Clinical Trials List
Protocol NumberONO-4538-35/CA209459
2016-02-01 - 2019-05-01
Phase III
Terminated7
ICD-10C22.0
Liver cell carcinoma
ICD-10C22
Malignant neoplasm of liver and intrahepatic bile ducts
A Randomized, Multi-center Phase III Study of Nivolumab versus Sorafenib as First-Line Treatment in Patients with Advanced Hepatocellular Carcinoma
-
Trial Applicant
PPD DEVELOPMENT (HK) LIMITED
-
Sponsor
Bristol-Myers Squibb Research and Development / ONO Pharmaceutical Co. Ltd.
-
Trial scale
Multi-Regional Multi-Center
-
Update
2025/08/20
Investigators and Locations
Co-Principal Investigator
- Ying-Chun Shen Division of Hematology & Oncology
- Ming-Chih Ho Division of Hematology & Oncology
- Chih-Hung Hsu Division of Hematology & Oncology
- YU-YUN SHAO Division of Hematology & Oncology
- 林宗哲 Division of Hematology & Oncology
- Chien-Hung Chen Division of Hematology & Oncology
- Chiun Hsu Division of Hematology & Oncology
- 呂理駿 Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Completed
Audit
None
Co-Principal Investigator
- Shang-Yin Wu Division of Hematology & Oncology
- Li-Tzong Chen Division of Hematology & Oncology
- 劉奕廷 Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Completed
Audit
None
Co-Principal Investigator
The Actual Total Number of Participants Enrolled
0 Completed
Co-Principal Investigator
- Yi-Ping Hung Division of Hematology & Oncology
- Yi-Hsiang Huang Digestive System Department
- Rheun-Chuan Lee Division of Pediatrics
- Chung-Pin Li Digestive System Department
The Actual Total Number of Participants Enrolled
4 Completed
Audit
None
Co-Principal Investigator
The Actual Total Number of Participants Enrolled
0 Completed
Co-Principal Investigator
Audit
None
Linkou Chang Gung Medical Foundation
Taiwan National PI
林錫銘
Co-Principal Investigator
- Jen-Shi Chen Division of Hematology & Oncology
- Ming-Mo Hou Division of Hematology & Oncology
- Ming-Chin Yu Division of Gastroenterological Surgery
- Wei-Chen Lee Division of Gastroenterological Surgery
- 呂嘉偉 Division of Radiology
The Actual Total Number of Participants Enrolled
4 Completed
Audit
None
Co-Principal Investigator
- Chang-Fang Chiu Division of Hematology & Oncology
- Hsueh-Chou Lai Digestive System Department
- 陳昇弘 Digestive System Department
- Po-Heng Chuang Digestive System Department
- 蘇文邦 Digestive System Department
- Hung-Yao Chen Digestive System Department
The Actual Total Number of Participants Enrolled
2 Stop recruiting
Condition/Disease
Hepatocellular Carcinoma
Objectives
Primary Objectives
To compare the overall survival (OS) and time to progression (TTP) of nivolumab to sorafenib in subjects with
advanced HCC who have not received prior systemic therapy. TTP will be determined from assessments by a
blinded independent central review (BICR) based on RECIST 1.1.
Secondary Objectives
To compare overall response rate (ORR) of nivolumab and sorafenib. ORR will be determined from
assessments by a blinded independent central review (BICR) based on RECIST 1.1
To evaluate progression free survival (PFS) rates of nivolumab and sorafenib. PFS will be determined from
assessments by a blinded independent central review (BICR) based on RECIST 1.1
To evaluate the relationship between tumor PD-L1 expression and efficacy
Test Drug
Nivolumab/Sorafenib
Active Ingredient
Nivolumab
Dosage Form
Solution for Infusion
Dosage
10mg/mL, 10mL/vial
Endpoints
Primary Endpoints
Time To Progression (TTP)
TTP, as determined based on BICR-assessed tumor response according to RECIST 1.1, is one of the co-primary
endpoints for this study. It is defined as the time from the date of randomization to the date of the first
objectively documented tumor progression. Subjects without progression will be censored at their last tumor
assessment date prior to subsequent anti-cancer therapy. Subjects who have no on-study tumor assessments will
be censored at the date of randomization. Detail of the censoring algorithm will be stated in the Statistical
Analysis Plan (SAP).
Overall Survival (OS)
OS is the other co-primary endpoint for this study. It is defined as the time from the date of randomization to the
date of death due to any cause. Subjects who are alive will be censored at the last known alive dates.
Secondary Endpoints
Overall Response Rate (ORR)
ORR, as determined based on BICR-assessed tumor response according to RECIST 1.1, is defined as the
proportion of all randomized subjects whose best overall response (BOR) is either a CR or PR. BOR is
determined by the best response designation recorded between the date of randomization and the date of first
objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first. For
subjects without documented progression or subsequent anti-cancer therapy, all available response designations
will contribute to the BOR determination.
Progression-Free Survival (PFS)
PFS is defined as the time from the date of randomization to the date of the first objectively documented tumor
progression as assessed by BICR according to RECIST 1.1or death due to any cause. Subjects who die without
a reported prior progression will be considered to have progressed on the date of their death. Subjects who did
not progress or die will be censored on the date of their last tumor assessment. Subjects who did not have any
on study tumor assessments and did not die will be censored on the date they were randomized. Subjects who
started any subsequent anti-cancer therapy without a prior reported progression will be censored at the last
tumor assessment prior to subsequent anti-cancer therapy.
PD-L1 expression
Definition of PD-L1 expression will be described in the SAP.
Time To Progression (TTP)
TTP, as determined based on BICR-assessed tumor response according to RECIST 1.1, is one of the co-primary
endpoints for this study. It is defined as the time from the date of randomization to the date of the first
objectively documented tumor progression. Subjects without progression will be censored at their last tumor
assessment date prior to subsequent anti-cancer therapy. Subjects who have no on-study tumor assessments will
be censored at the date of randomization. Detail of the censoring algorithm will be stated in the Statistical
Analysis Plan (SAP).
Overall Survival (OS)
OS is the other co-primary endpoint for this study. It is defined as the time from the date of randomization to the
date of death due to any cause. Subjects who are alive will be censored at the last known alive dates.
Secondary Endpoints
Overall Response Rate (ORR)
ORR, as determined based on BICR-assessed tumor response according to RECIST 1.1, is defined as the
proportion of all randomized subjects whose best overall response (BOR) is either a CR or PR. BOR is
determined by the best response designation recorded between the date of randomization and the date of first
objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first. For
subjects without documented progression or subsequent anti-cancer therapy, all available response designations
will contribute to the BOR determination.
Progression-Free Survival (PFS)
PFS is defined as the time from the date of randomization to the date of the first objectively documented tumor
progression as assessed by BICR according to RECIST 1.1or death due to any cause. Subjects who die without
a reported prior progression will be considered to have progressed on the date of their death. Subjects who did
not progress or die will be censored on the date of their last tumor assessment. Subjects who did not have any
on study tumor assessments and did not die will be censored on the date they were randomized. Subjects who
started any subsequent anti-cancer therapy without a prior reported progression will be censored at the last
tumor assessment prior to subsequent anti-cancer therapy.
PD-L1 expression
Definition of PD-L1 expression will be described in the SAP.
Inclution Criteria
1. Signed Written Informed Consent
a) Subjects must have signed and dated an IRB/IEC approved written informed consent
form in accordance with regulatory and institutional guidelines. This must be obtained
before the performance of any protocol related procedures that are not part of normal
subject care.
b) Subjects must be willing and able to comply with scheduled visits, treatment schedule,
laboratory testing, and other requirements of the study.
c) Subject Re-enrollment: This study permits the re-enrollment of a subject that has
discontinued the study as a pre-treatment failure (ie, subject has not been randomized /
has not been treated). If re-enrolled, the subject must be re-consented
2. Target Population
a) Subjects with advanced hepatocellular carcinoma
i) disease not eligible for curative surgical and/or locoregional therapies, OR
ii) progressive disease after surgical and /or locoregional therapies
b) No prior systemic therapy for hepatocellular carcinoma
c) Histologic confirmation of hepatocellular carcinoma.
i) Subjects with only a radiologic diagnosis of HCC may be enrolled for screening in
the study but histological confirmation is mandatory prior to the start of study
therapy.
ii) Tumor tissue (formalin-fixed, paraffin embedded archival or recent acquisition) must
be received by the central vendor (1 block or 15 unstained slides) for correlative
studies outlined in Section 5.6.1 in order to conduct the randomization call in the
IVRS (the tissue submitted will be assessed for quality with a H&E stain and only
those subjects who have meet tissue quality thresholds can be randomized). If
archived samples are not available, subjects must consent to a pre-treatment fresh
biopsy as a condition of protocol participation. (Note: Fine needle aspiration (FNA)
and bone metastases samples are not acceptable for submission).
d) At least one RECIST 1.1 measurable untreated lesion. All subjects must have at least one
previously untreated, unidimensionally measurable lesion by contrast-enhanced spiral
computed tomography (CT) 10 mm or contrast enhanced dynamic magnetic resonance
imaging (MRI) scan 10 mm (malignant lymph nodes must be 15 mm on short axis)
(additional details are included in Appendix 1)
i) The lesion can be accurately measured uni-dimensionally according to RECIST 1.1
criteria
ii) The lesion has not been previously treated with surgery, radiotherapy, and/or
locoregional therapy (eg: radiofrequency ablation [RFA], percutaneous ethanol [PEI]
or acetic acid injection [PAI], cryoablation, high-intensity focused ultrasound [HIFU],
transarterial chemoembolization [TACE], transarterial embolization [TAI], etc.)
e) For subjects who progressed after locoregional therapy, the locoregional procedure must
have been completed at least 4 weeks prior to the baseline scan. In addition, all acute
toxic effects of the locoregional procedure must have resolved to National Cancer
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Grade 1.
f) Cirrhotic status of Child-Pugh Class A (Appendix 2)
g) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1. See
Appendix 3 for ECOG Performance Status scale
h) Subjects are eligible to enroll if they have non-viral-HCC, or if they have HBV-HCC, or
HCV-HCC defined as follows:
i) HBV-HCC: Resolved HBV infection (as evidenced by detectable HBV surface
antibody, detectable HBV core antibody, undetectable HBV DNA, and undetectable
HBV surface antigen) or Chronic HBV infection (as evidenced by detectable HBV
surface antigen or HBV DNA). Subjects with chronic HBV infection must have HBV
DNA < 100 IU/mL and must be on antiviral therapy.
ii) HCV-HCC: Active or resolved HCV infection as evidenced by detectable HCV RNA
or antibody
i) Screening laboratory values must meet the following criteria, without continuous
supportive treatment such as growth factor administration, blood transfusion, coagulation
factors and/or platelet transfusion, or albumin transfusion, and should be obtained within
14 days prior to randomization)
i) Adequate hematologic function:
(1) WBC 2000/μL
(2) Neutrophils 1500/μL
(3) Platelets 60 x 103
/μL
(4) Hemoglobin 8.5 g/dL
ii) Prothrombin time (PT)-international normalized ratio (INR) 2.3 or Prothrombin
time (PT) 6 seconds above control
iii) Adequate hepatic function as documented by:
(1) serum albumin 2.8 g/dL
(2) total bilirubin 3 mg/dl, and
(3) AST 5 times the institutional upper limits of normal
(4) ALT 5 times the institutional upper limits of normal
iv) Adequate renal function with a serum creatinine of < 1.5x ULN or a creatinine
clearance > 50 mL/min (Cockcroft-Gault formula)
j) Adequate cardiac function with a left ventricular ejection fraction (LVEF) > 50% as
measured by 2-D echocardiography
3. Age and Reproductive Status
a) Males and Females, ages 18 years of age
b) Women of childbearing potential (WOCBP) must have a negative serum or urine
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within
24 hours prior to the start of study drug.
c) Women must not be breastfeeding
d) Women of childbearing potential (WOCBP) must agree to follow instructions for
method(s) of contraception as indicated in the informed consent form, for the duration of
treatment with study drug(s) [nivolumab or sorafenib] plus 5 half-lives of the study
drug(s) [nivolumab or sorafenib] plus 30 days (duration of ovulatory cycle):
i) Subjects randomized to nivolumab: total of 23 weeks post-treatment completion
ii) Subjects randomized to sorafenib: total of 40 days post-treatment completion
e) Males who are sexually active with WOCBP must agree to follow instructions for
method(s) of contraception as indicated in the informed consent form, for the duration of
treatment with study drug (s) [nivolumab or sorafenib] plus 5 half-lives of the study
drug(s) [nivolumab or sorafenib] plus 90 days (duration of sperm turnover):
i) Subjects randomized to nivolumab: total of 31 weeks post-treatment completion
ii) Subjects randomized to sorafenib: total of 100 days post-treatment completion
f) Azoospermic males and WOCBP who are continuously not heterosexually active are
exempt from contraceptive requirements. However they must still undergo pregnancy
testing as described in this section.
a) Subjects must have signed and dated an IRB/IEC approved written informed consent
form in accordance with regulatory and institutional guidelines. This must be obtained
before the performance of any protocol related procedures that are not part of normal
subject care.
b) Subjects must be willing and able to comply with scheduled visits, treatment schedule,
laboratory testing, and other requirements of the study.
c) Subject Re-enrollment: This study permits the re-enrollment of a subject that has
discontinued the study as a pre-treatment failure (ie, subject has not been randomized /
has not been treated). If re-enrolled, the subject must be re-consented
2. Target Population
a) Subjects with advanced hepatocellular carcinoma
i) disease not eligible for curative surgical and/or locoregional therapies, OR
ii) progressive disease after surgical and /or locoregional therapies
b) No prior systemic therapy for hepatocellular carcinoma
c) Histologic confirmation of hepatocellular carcinoma.
i) Subjects with only a radiologic diagnosis of HCC may be enrolled for screening in
the study but histological confirmation is mandatory prior to the start of study
therapy.
ii) Tumor tissue (formalin-fixed, paraffin embedded archival or recent acquisition) must
be received by the central vendor (1 block or 15 unstained slides) for correlative
studies outlined in Section 5.6.1 in order to conduct the randomization call in the
IVRS (the tissue submitted will be assessed for quality with a H&E stain and only
those subjects who have meet tissue quality thresholds can be randomized). If
archived samples are not available, subjects must consent to a pre-treatment fresh
biopsy as a condition of protocol participation. (Note: Fine needle aspiration (FNA)
and bone metastases samples are not acceptable for submission).
d) At least one RECIST 1.1 measurable untreated lesion. All subjects must have at least one
previously untreated, unidimensionally measurable lesion by contrast-enhanced spiral
computed tomography (CT) 10 mm or contrast enhanced dynamic magnetic resonance
imaging (MRI) scan 10 mm (malignant lymph nodes must be 15 mm on short axis)
(additional details are included in Appendix 1)
i) The lesion can be accurately measured uni-dimensionally according to RECIST 1.1
criteria
ii) The lesion has not been previously treated with surgery, radiotherapy, and/or
locoregional therapy (eg: radiofrequency ablation [RFA], percutaneous ethanol [PEI]
or acetic acid injection [PAI], cryoablation, high-intensity focused ultrasound [HIFU],
transarterial chemoembolization [TACE], transarterial embolization [TAI], etc.)
e) For subjects who progressed after locoregional therapy, the locoregional procedure must
have been completed at least 4 weeks prior to the baseline scan. In addition, all acute
toxic effects of the locoregional procedure must have resolved to National Cancer
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
Grade 1.
f) Cirrhotic status of Child-Pugh Class A (Appendix 2)
g) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1. See
Appendix 3 for ECOG Performance Status scale
h) Subjects are eligible to enroll if they have non-viral-HCC, or if they have HBV-HCC, or
HCV-HCC defined as follows:
i) HBV-HCC: Resolved HBV infection (as evidenced by detectable HBV surface
antibody, detectable HBV core antibody, undetectable HBV DNA, and undetectable
HBV surface antigen) or Chronic HBV infection (as evidenced by detectable HBV
surface antigen or HBV DNA). Subjects with chronic HBV infection must have HBV
DNA < 100 IU/mL and must be on antiviral therapy.
ii) HCV-HCC: Active or resolved HCV infection as evidenced by detectable HCV RNA
or antibody
i) Screening laboratory values must meet the following criteria, without continuous
supportive treatment such as growth factor administration, blood transfusion, coagulation
factors and/or platelet transfusion, or albumin transfusion, and should be obtained within
14 days prior to randomization)
i) Adequate hematologic function:
(1) WBC 2000/μL
(2) Neutrophils 1500/μL
(3) Platelets 60 x 103
/μL
(4) Hemoglobin 8.5 g/dL
ii) Prothrombin time (PT)-international normalized ratio (INR) 2.3 or Prothrombin
time (PT) 6 seconds above control
iii) Adequate hepatic function as documented by:
(1) serum albumin 2.8 g/dL
(2) total bilirubin 3 mg/dl, and
(3) AST 5 times the institutional upper limits of normal
(4) ALT 5 times the institutional upper limits of normal
iv) Adequate renal function with a serum creatinine of < 1.5x ULN or a creatinine
clearance > 50 mL/min (Cockcroft-Gault formula)
j) Adequate cardiac function with a left ventricular ejection fraction (LVEF) > 50% as
measured by 2-D echocardiography
3. Age and Reproductive Status
a) Males and Females, ages 18 years of age
b) Women of childbearing potential (WOCBP) must have a negative serum or urine
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within
24 hours prior to the start of study drug.
c) Women must not be breastfeeding
d) Women of childbearing potential (WOCBP) must agree to follow instructions for
method(s) of contraception as indicated in the informed consent form, for the duration of
treatment with study drug(s) [nivolumab or sorafenib] plus 5 half-lives of the study
drug(s) [nivolumab or sorafenib] plus 30 days (duration of ovulatory cycle):
i) Subjects randomized to nivolumab: total of 23 weeks post-treatment completion
ii) Subjects randomized to sorafenib: total of 40 days post-treatment completion
e) Males who are sexually active with WOCBP must agree to follow instructions for
method(s) of contraception as indicated in the informed consent form, for the duration of
treatment with study drug (s) [nivolumab or sorafenib] plus 5 half-lives of the study
drug(s) [nivolumab or sorafenib] plus 90 days (duration of sperm turnover):
i) Subjects randomized to nivolumab: total of 31 weeks post-treatment completion
ii) Subjects randomized to sorafenib: total of 100 days post-treatment completion
f) Azoospermic males and WOCBP who are continuously not heterosexually active are
exempt from contraceptive requirements. However they must still undergo pregnancy
testing as described in this section.
Exclusion Criteria
1. Target Disease Exceptions
a) Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
b) Prior liver transplant
c) History of hepatic encephalopathy
d) Clinically significant ascites as defined by:
i) Any ascites by physical examination at screening or
ii) Any prior or current ascites requiring treatment
e) Evidence of portal hypertension with bleeding esophageal or gastric varices within the
past 6 months
f) Active brain metastases or leptomeningeal metastases. Subjects with treated brain
metastases are eligible if the following criteria are fulfilled:
i) The brain lesions have been treated and there is no magnetic resonance imaging
(MRI) evidence of progression for at least 4 weeks after treatment is complete and
within 28 days prior to randomization. (If an MRI is contraindicated, a CT scan is
acceptable after discussion with the study Medical Monitor.)
ii) There is no requirement for immunosuppressive doses of corticosteroids
(> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug
administration
iii) The case is discussed with the study Medical Monitor
2. Medical History and Concurrent Diseases
a) Infections:
i) Active co-infection with:
(1) Both hepatitis B and C as evidenced by detectable HBV surface antigen or HBV
DNA and HCV RNA, OR
(2) Hepatitis D infection in subjects with hepatitis B
ii) Subjects with a history of coinfection with both hepatitis B and C, including
(1) HBV DNA positive or HBV surface antigen positive subjects with detectable
HCV antibody, OR
(2) HCV RNA positive subjects with resolved HBV infection as evidenced by
detectable HBV surface antibody, detectable HBV core antibody, undetectable
HBV DNA, and undetectable HBV surface antigen
iii) Known history of testing positive for human immunodeficiency virus (HIV) or
known acquired immunodeficiency syndrome (AIDS)
iv) Active bacterial or fungal infections requiring systemic treatment within 7 days prior
to screening
b) Interstitial lung disease that is symptomatic or may interfere with the detection and
management of suspected drug-related pulmonary toxicity
c) History of active cardiac disease as evidenced by the following:
i) Uncontrolled hypertension which is defined as systolic blood pressure > 150 mmHg
or diastolic blood pressure > 90 mmHg despite optimal medical management
ii) Congestive heart failure NYHA (New York Heart Association) class > 2
(Appendix 4)
iii) Active coronary artery disease, unstable or newly diagnosed angina or myocardial
infarction < 6 months prior to study entry
iv) Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or
digoxin
v) Valvular heart disease > CTCAE Grade 2
vi) QTc (Fridericia) > 450 msec on two consecutive ECGs (baseline ECG should be
repeated if QTc is found to be > 450 msec)
d) Thrombotic or embolic events (except HCC tumor thrombus) within the past 6 months,
such as cerebrovascular accident (including transient ischemic attacks), pulmonary
embolism
e) Any other hemorrhage/bleeding event CTCAE Grade 3 within 8 weeks except for
esophageal or gastric varices (Exclusion criteria 1.e.)
f) History of non-healing wounds or ulcers, or bone fractures within 3 months of study
entry
g) Major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks
prior to start of investigational product administration or those who receive minor
surgical procedures (eg, core biopsy or fine needle aspiration) within 1 week prior to the
start of investigational product.
h) Prior organ allograft or allogeneic bone marrow transplantation
i) Subjects who are unable to swallow tablets, requiring intravenous alimentation,
malabsorption syndrome, or any conditions affecting gastrointestinal absorption; or active
peptic ulcer disease.
j) Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the
normal range with medication.
k) Subjects with any active, known, or suspected autoimmune disease, with the following
exceptions:
i) Subjects with vitiligo, type 1 diabetes mellitus, resolved childhood asthma or atopy
are permitted to enroll.
ii) Subjects with suspected autoimmune thyroid disorders may be enrolled if they are
currently euthyroid or with residual hypothyroidism requiring only hormone
replacement.
iii) Subjects with psoriasis requiring systemic therapy must be excluded from enrollment
l) Prior malignancy active within the previous 3 years except for locally curable cancers
that have been apparently cured, such as basal or squamous cell skin cancer, superficial
bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
m) Subjects with a condition requiring systemic treatment with either corticosteroids
(> 10 mg/day prednisone equivalent) or other immunosuppressive medications within
14 days of study administration. Inhaled or topical steroids and adrenal replacement
doses > 10 mg/day prednisone equivalents are permitted in the absence of active
autoimmmune disease, with the exception of criteria 1f, ii
n) Any serious or uncontrolled medical disorder that in the opinion of the investigator may
increase the risk associated with study participation or study drug administration, impair
the ability of the subject to receive protocol therapy, or interfere with the interpretation of
study results.
3. Prior and Current Therapies
a) Subjects with history of life-threatening toxicity related to prior immune therapy
(eg. with anti-CTLA-4 or anti-PD-1/PD-L1 treatment) except those that are unlikely to
re-occur with standard countermeasures (eg. Hormone replacement after adrenal
crisis), VEGF inhibitors, Raf-kinase inhibitors, MEK inhibitors, Farnesyl transferase
inhibitors), or other immunotherapy agents for HCC
b) Prior use of systemic investigational agents for HCC
c) Treatment with strong CYP3A4 inducers within 7 days of study entry, including rifampin
(and its analogues) or St. John’s wort.
d) Current therapeutic anticoagulation therapy
e) Treatment with anti-platelet therapy (aspirin at dose 300 mg/day, clopidogrel at dose
75 mg/day)
f) Radiotherapy within 4 weeks prior to start of study drug. Palliative radiotherapy for
symptomatic control is acceptable (if completed at least 2 weeks prior to study drug
administration) and no additional radiotherapy for the same lesion is planned.
4. Physical and Laboratory Test Findings
a) Positive pregnancy test
b) Baseline serum sodium < 130 mmol/L
c) Baseline serum potassium < 3.5 mmol/L (potassium supplementation may be given to
restore the serum potassium above this level prior to study entry)
5. Allergies and Adverse Drug Reaction
a) Known or suspected allergy to nivolumab or sorafenib or study drug components
b) History of severe hypersensitivity reaction to any monoclonal antibody
6. Sex and Reproductive Status
a) WOCBP who are pregnant or breastfeeding
b) Women with a positive pregnancy test at enrollment or prior to administration of study
medication
7. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical
(eg, infectious disease) illness
a) Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC
b) Prior liver transplant
c) History of hepatic encephalopathy
d) Clinically significant ascites as defined by:
i) Any ascites by physical examination at screening or
ii) Any prior or current ascites requiring treatment
e) Evidence of portal hypertension with bleeding esophageal or gastric varices within the
past 6 months
f) Active brain metastases or leptomeningeal metastases. Subjects with treated brain
metastases are eligible if the following criteria are fulfilled:
i) The brain lesions have been treated and there is no magnetic resonance imaging
(MRI) evidence of progression for at least 4 weeks after treatment is complete and
within 28 days prior to randomization. (If an MRI is contraindicated, a CT scan is
acceptable after discussion with the study Medical Monitor.)
ii) There is no requirement for immunosuppressive doses of corticosteroids
(> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug
administration
iii) The case is discussed with the study Medical Monitor
2. Medical History and Concurrent Diseases
a) Infections:
i) Active co-infection with:
(1) Both hepatitis B and C as evidenced by detectable HBV surface antigen or HBV
DNA and HCV RNA, OR
(2) Hepatitis D infection in subjects with hepatitis B
ii) Subjects with a history of coinfection with both hepatitis B and C, including
(1) HBV DNA positive or HBV surface antigen positive subjects with detectable
HCV antibody, OR
(2) HCV RNA positive subjects with resolved HBV infection as evidenced by
detectable HBV surface antibody, detectable HBV core antibody, undetectable
HBV DNA, and undetectable HBV surface antigen
iii) Known history of testing positive for human immunodeficiency virus (HIV) or
known acquired immunodeficiency syndrome (AIDS)
iv) Active bacterial or fungal infections requiring systemic treatment within 7 days prior
to screening
b) Interstitial lung disease that is symptomatic or may interfere with the detection and
management of suspected drug-related pulmonary toxicity
c) History of active cardiac disease as evidenced by the following:
i) Uncontrolled hypertension which is defined as systolic blood pressure > 150 mmHg
or diastolic blood pressure > 90 mmHg despite optimal medical management
ii) Congestive heart failure NYHA (New York Heart Association) class > 2
(Appendix 4)
iii) Active coronary artery disease, unstable or newly diagnosed angina or myocardial
infarction < 6 months prior to study entry
iv) Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or
digoxin
v) Valvular heart disease > CTCAE Grade 2
vi) QTc (Fridericia) > 450 msec on two consecutive ECGs (baseline ECG should be
repeated if QTc is found to be > 450 msec)
d) Thrombotic or embolic events (except HCC tumor thrombus) within the past 6 months,
such as cerebrovascular accident (including transient ischemic attacks), pulmonary
embolism
e) Any other hemorrhage/bleeding event CTCAE Grade 3 within 8 weeks except for
esophageal or gastric varices (Exclusion criteria 1.e.)
f) History of non-healing wounds or ulcers, or bone fractures within 3 months of study
entry
g) Major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks
prior to start of investigational product administration or those who receive minor
surgical procedures (eg, core biopsy or fine needle aspiration) within 1 week prior to the
start of investigational product.
h) Prior organ allograft or allogeneic bone marrow transplantation
i) Subjects who are unable to swallow tablets, requiring intravenous alimentation,
malabsorption syndrome, or any conditions affecting gastrointestinal absorption; or active
peptic ulcer disease.
j) Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the
normal range with medication.
k) Subjects with any active, known, or suspected autoimmune disease, with the following
exceptions:
i) Subjects with vitiligo, type 1 diabetes mellitus, resolved childhood asthma or atopy
are permitted to enroll.
ii) Subjects with suspected autoimmune thyroid disorders may be enrolled if they are
currently euthyroid or with residual hypothyroidism requiring only hormone
replacement.
iii) Subjects with psoriasis requiring systemic therapy must be excluded from enrollment
l) Prior malignancy active within the previous 3 years except for locally curable cancers
that have been apparently cured, such as basal or squamous cell skin cancer, superficial
bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
m) Subjects with a condition requiring systemic treatment with either corticosteroids
(> 10 mg/day prednisone equivalent) or other immunosuppressive medications within
14 days of study administration. Inhaled or topical steroids and adrenal replacement
doses > 10 mg/day prednisone equivalents are permitted in the absence of active
autoimmmune disease, with the exception of criteria 1f, ii
n) Any serious or uncontrolled medical disorder that in the opinion of the investigator may
increase the risk associated with study participation or study drug administration, impair
the ability of the subject to receive protocol therapy, or interfere with the interpretation of
study results.
3. Prior and Current Therapies
a) Subjects with history of life-threatening toxicity related to prior immune therapy
(eg. with anti-CTLA-4 or anti-PD-1/PD-L1 treatment) except those that are unlikely to
re-occur with standard countermeasures (eg. Hormone replacement after adrenal
crisis), VEGF inhibitors, Raf-kinase inhibitors, MEK inhibitors, Farnesyl transferase
inhibitors), or other immunotherapy agents for HCC
b) Prior use of systemic investigational agents for HCC
c) Treatment with strong CYP3A4 inducers within 7 days of study entry, including rifampin
(and its analogues) or St. John’s wort.
d) Current therapeutic anticoagulation therapy
e) Treatment with anti-platelet therapy (aspirin at dose 300 mg/day, clopidogrel at dose
75 mg/day)
f) Radiotherapy within 4 weeks prior to start of study drug. Palliative radiotherapy for
symptomatic control is acceptable (if completed at least 2 weeks prior to study drug
administration) and no additional radiotherapy for the same lesion is planned.
4. Physical and Laboratory Test Findings
a) Positive pregnancy test
b) Baseline serum sodium < 130 mmol/L
c) Baseline serum potassium < 3.5 mmol/L (potassium supplementation may be given to
restore the serum potassium above this level prior to study entry)
5. Allergies and Adverse Drug Reaction
a) Known or suspected allergy to nivolumab or sorafenib or study drug components
b) History of severe hypersensitivity reaction to any monoclonal antibody
6. Sex and Reproductive Status
a) WOCBP who are pregnant or breastfeeding
b) Women with a positive pregnancy test at enrollment or prior to administration of study
medication
7. Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical
(eg, infectious disease) illness
The Estimated Number of Participants
-
Taiwan
60 participants
-
Global
726 participants
