Stereotactic Body Radiotherapy (SBRT) Followed by Immunotherapy in Liver Cancer

1.1 Primary Objective & Hypothesis Determine the safety and tolerability of SBRT followed by
nivolumab or ipilimumab with nivolumab for hepatocellular carcinoma by establishing the rates
of toxicity that occur within 6 months from start of SBRT. Hypothesis: SBRT followed by
nivolumab or nivolumab and ipilimumab will have similar toxicity to historical controls of
SBRT or nivolumab monotherapy.

1.2 Secondary Objectives and Hypotheses Estimate the investigator determined best overall
response rate. Hypothesis: Combining radiation and nivolumab or nivolumab and ipilimumab will
improve the best overall response rate compared to historical controls with SBRT or nivolumab
alone.

Estimate the rates of long-term adverse events (after 6 months) from the end of SBRT.
Hypothesis: Long-term toxicity from SBRT with nivolumab or nivolumab and ipilimumab will be
comparable to that observed with nivolumab monotherapy.

Summarize the distant disease control, progression-free survival, and overall survival.
Hypothesis: Disease control and survival will be comparable to (or better than) that observed
with nivolumab monotherapy.

Summarize the local control of the SBRT treated lesion. Hypothesis: Combining SBRT and
nivolumab or nivolumab and ipilimumab will have similar (or better) local control rates as
observed in SBRT only series.

1.3 Exploratory Objectives Explore changes in inflammatory biomarkers (including, but not
limited to CD8/Treg ratio, total CD4 counts, total lymphocyte count) in pretreatment and
on-treatment serially collected peripheral blood samples. Hypothesis: Changes in inflammatory
biomarkers after radiation therapy may correlate with a more favorable response to
immunotherapy.

Explore changes in the tumor microenvironment induced by radiation on pre and post treatment
biopsies. Hypothesis: Changes in the tumor microenvironment after radiation therapy will be
observed that may correlate with a more favorable response to immunotherapy.

Inclusion Criteria:

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

- Be ≥ 18 years of age on day of signing informed consent.

- Have ECOG performance status 0-1.

- Pretreatment CT chest /abdomen /pelvis within 28 days of protocol enrollment.

- Pathologic diagnosis of hepatocellular carcinoma (including fibrolamellar variants and
biphenotypic tumors with an HCC component).

- Child Pugh Class A (score = 5 or 6)cirrhosis (assessed within 14 days of SBRT)

- Deemed ineligible for curative intent therapy with surgical resection or liver
transplantation.

- Patients with diffuse/multifocal liver involvement are eligible.

- Patients with extrahepatic disease are eligible.

- Prior systemic therapies for HCC are allowed but not required.

- Must have at least one intrahepatic lesion amenable to SBRT.

- Prior transarterial chemoembolization (TACE) or radiofrequency ablation (RFA) allowed,
however, patient must have separate intrahepatic lesion amenable to SBRT and biopsy.

- Intrahepatic lesion amenable to pre and post SBRT biopsies, unless the investigator
determines that the tumor biopsies would be unsafe.

- Have measurable disease based on RECIST 1.1.

- Demonstrate adequate organ function as defined in Table 1. All screening labs should
be performed within 14 days of treatment initiation.

Table 1 - Adequate Organ Function Laboratory Values System Laboratory Value Hematological
Platelets ≥ 40,000 / mcL Hepatic Serum total bilirubin ≤ 3 mg/dL AST (SGOT) and ALT (SGPT)
≤ 5 X ULN

- Negative urine or serum pregnancy within 72 hours prior to receiving the first dose of
study medication for female subjects of childbearing age.

- Subjects should agree to use an adequate method of contraception starting with the
first dose of study therapy through 150 days after the last dose of study therapy (for
women of child-bearing potential) or 210 days after the last dose of study therapy
(for men who have partners of child-bearing potential).

- Have a life expectancy of greater than 6 months (in the opinion of the treating
physician).

Exclusion Criteria:

- Prior external beam radiation therapy to the liver (defined as > 1 Gy).

- Prior yttrium-90 radioembolization treatment.

- Patients with HBV viral load > 100 IU/mL (antiviral therapy per local practice is
required).

- Is currently participating and receiving study therapy or has participated in a study
of an investigational agent and received study therapy or used an investigational
device within 4 weeks of the first dose of treatment.

- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy at a dose
of >10 mg prednisone daily or equivalent at time of first dose of trial treatment.

- Has a known history of active TB (Bacillus Tuberculosis).

- Hypersensitivity to nivolumab or ipilimumab or any of its excipients.

- Has had prior anticancer therapy within 4 weeks of study Day 1 or has not recovered
(i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more
than 4 weeks earlier.

- Has a known additional malignancy that is progressing or requires active treatment.

- Has 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. Patients with allografts (including liver transplants) are
not eligible for this protocol.

- Has known history of, or any evidence of active, non-infectious pneumonitis.

- Has an active infection requiring systemic therapy.

- 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.

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

- 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.

- 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.