test Drug
Pembrolizumab (MK-3475)
Active Ingredient
Humanized anti-PD-1 mAb
Dosage Form
Injection
Dosage
100 mg/ 4 mL/ vial
Endpoints
Primary Objective(s) & Hypothesis(es)
1) Objective: To compare overall survival (OS) between two treatment arms
Hypothesis: Pembrolizumab prolongs OS compared to placebo
Secondary Objective(s) & Hypothesis(es)
1) Objective: To compare progression-free survival (PFS) per RECIST 1.1 as assessed
by a blinded central imaging vendor between two treatment arms
Hypothesis: Pembrolizumab prolongs PFS per RECIST 1.1, as assessed by a blinded
central imaging vendor compared to placebo
2) Objective: To compare the objective response rate (ORR) per RECIST 1.1 as
assessed by blinded central vendor between two treatment arms
Hypothesis: Pembrolizumab increases ORR per RECIST 1.1, as assessed by a
blinded central imaging vendor compared to placebo
3) Objective: To compare the duration of response (DOR) , disease control rate (DCR)
and time to progression (TTP), per RECIST 1.1 as assessed by a blinded central
imaging vendor between two treatment arms
4) Objective: To evaluate the safety and tolerability profile of pembrolizumab-treated
subjects compared with placebo-treated subjects
1) Objective: To compare overall survival (OS) between two treatment arms
Hypothesis: Pembrolizumab prolongs OS compared to placebo
Secondary Objective(s) & Hypothesis(es)
1) Objective: To compare progression-free survival (PFS) per RECIST 1.1 as assessed
by a blinded central imaging vendor between two treatment arms
Hypothesis: Pembrolizumab prolongs PFS per RECIST 1.1, as assessed by a blinded
central imaging vendor compared to placebo
2) Objective: To compare the objective response rate (ORR) per RECIST 1.1 as
assessed by blinded central vendor between two treatment arms
Hypothesis: Pembrolizumab increases ORR per RECIST 1.1, as assessed by a
blinded central imaging vendor compared to placebo
3) Objective: To compare the duration of response (DOR) , disease control rate (DCR)
and time to progression (TTP), per RECIST 1.1 as assessed by a blinded central
imaging vendor between two treatment arms
4) Objective: To evaluate the safety and tolerability profile of pembrolizumab-treated
subjects compared with placebo-treated subjects
Inclution 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 a HCC diagnosis confirmed by radiology, histology, or cytology (fibrolamellar,
and mixed hepatocellular/cholangiocarcinoma subtypes are not eligible).
Note: Radiologic confirmation diagnosis is provided by the study site. Definition of
radiological confirmation: Clinical findings consistent with the diagnosis of liver
cirrhosis and a liver mass measuring at least 2 cm with characteristic vascularization
(intense enhancement seen in the hepatic arterial-dominant phase and contrast
washout in the late portal venous phase) seen in either triphasic computed
tomography (CT) scan or magnetic resonance imaging (MRI).
4. Have Barcelona Clinic Liver Cancer (BCLC) Stage C diseases or BCLC Stage B
disease not amenable to locoregional therapy or refractory to locoregional therapy
and not amenable to a curative treatment approach (see Appendix 12.8).
5. Have a Child-Pugh A liver score within 7 days prior to first dose of study drug.
6. Have a predicted life expectancy of >3 months.
7. Have at least one measurable lesion based on RECIST 1.1 as determined by
investigator. Target lesions situated in a previously irradiated area are considered
measurable if progression has been demonstrated in such lesions.
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 during or after treatment with
sorafenib or oxaliplatin-based chemotherapy, or else intolerance to sorafenib or
oxaliplatin-based chemotherapy.
Note: (1) Sorafenib intolerance definition: Any Grade ≥2 drug-related AE which,
despite supportive therapy, recurred after a sorafenib treatment interruption of at least
7 days and dose reduction resulting in the subject requesting, or the physician
recommending discontinuation due to toxicity.
(2) Oxaliplatin-based chemotherapy intolerance definition: 1) having had at least one
dose of chemotherapy and 2) having a Grade ≥2 drug-related AE which both a)
persisted in spite of comprehensive supportive therapy according to institutional
standards and b) persisted or recurred after dose reduction and resulted in the subject
requesting or the physician recommending discontinuation due to the toxicity
10. Female subjects of childbearing potential must have a negative urine or serum
pregnancy test within 72 hours prior to receiving the first dose of study medication
(Cycle 1, Day 1). If the urine test is positive or cannot be confirmed as negative, a
serum pregnancy test will be required.
11. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an
adequate method of contraception as outlined in Section 5.7.2 – Contraception for the
course of the study, starting with the first dose of study medication through at least
120 days or longer based on local regulation after the last dose of study medication .
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception
for the subject.
12. Male subject of childbearing potential (Section 5.7.2) must agree to use an adequate
method of contraception as outlined in Section 5.7.2 - Contraception, starting with the
first dose of study medication (Cycle 1, Day 1) through 120 days after the last dose of
study medication
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. All screening laboratory
tests should be performed within 7 days prior to first dose of study drug.
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 a HCC diagnosis confirmed by radiology, histology, or cytology (fibrolamellar,
and mixed hepatocellular/cholangiocarcinoma subtypes are not eligible).
Note: Radiologic confirmation diagnosis is provided by the study site. Definition of
radiological confirmation: Clinical findings consistent with the diagnosis of liver
cirrhosis and a liver mass measuring at least 2 cm with characteristic vascularization
(intense enhancement seen in the hepatic arterial-dominant phase and contrast
washout in the late portal venous phase) seen in either triphasic computed
tomography (CT) scan or magnetic resonance imaging (MRI).
4. Have Barcelona Clinic Liver Cancer (BCLC) Stage C diseases or BCLC Stage B
disease not amenable to locoregional therapy or refractory to locoregional therapy
and not amenable to a curative treatment approach (see Appendix 12.8).
5. Have a Child-Pugh A liver score within 7 days prior to first dose of study drug.
6. Have a predicted life expectancy of >3 months.
7. Have at least one measurable lesion based on RECIST 1.1 as determined by
investigator. Target lesions situated in a previously irradiated area are considered
measurable if progression has been demonstrated in such lesions.
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 during or after treatment with
sorafenib or oxaliplatin-based chemotherapy, or else intolerance to sorafenib or
oxaliplatin-based chemotherapy.
Note: (1) Sorafenib intolerance definition: Any Grade ≥2 drug-related AE which,
despite supportive therapy, recurred after a sorafenib treatment interruption of at least
7 days and dose reduction resulting in the subject requesting, or the physician
recommending discontinuation due to toxicity.
(2) Oxaliplatin-based chemotherapy intolerance definition: 1) having had at least one
dose of chemotherapy and 2) having a Grade ≥2 drug-related AE which both a)
persisted in spite of comprehensive supportive therapy according to institutional
standards and b) persisted or recurred after dose reduction and resulted in the subject
requesting or the physician recommending discontinuation due to the toxicity
10. Female subjects of childbearing potential must have a negative urine or serum
pregnancy test within 72 hours prior to receiving the first dose of study medication
(Cycle 1, Day 1). If the urine test is positive or cannot be confirmed as negative, a
serum pregnancy test will be required.
11. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an
adequate method of contraception as outlined in Section 5.7.2 – Contraception for the
course of the study, starting with the first dose of study medication through at least
120 days or longer based on local regulation after the last dose of study medication .
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception
for the subject.
12. Male subject of childbearing potential (Section 5.7.2) must agree to use an adequate
method of contraception as outlined in Section 5.7.2 - Contraception, starting with the
first dose of study medication (Cycle 1, Day 1) through 120 days after the last dose of
study medication
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. All screening laboratory
tests should be performed within 7 days prior to first dose of study drug.
Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Is currently participating, or has participated in any study of an investigational agent
and received its study therapy, or herbal/complementary oral or IV medicine used as
systemic anti-cancer therapy, or used an investigation device within 4 weeks prior to
the first dose of our study 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 or oxaliplatin-based chemotherapy within 14 days of first dose
of study medication.
3. Has had esophageal or gastric variceal bleeding within the last 6 months.
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 clinically diagnosed hepatic encephalopathy in the last 6 months. Subjects
on rifaximin or lactulose to control their encephalopathy are not allowed.
7. Has had a solid organ or hematologic transplant.
8. Had prior systemic therapy for HCC in the advanced (incurable) setting other than
sorafenib or oxaliplatin-based chemotherapy, prior to start study drug.
9. Has a known severe hypersensitivity (≥ Grade 3) to pembrolizumab, its active
substance and/or any of its excipients. (Refer to the respective Investigator’s
Brochure for a list of excipients.)
10. 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.
11. 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.
Physiologic dose of corticosteroid definition: ≤10 mg/day prednisone or equivalent
12. Has received locoregional therapy to liver (transcatheter chemoembolization [TACE],
transcatheter embolization [TAE], hepatic arterial infusion [HAI], radiation,
radioembolization, or ablation) or other site within 4 weeks prior to the first dose of
study drug.
Subject is not eligible if aforementioned treatments were administered between last
dose of sorafenib or oxaliplatin-based chemotherapy and first dose of study
medication.
13. Has had major surgery to liver or other site within 4 weeks prior to the first dose of
study drug.
14. Has had a minor surgery (e.g., simple excision, tooth extraction) ≤7 days prior to the
first dose of study treatment (Cycle 1, Day 1).
15. Has not recovered adequately (i.e., Grade ≤1 or baseline) from the toxicity and/or
complications from any intervention prior to starting therapy.
16. Has a diagnosed additional malignancy within 3 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 cancers.
17. Has a known history of, or any evidence of, central nervous system (CNS) metastases
and/or carcinomatous meningitis as assessed by local site investigator.
18. Has a history of (non-infectious) pneumonitis that required steroids or current
pneumonitis.
19. Has an active infection requiring systemic therapy.
20. 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.
21. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
22. Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the first dose of study medication through
120 days or longer based on local regulation after the last dose of trial treatment.
23. 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.
24. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
25. Has untreated active Hepatitis B. (Please refer to Table 17)
Note: Controlled (treated) hepatitis B subjects will be allowed if they meet the
following criteria:
Antiviral therapy for HBV must be given for at least 1 month prior to first dose of
study drug, and HBV viral load must be less than 2000 IU/mL (104
copies/ml) prior to
first dose of study drug. Those on active HBV therapy with viral loads under 2000
IU/mL (104
copies/ml) should stay on the same therapy throughout study treatment.
Those subjects who are anti-HBc (+) and negative for HBsAg, anti-HBs and HBV
viral load do not require HBV prophylaxis, but need close monitoring for reactivation
as described.
26. Have hepatitis C in which subjects received therapy for HCV <4 weeks from the start
of pembrolizumab.
Note: Subjects with chronic infection by HCV who are untreated are allowed on
study. In addition, subjects with successful treatment (defined as sustained virologi c
response [SVR] 12 or SVR 24) are allowed as long as 4 weeks between achieving
sustained viral response (SVR12 or SVR24) and start of study drug.
27. Has received a live vaccine within 30 days of planned start of study therapy (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.
1. Is currently participating, or has participated in any study of an investigational agent
and received its study therapy, or herbal/complementary oral or IV medicine used as
systemic anti-cancer therapy, or used an investigation device within 4 weeks prior to
the first dose of our study 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 or oxaliplatin-based chemotherapy within 14 days of first dose
of study medication.
3. Has had esophageal or gastric variceal bleeding within the last 6 months.
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 clinically diagnosed hepatic encephalopathy in the last 6 months. Subjects
on rifaximin or lactulose to control their encephalopathy are not allowed.
7. Has had a solid organ or hematologic transplant.
8. Had prior systemic therapy for HCC in the advanced (incurable) setting other than
sorafenib or oxaliplatin-based chemotherapy, prior to start study drug.
9. Has a known severe hypersensitivity (≥ Grade 3) to pembrolizumab, its active
substance and/or any of its excipients. (Refer to the respective Investigator’s
Brochure for a list of excipients.)
10. 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.
11. 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.
Physiologic dose of corticosteroid definition: ≤10 mg/day prednisone or equivalent
12. Has received locoregional therapy to liver (transcatheter chemoembolization [TACE],
transcatheter embolization [TAE], hepatic arterial infusion [HAI], radiation,
radioembolization, or ablation) or other site within 4 weeks prior to the first dose of
study drug.
Subject is not eligible if aforementioned treatments were administered between last
dose of sorafenib or oxaliplatin-based chemotherapy and first dose of study
medication.
13. Has had major surgery to liver or other site within 4 weeks prior to the first dose of
study drug.
14. Has had a minor surgery (e.g., simple excision, tooth extraction) ≤7 days prior to the
first dose of study treatment (Cycle 1, Day 1).
15. Has not recovered adequately (i.e., Grade ≤1 or baseline) from the toxicity and/or
complications from any intervention prior to starting therapy.
16. Has a diagnosed additional malignancy within 3 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 cancers.
17. Has a known history of, or any evidence of, central nervous system (CNS) metastases
and/or carcinomatous meningitis as assessed by local site investigator.
18. Has a history of (non-infectious) pneumonitis that required steroids or current
pneumonitis.
19. Has an active infection requiring systemic therapy.
20. 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.
21. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
22. Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the first dose of study medication through
120 days or longer based on local regulation after the last dose of trial treatment.
23. 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.
24. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
25. Has untreated active Hepatitis B. (Please refer to Table 17)
Note: Controlled (treated) hepatitis B subjects will be allowed if they meet the
following criteria:
Antiviral therapy for HBV must be given for at least 1 month prior to first dose of
study drug, and HBV viral load must be less than 2000 IU/mL (104
copies/ml) prior to
first dose of study drug. Those on active HBV therapy with viral loads under 2000
IU/mL (104
copies/ml) should stay on the same therapy throughout study treatment.
Those subjects who are anti-HBc (+) and negative for HBsAg, anti-HBs and HBV
viral load do not require HBV prophylaxis, but need close monitoring for reactivation
as described.
26. Have hepatitis C in which subjects received therapy for HCV <4 weeks from the start
of pembrolizumab.
Note: Subjects with chronic infection by HCV who are untreated are allowed on
study. In addition, subjects with successful treatment (defined as sustained virologi c
response [SVR] 12 or SVR 24) are allowed as long as 4 weeks between achieving
sustained viral response (SVR12 or SVR24) and start of study drug.
27. Has received a live vaccine within 30 days of planned start of study therapy (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
16 participants
-
Global
450 participants
