The Role of Checkpoint Inhibition in Relapsed/Refractory Pediatric Hepatocellular Carcinoma: Clinical Efficacy and Biologic Correlates. A Phase II Study.

This research study is studying an immunotherapy drug (pembrolizumab or KEYTRUDA) as a
possible treatment for pediatric hepatocellular carcinoma or hepatocellular neoplasm not
otherwise specified (HCN NOS).

Inclusion Criteria:

- Age: Patients must be <30 years of age at the time of study enrollment.

- Diagnosis: Patients must have relapsed/refractory, histologically confirmed HCC to be
eligible for enrollment. Patients with hepatocellular neoplasm not otherwise specified
(HCN NOS) will also be eligible.

- Disease Status: Participants must have measurable disease by RECIST criteria, defined
as at least one lesion that can be accurately measured in at least one dimension
(longest diameter to be recorded for non-nodal lesions and short axis for nodal
lesions) measured at ≥20 mm with conventional technique or ≥10 mm with spiral CT scan,
MRI, or calipers by clinical exam. See Section 10 for the evaluation of measurable
disease.

- Performance Level: Karnofsky performance status ≥ 60% for patients ≥ 16 years of age
or Lansky ≥ 60% for patients < 16 years of age.

- Prior Therapy: Patients must have fully recovered from the acute toxic effects of all
prior anti-cancer therapy.

- Patients must not have received standard or targeted treatment regimens within 14 days
of initiation of treatment with pembrolizumab.

- Patients must not have received prior radiotherapy within 7 days of initiation of
treatment with pembrolizumab. Patients who have experienced radiation-induced adverse
events must recover to a grade 1 prior to enrollment.

- Organ Function Requirements: Participants must have normal organ and marrow function
as defined below:

- Adequate Bone Marrow Function defined as:

- Peripheral absolute neutrophil count (ANC) ≥ 750/μL

- Platelet count ≥ 75,000/μL (can be transfused)

- Adequate Liver Function defined as:

- Total bilirubin < 1.5 x institutional upper limit of normal (ULN)

- AST(SGOT) ≤ 2.5 x ULN

- ALT(SGPT) ≤ 2.5 x ULN

- If liver function studies are more elevated than the thresholds above, and
if if this elevation is felt secondary to tumor, patients may still be
eligible for enrollment after discussion with the study PI.

- Adequate Renal and Metabolic Function defined as:

- A serum creatinine based on age/gender as follows:

- Age Maximum Serum Creatinine (mg/dL) Male Female

- 1 to <2 years 0.6 0.6

- 2 to <6 years 0.8 0.8

- 6 to <10 years 1.0 1.0

- 10 to <13 years 1.2 1.2

- 13 to <16 years 1.5 1.4

- >16 years 1.7 1.4

- OR

- Creatinine clearance ≥60 mL/min/1.73 m2 for participants with creatinine
levels above institutional normal.

- Amylase ≤ 1.5 x ULN

- Lipase ≤ 1.5 x ULN

- If liver function studies are more elevated than the thresholds above, and if this
elevation is felt secondary to tumor, patients may still be eligible for enrollment
after discussion with the study PI.

-- Adequate Thyroid Function defined as:

--- TSH ≤1.5 ULN. Patients can be receiving thyroid supplementation.

- Confirmation of Insurance Pre-authorization approval for Pembrolizumab.

- Patients, their parent, and/or legally authorized representative must be able to
understand and be willing to sign a written informed consent document. Assent for
participants < 18 years will follow institutional guidelines. The protocol will
require approval by each institution's Institutional Review Board.

- The effects of pembrolizumab on the developing human fetus are unknown. For this
reason, patients of child-bearing and child-fathering potential must agree to use
adequate contraception (hormonal or barrier method of birth control; abstinence) prior
to study entry, for the duration of study participation, and for 4 months after
completion of pembrolizumab administration. Should a female become pregnant or suspect
she is pregnant while she or her partner is participating in this study, she should
inform her treating physician immediately. Males treated or enrolled on this protocol
must also agree to use adequate contraception prior to the study, for the duration of
study participation, and 4 months after completion of pembrolizumab administration.

- Women of child bearing potential (WOCBP) must have a negative serum or urine pregnancy
test within 24 hours of each treatment.

- A tumor sample must be available for submission to the central laboratory (Dana-Farber
Cancer Institute, see Section 9). If surgery was performed at the time of recurrence,
this sample, in addition to a diagnostic sample should be submitted. If no
re-operation was performed, archived tissue from diagnosis or the most recent
procedure should be submitted (see section 9 for further details regarding tissue
specifications).

Exclusion Criteria:

- Participants who are receiving any other investigational agents are not eligible.

- Participants who have received checkpoint inhibitors (PD-1, PD-L1, and CTLA-4
inhibitors) are not eligible.

- Participants who have received antibody-based therapies are not eligible if they are
within 3 half-lives of receipt of the last antibody dose.

- Participants who are receiving chronic steroids are not eligible.Chronic steroids are
defined as either > or = 2mg/kg/day of body weight or > or = 20mg/day of prednisone or
equivalent for persons who weigh > or = 10kg administered for > or = 14 consecutive
days.

- Participants who are receiving anti-inflammatory or immunosuppressive medications are
not eligible.

- Participants with known autoimmune disease, with the exceptions of childhood asthma or
atopic dermatitis, are not eligible.

- Patients with a history of a positive test for human immunodeficiency virus or
acquired immunodeficiency syndrome are not eligible.

- Patients with a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to pembrolizumab are not eligible. History of severe
allergy to monoclonal antibody therapies (i.e. anaphylaxis) are likewise an exclusion.

- Patients with uncontrolled intercurrent illness including, but not limited to, ongoing
or active infection, symptomatic congestive heart failure, or psychiatric
illness/social situations that would limit compliance with study requirements are not
eligible.

- Patients with prior solid organ transplantation are not eligible.