Study Evaluating Nivolumab (Anti-PD-1 Antibody) Alone Versus Nivolumab Plus Ipilimumab (Anti-CTLA-4 Antibody) in Patients With Resectable and Potentially Resectable Hepatocellular Carcinoma (HCC) (CA209-956)

Groups A and B:

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a study
group.

If you are likely to be eligible for standard-of-care liver surgery, you will be randomly
assigned (as in the flip of a coin) to either Group A or B.

Group A participants will receive nivolumab alone.

Group B participants will receive nivolumab and ipilimumab.

Study Drug Administration:

Each cycle is about 2 weeks.

You will receive nivolumab by vein over 30 minutes on Day 1 of each cycle.

If you are in Group B, you will receive ipilimumab by vein over 90 minutes on Day 1 of Cycles
1, 6, and every 3 cycles after that (Cycles 9, 12, and so on).

You will have standard-of-care liver surgery on Day 1 of Cycle 4, if still eligible. You will
be asked to sign a separate consent form for the surgery.

Length of Treatment:

You may continue taking the study drugs for up to 2 years if you are in Group A or B, if the
doctor thinks it is in your best interest. If you are in Group C, you may continue taking the
study drugs until you are eligible to have surgery or up to 2 years, whichever is sooner.

You will no longer be able to take the study drugs if the disease gets worse, if intolerable
side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over after the follow-up visits.

Study Visits:

On Day 1 of Cycle 1:

- You will have a physical exam.

- Blood (about 6 tablespoons) will be drawn for routine, thyroid, biomarker (including
genetic biomarker), and tumor marker testing, to check the status of the disease, and to
check for inflammation. If needed, this blood will also be used for hepatitis C testing.

- Urine will be collected for routine tests. If you can become pregnant, part of the blood
and/or urine sample will be used for a pregnancy test.

- You will have an MRI or CT scan.

On Day 1 of Cycles 2 and 3:

- You will have a physical exam.

- Blood (about 5 tablespoons) will be drawn for routine, thyroid, and biomarker testing,
including genetic biomarkers.

- Urine will be collected for routine tests.

On the day of surgery (Day 1 of Cycle 4):

- You will have a physical exam.

- Blood (about 5 tablespoons) will be drawn for routine, thyroid, biomarker (including
genetic biomarker), and tumor marker testing, and to check for inflammation and to check
the status of the disease. If needed, this blood will also be used for hepatitis B
and/or C testing.

- Urine will be collected for routine tests.

- You will have an MRI or CT scan.

On Day 1 of Cycle 7:

- You will have a physical exam.

- Blood (about 5 tablespoons) will be collected for routine, thyroid, biomarker (including
genetic biomarker), and tumor marker testing, and to check for inflammation and to check
the status of the disease. If needed, this blood will also be used for hepatitis B
and/or C testing.

- Urine will be collected for routine tests. If you can become pregnant, part of the blood
and/or urine sample will be used for a pregnancy test.

- You will have an MRI or CT scan.

On Day 1 of Cycles 8 and beyond:

- You will have a physical exam.

- Blood (about 3 tablespoons) will be drawn for routine testing.

On Day 1 of Cycle 13 and every 6 cycles after that:

- You will have a physical exam.

- Blood (about 5 tablespoons) will be drawn for routine, thyroid, biomarker (including
genetic biomarker), and tumor marker testing, and to check for inflammation and to check
the status of the disease. If needed, this blood will also be used for hepatitis B
and/or C testing.

- Urine will be collected for routine tests.

- You will have an MRI or CT scan.

End-of-Treatment Visit:

As soon as possible after your last study drug dose:

- You will have a physical exam.

- Blood (about 5 tablespoons) will be collected for routine, thyroid, biomarker (including
genetic biomarker), and tumor marker testing, and to check for inflammation and to check
the status of the disease. If needed, this blood will also be used for hepatitis B
and/or C testing.

- Urine will be collected for routine tests.

- You will have an MRI or CT scan.

Follow-Up:

At 30 days after your last study drug dose:

- You will have a physical exam.

- Blood (about 3 tablespoons) will be drawn for routine, and tumor marker testing. If you
can become pregnant, part of this blood sample will be used and/or a urine sample will
be collected for a pregnancy test.

During the 30 days after your last study drug dose, the study staff may call to ask about
your health and any drugs you may be taking. The calls should take about 15 minutes.

After that, the study staff will call to ask how you are doing about every 9 weeks until the
study ends. If at any time after you complete your treatment the cancer gets worse, or you
start a new cancer treatment, these calls will be about every 12 weeks until the study ends.

Group C:

Study Drug Administration:

Each cycle is about 2 weeks.

You will receive nivolumab by vein over 30 minutes on Day 1 of each cycle.

You will receive ipilimumab by vein over 90 minutes on Day 1 of Cycle 1, 4, and every 3
cycles after that (Cycles 7, 10, and so on).

Length of Treatment:

You may continue taking the study drugs until you are eligible to have surgery or up to 2
years, whichever is sooner.

You will no longer be able to take the study drugs if the disease gets worse, if intolerable
side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over after the follow-up visits.

Study Visits:

On Day 1 of Cycle 1:

- You will have a physical exam.

- Blood (about 6 tablespoons) will be drawn for routine, thyroid, biomarker (including
genetic biomarker), and tumor marker testing, to check the status of the disease, and to
check for inflammation. If needed, this blood will also be used for hepatitis C testing.

- Urine will be collected for routine tests. If you can become pregnant, part of the blood
and/or urine sample will be used for a pregnancy test.

On Day 1 of Cycles 2 and 3:

- You will have a physical exam.

- Blood (about 5 tablespoons) will be drawn for routine, thyroid, and biomarker testing,
including genetic biomarkers.

- Urine will be collected for routine tests.

On Day 1 of Cycle 4:

- You will have a physical exam.

- Blood (about 5 tablespoons) will be collected for routine, thyroid, biomarker (including
genetic biomarker), and tumor marker testing, and to check for inflammation and to check
the status of the disease. If needed, this blood will also be used for hepatitis B and C
testing.

- Urine will be collected for routine tests. If you can become pregnant, part of the blood
and/or urine sample will be used for a pregnancy test.

- You will have a core tumor biopsy for testing on biomarkers related to the immune
system.

- You will have an MRI or CT scan.

On Day 1 of Cycles 5 and beyond:

- You will have a physical exam.

- Blood (about 3 tablespoons) will be drawn for routine testing. On Day 1 of Cycle 6 and
any other time the doctor thinks it is needed, if you can become pregnant, part of this
blood sample will be used and/or a urine sample will be collected for a pregnancy test.

On Day 1 of Cycle 10 and every 6 cycles after that:

- You will have a physical exam.

- Blood (about 5 tablespoons) will be collected for routine, thyroid, biomarker (including
genetic biomarker), and tumor marker testing, and to check for inflammation and to check
the status of the disease. If needed, this blood will also be used for hepatitis B and C
testing.

Urine will be collected for routine tests.

°You will have an MRI or CT scan.

End-of-Treatment Visit:

As soon as possible after your last study drug dose:

- You will have a physical exam.

- Blood (about 5 tablespoons) will be collected for routine, thyroid, biomarker (including
genetic biomarker), and tumor marker testing, and to check for inflammation and to check
the status of the disease. If needed, this blood will also be used for hepatitis B
and/or C testing.

- Urine will be collected for routine tests.

- You will have an MRI or CT scan.

Follow-Up:

At 30 days after your last study drug dose:

- You will have a physical exam.

- Blood (about 3 tablespoons) will be drawn for routine, and tumor marker testing. If you
can become pregnant, part of this blood sample will be used and/or a urine sample will
be collected for a pregnancy test.

During the 30 days after your last study drug dose, the study staff may call to ask about
your health and any drugs you may be taking. The calls should take about 15 minutes.

After that, the study staff will call to ask how you are doing about every 9 weeks until the
study ends. If at any time after you complete your treatment the cancer gets worse, or you
start a new cancer treatment, these calls will be about every 12 weeks until the study ends.

Inclusion Criteria:

1. Patients must give written informed consent prior to initiation of therapy, in keeping
with the policies of the institution. Patients with a history of major psychiatric
illness must be judged able to fully understand the investigational nature of the
study and the risks associated with the therapy.

2. Patients with histologically confirmed HCC (Documentation of original biopsy for
diagnosis is acceptable if tumor tissue is unavailable) or clinical diagnosis by AASLD
criteria in cirrhotic subjects is required (presence of arterial hypervascularity with
venous washout). For subjects without cirrhosis, histological confirmation is
mandatory. The determination of resectability status will ultimately lie in the
clinical judgment of the surgical oncologist and medical oncologist involved in the
care of the patient.

3. Patient must have measurable disease defined as a lesion that can be accurately
measured in at least one dimension (longest diameter to be recorded) and measures =/>
15 mm with conventional techniques or =/> 10 mm with more sensitive techniques such as
MRI or spiral CT scan.

4. Patient can have had prior treatment for HCC including prior surgery, radiation
therapy, local-regional therapy (ablation or arterial directed therapies), and
systemic therapy including sorafenib or chemotherapy (but not anti-PD-1 or anti-CTLA-4
therapy).

5. ECOG performance status =/< 1.

6. Within 14 days of the first dose of study drug, patients must have adequate organ and
marrow function as defined below: a) Absolute neutrophil count =/> 1,500/μL; b)
Platelets =/>100,000/μL; c) Hgb > 9.0 g/dL (may be transfused or receive epoetin alfa
[e.g., Epogen®] to maintain or exceed this level); d) Total bilirubin =/< 1.5 mg/dl;
e) Serum creatinine =/< 1.5 times the upper limit of normal or estimated CrCL
>40mL/min.; f) AST (SGOT) and/or ALT (SGPT) =/< 5 X institutional upper limit of
normal.

7. Men and women =/> 18 years of age

8. 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.

9. Women must not be breastfeeding.

10. WOCBP must agree to follow instructions for method(s) of contraception from the time
of enrollment for the duration of treatment with study drug (s) plus 5 half-lives of
study drug (s) plus 30 days (duration of ovulatory cycle) for a total of 5 months post
treatment completion.

11. Men who are sexually active with WOCBP must agree to follow instructions for method(s)
of contraception for the duration of treatment with study drug (s) plus 5 half-lives
of study drug (s) plus 90 days (duration of sperm turnover) for a total of 7 months
post-treatment completion.

12. Azoospermic males and WOCBP who are continuously not heterosexually active are exempt
from contraceptive requirements. However, WOCBP must still undergo pregnancy testing
as described in these sections.

Exclusion Criteria:

1. Any other malignancy from which the patient has been disease-free for less than 2
years, except for non-melanoma skin cancer, or in situ carcinoma of any site.

2. Patients who have organ allografts.

3. Patients who have had a major surgical procedure, open biopsy, or significant
traumatic injury with poorly healed wound within 6 weeks prior to first dose of study
drug; or anticipation of need for major surgical procedure during the course of the
study (other than defined by protocol); or fine needle aspirations or core biopsies)
within 7 days prior to first dose of study drug. NOTE: Patients will be allowed to
start cycle 1 day 1 therapy after 24 hours from pre-treatment biopsy.

4. Autoimmune disease: Patients with a history of inflammatory bowel disease (including
crohn's disease and ulcerative colitis) are excluded from this study as are patients
with a history of autoimmune disease (e.g., rheumatoid arthritis, systemic progressive
sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g.,
wegener's granulomatosis]).

5. Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS).

6. Any underlying medical condition, which in the opinion of the Investigator, will make
the administration of study drug hazardous or obscure the interpretation of adverse
events, such as a condition associated with frequent diarrhea.

7. Patients who have had a history of acute diverticulitis, abdominal fistula,
gastrointestinal perforation, intra-abdominal abscess, GI obstruction, abdominal
carcinomatosis which are known risks factors for bowel perforation, should be excluded
from the study.

8. Patients who have a primary brain tumor (excluding meningiomas and other benign
lesions), any brain metastases, leptomeningeal disease, seizure disorders not
controlled with standard medical therapy, or history of stroke within the past year.

9. History of serious systemic disease, including myocardial infarction or unstable
angina within the last 12 months, history of hypertensive crisis or hypertensive
encephalopathy, uncontrolled hypertension (blood pressure of >140/90 mmHg) at the time
of enrollment, New York Heart Association (NYHA) Grade II or greater congestive heart
failure, unstable symptomatic arrhythmia requiring medication (patients with chronic
atrial arrhythmia, i.e., atrial fibrillation or paroxysmal supraventricular
tachycardia are eligible), significant vascular disease or symptomatic peripheral
vascular disease.

10. Patients who have history of other diseases, metabolic dysfunction, physical
examination finding, or clinical laboratory finding giving reasonable suspicion of a
disease or condition that contraindicates the use of an investigational drug or that
might affect the interpretation of the results of the study or render the subject at
high risk from treatment complications.

11. Patients who are on high dose steroid (e.g. > 10 mg prednisone daily or equivalent) or
other more potent immune suppression medications (e.g. infliximab).

12. Patients who have had influenza, hepatitis, or other vaccines within a month prior to
initiation of study drugs.

13. Patients who have clinical history of coagulopathy, bleeding diathesis or thrombosis
within the past year.

14. Patients who have serious, non-healing wound, ulcer, or bone fracture.

15. Pregnancy (positive pregnancy test) or lactation.

16. Patients with prior orthotropic liver transplantation.

17. Patients with cirrhosis and severe synthetic liver dysfunction (Child Pugh B-C).

18. Patients must not have received prior anticancer therapy with anti-CLTA-4 or anti-PD1
for HCC. Patients receiving any concomitant systemic therapy for HCC are excluded.

19. Patients must not be scheduled to receive another experimental drug while on this
study.

20. Patients who require ongoing anticoagulation will be excluded. Only aspirin will be
permitted. Pre and post-surgical prophylactic anti-coagulation treatment is permitted.

21. Patients must not require total parenteral nutrition with lipids.

22. Any patient who cannot be compliant with the appointments required in this protocol
must not be enrolled in this study.