Study of Y90-Radioembolization With Nivolumab in Asians With Hepatocellular Carcinoma

Inclusion Criteria:

1. Patients with hepatocellular carcinoma (HCC) that is not suitable for resection orliver transplant, who are planned for Y90 radioembolization as per institutionalpractice.

2. Patients must have measurable disease with target lesion in liver, defined as atleast one lesion that can be accurately measured in at least one dimension (longestdiameter to be recorded) as >20 mm with conventional techniques or as >10 mm withspiral CT scan.

3. Diagnosis of HCC confirmed by histology/cytology or clinically by AASLD criteria incirrhotic subjects. Patients without cirrhosis require histological confirmation ofdiagnosis

4. No prior Y90 radioembolization therapy. Prior local therapies, such as surgery,hepatic artery embolization/chemoembolization, radiofrequency ablation, percutaneousethanol injection or cryoabalastion is allowed, if the index lesion(s) remainsoutside of the treatment field or has progressed since prior treatment. Localtherapy must have been completed at least 4 weeks prior to the baseline scan

5. Age ≥ 21 years.

6. ECOG performance status ≤ 2

7. Life expectancy of greater than 3 months

8. Only patients with Child-Pugh score for liver cirrhosis of A (sum of scores for fiveparameters: 5-6) will be allowed into this trial

9. Subjects with HBV infection must be on antiviral therapy per regional standard ofcare guidelines prior to initiation of study therapy. Both HBeAg positive andnegative subjects will be included.

10. Patients must have lesions in the liver that are amenable to CT-guided liver biopsy

11. Patients must have normal organ and marrow function as defined below:

• Haemoglobin ≥ 8.5g/dL

• Absolute Neutrophil Count ≥ 1.5 x 10^9/L

• Platelets ≥ 50 x 10^9/L

• Total Bilirubin < 3 mg/dL

• AST(SGOT)/ALT (SGPT) ≤ 3 x ULN

• Creatinine ≤ 1.5 x ULN or measured/calculated Creatinine Clearance (CrCl) ≥ 60ml/min

12. Ability to understand and the willingness to sign a written informed consentdocument.

13. Any surgery must be more than 28 days before start of study drug and any surgicalwounds must be completely healed

14. Female subjects of childbearing potential must have a negative serum or urinepregnancy test within 3 days prior to receiving the first dose of study medication,and must agree to adequate contraception use from time of signing the informedconsent through to 120 days after the last dose of the study drug. Male subjectsmust agree to adequate contraception use from time of signing the informed consentthrough 120 days after the last dose of the study drug.

Exclusion Criteria:

1. Patients are excluded if they are receiving any other investigational agents orusing an investigational device within 4 weeks of first dose of treatment. Patientsare excluded if they are receiving other systemic therapy within 2 weeks of firstdose of treatment.

2. Patients with known brain metastases should be excluded from this clinical trialbecause of their poor prognosis and because they often develop progressiveneurologic dysfunction that would confound the evaluation of neurologic and otheradverse events.

3. Prior use of anti-PD1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody,or any drug specifically targeted T-cell costimulatory checkpoint pathways

4. Uncontrolled intercurrent illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, uncontrolled hypertension or psychiatric illness/social situations thatwould limit compliance with study requirements.

5. Subjects with any active autoimmune disease or history of known or suspectedautoimmune disease requiring systemic therapy within the past 2 years, except forsubjects with vitiligo, resolved childhood asthma/atopy or euthyroid patients with ahistory of Grave's disease (subjects with suspected autoimmune thyroid disordersmust be negative for thyroglobulin and thyroid peroxidase antibodies and thyroidstimulating immunoglobulin prior to randomization). Replacement therapy (e.g. withthyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal orpituitary insufficiency etc) is not considered a form of systemic treatment

6. Pregnant women or breastfeeding mothers are excluded from this study because of thepotential risks to the foetus or baby. Women of child-bearing potential and men mustagree to use adequate contraception (hormonal or barrier method of birth control;abstinence) prior to study entry and for the duration of study participation. Shoulda woman become pregnant or suspect she is pregnant while participating in thisstudy, she should inform her treating physician immediately.

7. Diagnosis of immunodeficiency, including HIV/AIDS

8. Prior organ allograft or allogeneic bone marrow transplantation

9. History of severe hypersensitivity reactions to other monoclonal antibodies.

10. Prisoners or subjects who are involuntarily incarcerated

11. Subjects who are compulsorily detained for treatment of either a psychiatric orphysical (eg, infectious disease) illness

12. Inability to comply with restrictions and prohibited activities/treatments in thisstudy

13. Chronic treatment with systemic steroids or other immunosuppressive agent.

14. Subjects with concomitant second malignancies (except adequately treatednon-melanomatous skin cancers, in situ cervical cancers, localized prostate canceror in situ breast cancer) are excluded unless a complete remission was achieved atleast 3 years prior to study entry and no additional therapy is required oranticipated to be required

15. Prior radiation therapy to the liver or upper abdomen

16. Inability to undergo Y-90 radioembolisation due to inability to cathterise thehepatic artery, portal vein thrombosis/occlusion limiting the ability to performselective infusion, Tc-99M MAA scan showing unfavourable shunt fraction between theliver and pulmonary parenchyma, any other contraindications to RE as determined bythe interventional radiologist (e.g. other anatomic variants precluding safeadministration of Y90, severe peripheral vascular disease, uncorrectablecoagulopathy etc)