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Clinical Trials List

Protocol NumberONO-4538-70/CA2099DX
NCT Number(ClinicalTrials.gov Identfier)NCT03383458
Active

2018-06-01 - 2026-08-31

Phase III

Recruiting1

Terminated10

ICD-10C22

Malignant neoplasm of liver and intrahepatic bile ducts

ICD-10C22.0

Liver cell carcinoma

A Phase 3, Randomized, Double-blind Study of Adjuvant Nivolumab versus Placebo for Participants with Hepatocellular Carcinoma Who Are at High Risk of Recurrence after Curative Hepatic Resection or Ablation

  • Trial Applicant

    PPD DEVELOPMENT (HK) LIMITED

  • Sponsor

    ONO Pharmaceutical Co., Ltd.

  • Trial scale

    Multi-Regional Multi-Center

  • Update

    2026/02/01

Investigators and Locations

Principal Investigator Long-Bin Jeng Division of Others -
China Medical University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Completed

Principal Investigator Yan-Shen Shan Division of General Surgery
National Taiwan University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Completed

Audit

None

Principal Investigator Yi-Hsiang Huang Digestive System Department
Taipei Veterans General Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

13 Completed

Audit

None

Principal Investigator TENG-YU LEE Digestive System Department
Taichung Veterans General Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Completed

Principal Investigator 洪肇宏 Digestive System Department
Chiayi Chang Gung Memorial Hospital of the C.G.M.F.

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Completed

Principal Investigator 林正耀 Division of Hematology & Oncology
Chi Mei Hospital, Liouying

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Completed

Principal Investigator 方佑仁 Division of General Internal Medicine
National Taiwan University Hospital Yunlin Branch 

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Completed

Principal Investigator Jing-Houng Wang Digestive System Department
Kaoshiung Chang Gung Memorial Hospital of the C.G.M.F.

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Completed

Principal Investigator Long-Bin Jeng 未分科
China Medical University Hospital-Taipei

Co-Principal Investigator

Audit

None

Principal Investigator Shi-Ming Lin Digestive System Department
Linkou Chang Gung Medical Foundation

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

15 Completed

Audit

None

Principal Investigator Ming-Chih Ho Division of General Surgery
National Taiwan University Hospital

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Completed

Audit

None

Principal Investigator 方佑仁 Division of General Internal Medicine
國立臺灣大學醫學院附設醫院雲林分院

Co-Principal Investigator

The Actual Total Number of Participants Enrolled

0 Recruiting

Condition/Disease

Hepatocellular Carcinoma Who Are at High Risk of Recurrence after Curative Hepatic Resection or Ablation

Objectives

 To compare recurrence-free survival (RFS) (based on BICR assessment) of nivolumab vs placebo in all randomized participants.

Test Drug

Nivolumab

Active Ingredient

Nivolumab

Dosage Form

Solution for Injection

Dosage

100 mg/Vial (10 mg/mL)

Endpoints

Primary
 RFS, defined as the time from randomization to the
first documented disease recurrence (ie, intrahepatic
recurrence of primary tumor or occurrence of a new
HCC primary tumor, or extrahepatic recurrence) or
death (by any cause), whichever occurs first.

Secondary
 OS, defined as the time between the date of
randomization and the date of death (by any cause).
 TTR, defined as the time from randomization to the
first documented disease recurrence (ie, intrahepatic
recurrence of primary tumor or occurrence of a
secondary HCC primary cancer, or extrahepatic
recurrence).

Inclution Criteria

Inclusion Criteria
1) Signed Written Informed Consent
a) Participants 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
participant care.
b) Participants must be willing and able to comply with scheduled visits, treatment schedule,
laboratory tests, tumor biopsies, and other requirements of the study.
2) Type of Participant and Target Disease Characteristics
a) Participants must have a first diagnosis of HCC amenable for management with curative
intent by resection or local ablation.
b) Participants are eligible to enroll if they have non-viral related-HCC, or if they have
HBV-HCC, or HCV-HCC defined as follows:
i) Non-HBV non-HCV related HCC
ii) HBV-HCC:
(1) Resolved HBV infection (as evidenced by detectable HBV surface antibody,
detectable HBV core antibody, undetectable HBV DNA, and undetectable HBV
surface antigen), OR
(2) Chronic HBV infection as evidenced by detectable HBV surface antigen or HBV
DNA. Participants with chronic HBV infection must be on antiviral therapy and
must have HBV DNA < 500 IU/mL
iii) HCV-HCC:
(1) Resolved HCV infection as evidenced by detectable antibody, OR
(2) Chronic HCV infection as evidenced by detectable HCV RNA.
c) Participants are eligible to enroll if they have undergone:
i) Hepatic resection and have the following tumor characteristics:
(1) Up to three tumors, at least one with a diameter > 5 cm, and with no evidence of
macrovascular invasion, OR
(2) Up to three tumors, none with a diameter > 5 cm but with confirmation of
microvascular invasion (as defined by the presence of tumor emboli within the
central hepatic vein, the portal vein, or the large capsular vessels) or
poorly/undifferentiated HCC (G3-G4) in the pathological report of the resected
specimens. Note: Participants with evidence of macrovascular invasion in the
pathology report are allowed to enroll only if pre-operative imaging tests confirmed
no presence of macrovascular invasion before resection, OR
(3) More than three tumors, none with a diameter > 5 cm, and with no evidence of
macrovascular invasion
ii) Local ablation [radiofrequency ablation (RFA) or microwave ablation (MWA)] and
have the following tumor characteristics:
(1) Solitary tumor  3 cm but  5 cm, OR
(2) Multiple tumors (up to 4), none with a diameter > 5 cm
d) Participants must have complete resection documented in the pathology report [surgically
rendered free of disease with negative margins on resected specimens (R0)], or must have
achieved radiologically documented complete response (non-stained low-concentration
area overlapping the tumor image observed before complete cure) after local ablation.
e) Histological confirmation prior to initiation of study therapy is required. Fresh tumor tissue
obtained from the resected site or from a biopsy prior to ablation (within 3 months) or at
the time of ablation, is required for randomization. Biopsy should be excisional, incisional
or core needle. Fine needle aspiration is unacceptable for submission. Either FFPE or
charged unstained slides, with an associated pathology report, must be submitted to a
central laboratory prior to randomization. Central lab must provide IRT with confirmation
of receipt of evaluable tumor tissue prior to randomization. If the initial tumor sample
submission does not meet the qualitative criteria, an additional tissue submission
(if available) is allowed.
f) All participants are required to have imaging studies (CT chest, tri-phasic CT/MRI of the
liver, contrast-enhanced CT/MRI of abdomen and pelvis and other suspected/known sites
of disease, and bone scans if indicated) confirming disease-free status at least 4 weeks after
either complete tumor removal after surgical resection or local ablation, and within 4 weeks
prior to randomization. BICR confirmation of disease-free status is required for
randomization.
Note: Lymph nodes < 10 mm in a short axis at baseline are considered non-pathological
and allowed for randomization.
g) Child-Pugh Score 5 or 6
h) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
i) Life expectancy  6 months
j) Screening laboratory values must meet the following criteria, and should be obtained
within 14 days prior to randomization
i) Adequate hematologic function:
(1) WBC  2,000/μL (stable, off any growth factor within 4 weeks of study treatment
administration);
(2) Neutrophils Absolute  1,500/ μL (stable, off any growth factor within 4 weeks of
study treatment administration);
(3) Hemoglobin  8.5 g/dL (may be transfused to meet this requirement);
(4) Platelet count  60 × 103
/μL (transfusion to achieve this level is not permitted);
ii) Adequate hepatic function:
(1) Serum albumin > 2.8 g/L (transfusion to meet this level is not permitted); and
(2) Serum total bilirubin < 3 mg/dL, and
(3) Serum Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT)
 5 × ULN;
iii) Prothrombin time (PT)-international normalized ratio (INR) < 2.3 or Prothrombin time
(PT) < 6 seconds (transfusion to achieve this level is not permitted)
iv) Adequate renal function with a serum creatinine of < 1.5 × ULN or a creatinine
clearance > 40 mL/min (Cockcroft-Gault formula)
3) Age and Reproductive Status
a) Males and females, ages 18 or older.
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 treatment.
c) Women must not be breastfeeding.
d) WOCBP must agree to follow instructions for method(s) of contraception (Appendix 4) for
the duration of study treatment with nivolumab and 5 months after the last dose of study
treatment.
e) Males who are sexually active with WOCBP must agree to follow instructions for
method(s) of contraception (Appendix 4) for the duration of study treatment with
nivolumab and 7 months after the last dose of study treatment. In addition, male
participants must be willing to refrain from sperm donation during this time.
f) Azoospermic males are exempt from contraceptive requirements. WOCBP who are
continuously not heterosexually active are also exempt from contraceptive requirements,
and still must undergo pregnancy testing as described in this section.
Investigators shall counsel WOCBP, and male participants who are sexually active with WOCBP,
on the importance of pregnancy prevention and the implications of an unexpected pregnancy.
Investigators shall advise on the use of highly effective methods of contraception, which have a
failure rate of < 1% when used consistently and correctly

Exclusion Criteria

Exclusion Criteria
1) Target Disease Exceptions
a) Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
b) Prior recurrence of HCC.
c) Any evidence of tumor metastasis or co-existing malignant disease.
d) Participants showing evidence of macrovascular invasion on imaging tests.
e) Participants who have undergone a liver transplant or those who are in the waiting list for
liver transplantation.
2) Medical Conditions
a) Active co-infection with:
i) Both hepatitis B and C as evidenced by detectable HBV surface antigen (HBs Ag) or
HBV DNA and HCV RNA, OR
ii) Hepatitis D infection in participants with hepatitis B
b) Known history of positive test for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS). Note: Testing for HIV must be performed
at sites where mandated locally (see Appendix 8).
c) 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 participant to receive protocol therapy, or interfere with the interpretation
of study results.
d) Participants with an active, known or suspected autoimmune disease. Participants with type
I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not
expected to recur in the absence of an external trigger are permitted to enroll.
e) Participants with a condition requiring systemic treatment with either corticosteroids
( > 10 mg daily prednisone equivalent) or other immunosuppressive medications within
14 days of start of study treatment. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active
autoimmune disease.
f) 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.
3) Prior/Concomitant Therapy
a) Participants previously receiving any prior therapy for HCC, including loco-regional
therapies, before or after resection or ablation.
b) Participants receiving or expected to receive IFN-based therapies during the study period.
c) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or
any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint
pathways.
d) Treatment with botanical preparations (eg, herbal supplements or traditional Chinese
medicines) intended for general health support or to treat the disease under study within
2 weeks prior to start of therapy.
4) Physical and Laboratory Test Findings
a) Positive pregnancy test.
5) Allergies and Adverse Drug Reaction
a) History of severe hypersensitivity to a monoclonal antibody.
b) History of allergy or hypersensitivity to study drug components.
6) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific
circumstances a person who has been imprisoned may be included or permitted to continue
as a participant. Strict conditions apply and Bristol-Myers Squibb or designee approval is
required.
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical
(eg, infectious disease) illness.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study
participants and that the results of the study can be used. It is imperative that participants fully
meet all eligibility criteria.

The Estimated Number of Participants

  • Taiwan

    84 participants

  • Global

    883 participants

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