Pembrolizumab (Keytruda) in Advanced Hepatocellular Carcinoma

The study will be an open-label, single-institution, non-randomized, single-arm, Phase II
study of pembrolizumab therapy in patients with advanced HCC. Patients will be treated in
three-week cycles, with intravenous (IV) administration of pembrolizumab on day 1 of each
3-week cycle. Trial therapy will last until withdrawal of consent, disease progression and/or
unacceptable toxicity, whichever occurs first.

Correlative studies investigating PD-L-1 expression in tumor tissue will be assessed with
clinical outcome. Peripheral blood will also be drawn to perform immunologic markers and
hepatitis B or C viral titers. This is to determine if viral titers change with treatment.
These studies are included for all patients who consent to the correlative studies (See
Appendix F). There is an additional consent for the correlative studies.

Up to 35 patients will be enrolled at Sylvester Comprehensive Cancer Center (SCCC).
Investigators expect to enroll 10-12 patients per year based on the institution's enrollment
capacity. Expected time to complete total accrual is approximately 1.5 years. Expected time
to study completion is 3 years from date open to enrollment to allow for survival data. An
interim analysis is planned after 14 evaluable patients are assessed for DCR to determine
whether to continue with an additional 14 more.

Inclusion Criteria:

1. Patients must have diagnosis of advanced hepatocellular cancer (HCC) by one of the
following:

- Histopathology

- Elevated serum alpha-fetoprotein (AFP) >400 ng/ml and findings on magnetic
resonance imaging (MRI) or computed tomography (CT) scans characteristic of HCC

- Findings on triple phase MRI or CT scans characteristic of HCC in patients with
cirrhosis and tumors at least 1 cm or greater, without a curative treatment
option (transplant, resection, or ablation).

2. Measurable disease as defined by RECIST v1.1 (provided in Section 14.0).

3. Radiographic progression on previously treated areas (as defined by RECIST v1.1).

4. Subject refusal for sorafenib treatment or intolerance to sorafenib are also allowed
(intolerance is defined as ≥ 28 days of sorafenib (not necessarily consecutive) or
≥grade 3 toxicity due to sorafenib which does not resolve with appropriate supportive
care).

5. Patients should have failed at least one prior systemic therapy regimen which could
include sorafenib. Patients may have progressed on sorafenib, been intolerant of, or
refused sorafenib. Patients who are documented to refuse systemic chemotherapy or
sorafenib are also eligible. No limit to prior systemic therapy. Prior locoregional
therapy such as surgery, radiofrequency ablation or transarterial chemoembolization
are also allowed, provided that progression has been documented after these therapies,
and ≥4 weeks have elapsed since the last therapy; (these will not be counted as
systemic therapy).

6. Child-Pugh Classification with score ≤ 7 points. See Appendix G for criteria.

7. Age ≥ 18 years

8. Estimated life expectancy, in the judgement of the Investigator, of at least ≥ 12
weeks.

9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. See Appendix
C.

10. Adequate bone marrow function as defined below:

- absolute neutrophil count (ANC) ≥ 1.2 x 10^9/L,

- platelets (PLT) ≥ 50 x 10^9/L

11. Adequate liver function as defined below:

- serum bilirubin < 2 mg/dl

- Aspartate transaminase (AST/SGOT) ≤ 5 x upper limit of normal (ULN),

- Alanine transaminase (ALT/SGPT) ≤ 5 x ULN

12. Adequate coagulation as defined by:

- serum prothrombin time (PT) ≤ 16 seconds

13. Adequate renal function as defined by one of the following:

- serum Creatinine ≤ 1.5 x ULN OR

- (measured or calculated) Creatinine clearance ≥ 60 mL/min for patients with serum
creatinine levels > 1.5 x ULN.

14. Suitable venous access to allow for all study-related blood sampling.

15. Female subject of childbearing potential (CBP) must have a negative urine or serum
pregnancy within 3 days prior to receiving the first dose of study medication.

16. Females of child bearing potential that are sexually active must agree to either
practice 2 medically accepted highly effective methods of contraception at the same
time or abstain from heterosexual intercourse from the time of signing the informed
consent through 120 days after the last dose of study drug. See Appendix H for
protocol-approved highly effective methods of contraceptive combinations. Subjects of
childbearing potential are those who have not been surgically sterilized or have not
been free from menses for > 1 year.

17. Negative test for pregnancy is required of females of child-bearing potential; A
female of child bearing potential is any woman, regardless of sexual orientation or
whether they have undergone tubal ligation, who meets the following criteria:

- has not undergone a hysterectomy or bilateral oophorectomy; or

- has not been naturally postmenopausal for at least 24 consecutive months (i.e.,
has had menses at any time in the preceding 24 consecutive months or 730 days).

18. Conception while on treatment must be avoided

19. Male subjects should agree to use an adequate method of contraception starting with
the first dose of study therapy through 120 days after the last dose of study therapy.

20. Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

1. Active autoimmune disease that has required systemic treatment in the 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.

2. Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other
form of immunosuppressive therapy within 2 years prior to the first dose of trial
treatment.

3. Major surgical procedure within 28 days prior to enrollment. Note: If subject received
major surgery, they must have recovered adequately from the toxicity and/or
complications from the intervention prior to starting therapy.

4. Any unresolved toxicity > CTCAE grade 2 despite optimal care/support, from previous
anti-cancer therapy, within 28 days prior to first dose of study drug. [Exceptions:
Alopecia and ≤grade 2 neuropathy.]

5. Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

6. Receipt of anti-cancer monoclonal antibody within 4 weeks prior to first dose of study
drug.

7. Prior treatment with any other chemotherapy, radiotherapy, immunotherapy, or
anticancer drug, agent or biologic within 4 weeks prior to first dose of study drug.

8. Has received a live vaccine within 30 days of planned start of study therapy. Note:
Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live
attenuated vaccines, and are not allowed.

9. Receipt of any other investigational agents for their cancer ≤4 weeks of the first
dose of study treatment.

10. Known history of active TB (Bacillus Tuberculosis).

11. Known history of, or any evidence of active, non-infectious pneumonitis or has a
history of (non-infectious) pneumonitis that required steroids or current pneumonitis.

12. Known history of Human Immunodeficiency Virus (HIV), HIV-1/2 antibodies.

13. Known hypersensitivity to pembrolizumab or any of its excipients.

14. Known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
[Exception: Subjects with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging, for at least 4 weeks
prior to the first dose of study drug and any neurologic symptoms have returned to
baseline), have no evidence of new or enlarging brain metastases, and are not using
steroids for at least 7 days prior to trial treatment. This exception does not apply
to carcinomatous meningitis which is excluded regardless of clinical stability.]

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

16. Any uncontrolled, intercurrent illness including but not limited to ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia.

17. Has a known additional malignancy that is progressing or requires active treatment.
[Exception: Basal cell carcinoma of the skin or squamous cell carcinoma of the skin
that has undergone potentially curative therapy, or in situ cervical cancer.]

18. Any other serious medical or psychiatric illness/condition likely in the judgment of
the Investigator(s) to interfere or limit compliance with study
requirements/treatment.

19. Treatment for active hepatitis C virus (HCV) within 60 days of study entry. [Note:
Untreated HCV positive subjects are eligible, and if stable on pembrolizumab for 6
months after study entry, consideration may be given to starting anti-HCV therapy, at
the discretion of the treating Investigator.]

20. HCC patients with evidence of prior hepatitis B virus (HBV) must fulfill the following
criteria in order to be eligible for the study: HBV viral load (VL) <100 IU/mL before
study enrollment, and subjects with active HBV need to be on anti-HBV suppression ≥3
months, throughout treatment and for 6 months after.