Nivolumab and Bevacizumab in Patients With Advanced and or Metastatic Hepatocellular Carcinoma

Inclusion Criteria:

- Confirmed unresectable or metastatic hepatocellular carcinoma. Confirmation either by
histologic confirmation or accepted radiographic criteria.

- Received at least one line of therapy with a TKI (including, but not limited to
sorafenib, lenvatinib, and/or regorafenib) with evidence of disease progression
clinically or radiographically as deemed by investigator, or refused therapy with a
TKI. No more than two lines of prior therapy are allowed.

- Measurable disease per RECIST1.1.

- Age ≥18 years.

- ECOG performance status of 0 to 1.

- Life expectancy ≥ 12 weeks.

- Childs Pugh A (5-6 points). Demonstrate adequate organ function as defined in the
table below

Hematologic:

Absolute neutrophil count (ANC) ≥ 1.5 k/µL. Platelets ≥ 100 k/µL Hemoglobin ≥ 9 g/dL

Renal:

Creatinine < 2 × ULN OR

- Able to provide informed consent and willing to sign an approved consent form that
conforms to federal and institutional guidelines.

Exclusion Criteria:

- Prior treatment with anti-PD1 or anti-PD-L1 antibody therapy.

- Subjects with a prior history of DVT/PE, who have not been on stable doses of
anticoagulation with low molecular weight heparin or oral anticoagulant for at least
two weeks.

- History of arterial thromboembolic event in past 6 months (including CVA, MI).

- Systemic anti-cancer treatment within 2 weeks, all ongoing adverse events related to
previous systemic anti-cancer therapy resolved to grade ≤1.

- Radiotherapy within 2 weeks of first dose of study medications.

- Major surgery within 6 weeks of first dose of study medications. Minor procedures
(e.g. port placement, endoscopy with intervention) within 4 weeks of first dose of
study medications.

- Presence of ≥ CTCAE grade 2 toxicity due to prior cancer therapy (except alopecia,
peripheral neuropathy which are excluded if ≥ CTCAE grade 3).

- Medical condition that requires chronic systemic steroid therapy, or any other form of
immunosuppressive medication.

- Active ongoing infection requiring therapy.

- Active HIV infection.

- History of severe hypersensitivity reaction to another monoclonal antibody.

- Active central nervous system metastases and/or carcinomatous meningitis (stable
treated brain metastases not requiring steroids >4 weeks allowed).

- Cardiac conditions: class 3-4 New York Heart Association congestive heart failure,
known baseline LVEF < 50%, transmural myocardial infarction, uncontrolled
hypertension, angina pectoris requiring medication, clinically significant valvular
disease, high-risk arrhythmia in the past 12 months.

- Any history of autoimmune disease requiring treatment in the past 5 years or felt to
be at risk to reactivate autoimmune disease. Patients who are felt to no longer be at
risk of activating a known autoimmune disease (e.g. type 1 diabetes, ulcerative
colitis s/p complete colectomy, autoimmune thyroiditis s/p thyroidectomy or medical
ablation, etc.) may be allowed to participate after discussion with the PI

- Pregnant, breast feeding, or planning to become pregnant.

- Women of childbearing potential (WOCBP) must agree to follow instructions for
method(s) of contraception for the duration of study treatment with nivolumab and 5
months after the last dose of study treatment i.e., 30 days (duration of ovulatory
cycle) plus the time required for the investigational drug to undergo approximately
five half-lives. Contraception as described in section 7.3

- Males who are sexually active with WOCBP must agree to follow instructions for
method(s) of contraception for the duration of study treatment with nivolumab and 7
months after the last dose of study treatment i.e., 90 days (duration of sperm
turnover) plus the time required for the investigational drug to undergo approximately
five half-lives. Contraception as described in section 7.3

- Received any live vaccine within the last 30 days.

- Other malignancy requiring treatment in the prior 2 years with the exception of
locally treated squamous or basal cell carcinoma.