Pembrolizumab (MK-3475) in Hepatocellular Carcinoma

Study Drug Administration:

If you are found to be eligible to take part in this study, you will receive pembrolizumab by
vein over about 30 minutes on Day 1 of each 21-day cycle.

Length of Study:

You may receive pembrolizumab for up to 35 cycles (about 2 years). You will no longer be able
to take the study drug if the disease gets worse, if intolerable side effects occur, or if
you are unable to follow study directions.

Study Visits:

On Day 1 of Cycle 1:

- You will have a physical exam.

- Blood (about 2½ tablespoons) will be drawn for genetic testing; to test for hepatitis B
and C (if the doctor thinks it is needed); and pharmacodynamic (PD) testing. PD testing
measures how the level of study drug in your body may affect the disease.

- Blood (about 2 teaspoons) will be drawn to measure how some genes (DNA, genetic
material) in your body may react to pembrolizumab; and to check the status of the
disease, and to check for signs of inflammation.

- You will have an MRI or CT scan.

- If you can become pregnant, part of the above blood sample will used for a pregnancy
test.

On Day 1 of Cycles 2 and beyond:

- You will have a physical exam.

- Blood (about 1½ tablespoons) will be drawn for routine tests. If the study doctor thinks
it is needed, this sample will also be used to check for hepatitis B and C.

- At Cycle 2, blood (about 1½ tablespoons) will be drawn for PD testing.

- At Cycles 2, 5, and 6, blood (about 3 teaspoons) will be drawn to check the status of
the disease and to check for signs of inflammation.

- If you can become pregnant, part of the above blood sample will used for a pregnancy
test.

On Day 1 of Cycles 3, 6, 9, 12, and every 9 weeks after that, you will have an MRI or CT
scan.

After 1 year, you will have an MRI or CT scan every 12 weeks.

On Day 1 of even-numbered cycles (Cycles 2, 4, 6, and so on), urine will be collected for
routine tests.

After you have received the study drug for about 6 weeks (at about Cycle 2), you will have a
biopsy to check the status of the disease and for biomarker testing.

End-of- Study Visit:

As soon as possible after your last dose of study drug:

- You will have a physical exam.

- Blood (about 7 teaspoons) will be drawn for routine tests; genetic and PD testing; to
check for signs of inflammation; and to check the status of the disease.

- Urine will be collected for routine tests

- You may have a CT scan or MRI.

- If you can become pregnant, part of the above blood or urine sample will used for a
pregnancy test.

Follow-Up Visit:

About 30-90 days after your last dose of study drug:

- You will have a physical exam.

- Blood (about 7 teaspoons) will be drawn for routine tests and to check the status of the
disease. If the study doctor thinks it is needed, this sample will also be used to check
for hepatitis B and C.

- Depending on when your last scan was performed, you may have a CT scan or MRI.

- If you can become pregnant, part of the blood sample or a urine sample will used for a
pregnancy test.

Long-Term Follow-Up:

Every 9 weeks after your last dose of study drug, you will have an MRI or CT scan.

If you stopped taking the study drug because the disease appeared to get worse or because you
wanted to start a new anti-cancer therapy, you will be called by the study staff every 12
weeks to ask how you are doing. This call should last about 10-15 minutes.

Inclusion Criteria:

1. Male/female subjects with advanced HCC with no curative option will be enrolled in
this trial.

2. Be willing and able to provide written informed consent for the trial.

3. Be =/>18 years of age on day of signing informed consent.

4. Have histologically or cytologically documented 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. For subjects without cirrhosis
histological confirmation is mandatory.

5. Have Barcelona Clinic Liver Cancer (BCLC) Stage C disease or BCLC Stage B disease not
amenable to locoregional therapy or refractory to locoregional therapy, and not
amenable to a curative treatment approach.

6. Have a Child-Pugh A liver score within 7 days of first dose of study drug.

7. Have a predicted life expectancy of greater than 3 months.

8. Have measurable disease based on RECIST 1.1 as confirmed by the blinded MD Anderson
radiology. 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.

9. 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.

10. Have documented objective radiographic progression after stopping treatment with
sorafenib or else intolerance to sorafenib. Intolerance to sorafenib is defined as:
CTCAE Grade =/>2 drug-related adverse event(s) which both a) persisted in spite of
comprehensive supportive therapy according to institutional standards and b) persisted
or recurred after sorafenib treatment interruption of at least 7 days and dose
reduction by one dose level. Patients treated on sorafenib as the last treatment may
start pembrolizumab at least 14 days after the last dose of sorafenib.

11. Subjects with chronic infection by HCV who are treated or untreated are allowed on
study. Subjects with a past or resolved HBV infection, defined as having a negative
HBsAg test and a positive total hepatitis B core antibody (HBcAb) test and negative
HBV DNA test at screening, are eligible for the study. In addition, subjects with
successful treatment (defined as sustained virologic response [SVR12] or SVR24) are
allowed as long as 4 weeks have passed between completion of HCV therapy and start of
study drug.

12. Have a negative urine or serum pregnancy test within 72 hours prior to receiving the
first dose of study medication (Cycle 1, Day 1) (female subjects of childbearing
potential). If the urine test is positive or cannot be confirmed as negative, a serum
pregnancy test will be required.

13. Be willing to use an adequate method of contraception for the course of the study
through 120 days after the last dose of study medication (male and female subjects of
childbearing potential. Acceptable methods of contraception are as follows: A) Single
method (one of the following is acceptable): a) intrauterine device (IUD); b)
vasectomy of a female subject's male partner; c) contraceptive rod implanted into the
skin B) Combination method (requires use of two of the following): a) diaphragm with
spermicide (cannot be used in conjunction with cervical cap/spermicide); c) cervical
cap with spermicide (nulliparous women only); d) contraceptive sponge (nulliparous
women only); e) male condom or female condom (cannot be used together); f) hormonal
contraceptive: oral contraceptive pill (estrogen/ progestin pill or progestin- only
pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous
contraceptive injection

14. (Continuation of inclusion criteria #13) Abstinence (relative to heterosexual
activity) can be used as the sole method of contraception if it is consistently
employed as the subject's preferred and usual lifestyle and if considered acceptable
by local regulatory agencies and ERCs/IRBs. Periodic abstinence (e.g., calendar,
ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not
acceptable methods of contraception. If a contraceptive method listed above is
restricted by local regulations/guidelines, then it does not qualify as an acceptable
method of contraception for subjects participating at sites in this country/region.

15. Demonstrate adequate organ function. All screening laboratory tests should be
performed within 7 days of treatment initiation: a) Hematological - Absolute
neutrophil count =/>1200/µL; Platelets =/> 60,000/µL; Hemoglobin =/> 8 g/dL without
transfusion or EPO dependency within 7 days; b) Renal - Creatinine OR Measured or
calculated creatinine clearance (GFR can also be used in place of creatinine or
creatinine clearance) =/<1.5 × ULN OR =/>60 mL/min for subject with creatinine levels
>1.5 × institutional ULN. Note: Creatinine clearance should be calculated per
institutional standard; c) Hepatic - Total bilirubin =/<2 mg/dL, or direct bilirubin
=/2×ULN; AST (SGOT) and ALT (SGPT) =/<5 × ULN ;
Albumin =/>3 g/dL; d) Coagulation - INR or PT aPTT =/<1.5 × ULN unless subject is
receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of
intended use of anticoagulants.

Exclusion Criteria:

1. Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy, herbal/complementary oral or
IV medicine, or used an investigation device within 4 weeks of the first dose of
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 had esophageal or gastric variceal bleeding within the last 6 months. All subjects
will be screened for esophageal varices, unless such screening has been performed in
the past 12 months before first dose of treatment. If varices are present, they should
be treated according to institutional standards before starting study treatment.

3. Subjects with ALT >5x ULN at Day 1 are not eligible for enrollment.

4. Subjects with Total Bilirubin >2.0 mg/dL at Day 1 are not eligible for enrollment

5. Subjects with clinically apparent ascites or encephalopathy, or untreated varices are
not eligible for enrollment

6. Portal vein invasion at the main portal branch (Vp4), inferior vena cava, or cardiac
involvement of HCC based on imaging.

7. Has had encephalopathy in the last 6 months. Subjects on rifaximin or lactulose to
control their encephalopathy are not allowed.

8. Had a solid organ or hematologic transplant.

9. Had prior systemic therapy for HCC other than sorafenib, or intercurrent local therapy
to the liver tumor between sorafenib and study drug.

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.

12. Has received locoregional therapy to liver (TACE, TAE, radiation, radioembolization,
or ablation) or surgery to liver or other site within 6 weeks prior to the first dose
of study drug. Minor surgery must have occurred at least 7 days prior to the first
dose of study treatment (Cycle 1, Day 1). Subjects must have recovered adequately
(i.e., Grade =/<1 or baseline) from the toxicity and/or complications from any
intervention prior to starting therapy.

13. Has a diagnosed additional malignancy within 3 years prior to first dose of study
treatment with the exception of any curatively treated in-situ cancer.

14. Has radiographically detectable (even if asymptomatic and/or previously treated)
central nervous system (CNS) metastases and/or carcinomatous meningitis as assessed by
local site investigator and radiology review/CIV.

15. Has a history of (non-infectious) pneumonitis that required steroids or there is
current pneumonitis.

16. Has an active infection requiring systemic therapy.

17. 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.

18. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.

19. Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the screening visit through 120 days
after the last dose of trial treatment.

20. 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.

21. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).

22. Has untreated active Hepatitis B. Note: To qualify for enrollment, antiviral therapy
for HBV must be given for at least 3 months prior to first dose of study drug, and HBV
viral load must be less than 100 IU/mL prior to first dose of study drug. Those on
active HBV therapy with viral loads under 100 IU/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.

23. Subjects who have received therapy for HCV ≤ 4weeks from the start of pembrolizumab.
Note: Those with untreated HCV and those who completed HCV therapy ≥4 weeks of study
treatment start are eligible.

24. Has dual infection with HBV/HCV or other hepatitis combinations at study entry.

25. 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.

26. Has received sorafenib within 14 days of first dose of study medication