Nivolumab (Anti-PD1), Tadalafil and Oral Vancomycin in People With Refractory Primary Hepatocellular Carcinoma or Liver Dominant Metastatic Cancer From Colorectal or Pancreatic Cancers

Background:

- Current treatment options for patients with liver cancers, including hepatocellular
carcinoma(HCC) and advanced liver cancers are limited and take no account of the known
biological and genetic heterogeneity in these diseases. Median survival for advanced
disease remains poor at approximately 1 year.

- Nivolumab is a fully human monoclonal immunoglobulin G4 (IgG4) antibody that is specific
for human programmed death-1 (PD-1, cluster of differentiation 279 [CD279]) cell surface
membrane receptor. Nivolumab has been approved by FDA for the treatment of HCC and other
solid tumors.

- Tadalafil is a phosphodiesterase type 5 (PDE5) inhibitor which have been approved by the
FDA for the treatment of pulmonary arterial hypertension, benign prostatic hyperplasia
and erectile dysfunction, with a relative safe clinical profile. PDE5 inhibitors have
been examined in multiple malignancies and cancer cell lines for their direct anticancer
activities, for their

efficacy as chemo-sensitizers and for cancer chemoprevention.

- Oral vancomycin is antibiotic that has effect on altering gut commensal bacteria
subsequently inducing a liver-selective anti-tumor effect.

- The aim of the study is to evaluate whether the immunomodulatory effect induced by PDE5
inhibitor and oral vancomycin can be enhanced by immune checkpoint inhibition in
advanced liver cancer.

Objective:

-To determine the Best Overall Response (BOR) according to Response Evaluation Criteria
(RECIST 1.1) to combined treatment of nivolumab, oral vancomycin and tadalafil in patients
with refractory primary HCC or liver dominant metastatic cancer from colorectal cancer (CRC)
or pancreatic adenocarcinoma (PDAC).

Eligibility:

- Histologically confirmed, hepatocellular carcinoma (HCC) Or

- Histologically confirmed carcinoma highly suggestive of a diagnosis of HCC Or

- Histologically confirmed advanced colorectal or pancreatic malignancy with liver
involvement as dominant site of metastasis

- Measurable lesion, accessible for biopsy.

- Age greater than or equal to 18 years

- ECOG less than or equal to 1

- Acceptable renal, bone marrow and liver function.

- Willingness to undergo two mandatory tumor biopsies.

Design:

- The proposed study is a phase II study of combined nivolumab, oral vancomycin and
tadalafil treatment in patients with HCC or liver dominant metastatic cancer from
colorectal or pancreatic cancers.

- Treatment will be delivered in cycles consisting of 4 weeks (+/- 3 days) until
progression or unacceptable toxicity.

- Patients will be seen in Clinical Center on monthly basis with disease status evaluation
every

8 (+/-1) weeks after start of study therapy.

- INCLUSION CRITERIA:

- Patients must have

- histopathological confirmation of HCC by the NCI Laboratory of Pathology (Cohort
1) OR

- histopathological confirmation of carcinoma by the NCI Laboratory of Pathology in
the setting of clinical and radiological characteristics which, together with the
pathology, are highly suggestive of a diagnosis of HCC (Cohort 1) OR

- histopathological confirmation of advanced colorectal or pancreatic malignancy by
the NCI Laboratory of Pathology with liver involvement as dominant site of
metastasis (Per multidiscipline tumor board review and approval) (Cohort 2).

- Patients must have disease that is not amenable to potentially curative resection,
transplantation or ablation.

- Patients must have progressed on, been intolerant to, or refused prior
sorafenib/lenvatinib therapy (Cohort 1 only).

- Subjects must have progressed on or after standard systemic chemotherapy (at least one
line of chemotherapy for patients with liver metastasis from PDAC, at least two lines
of chemotherapy for patients with liver metastasis from CRC) (Cohort 2 only).

- Patients must have evaluable or measurable disease per RECIST 1.1

- Patients must have lesion accessible for biopsy and be willing to undergo pre- and
posttreatment biopsies.

- ECOG performance status of 0 to 1

- If liver cirrhosis is present, patient must have a Child-Pugh score less than or equal
to 7

- Active chronic HBV infected subjects must be on antivirals and have HBV DNA <100IU/mL.
HCV infected subjects can be enrolled with close HCV RNA level monitoring.

- Age greater than or equal to 18 years. Because no dosing or adverse event data are
currently available on the use of nivolumab in combination with tadalafil and
vancomycin in patients less than 18 years of age, children are excluded from this
study, but will be eligible for future pediatric trials

- Adequate hematological function defined by:

- white blood cell (WBC) count greater than or equal to 3 (SqrRoot) 10^9/L

- absolute neutrophil count (ANC) greater than or equal to 1.5 (SqrRoot) 10^9/L,

- lymphocyte count greater than or equal to 0.5 (SqrRoot) 10^9/L,

- platelet count greater than or equal to 120 (SqrRoot) 10^9/L, and

- Hgb greater than or equal to 9 g/ dL (more than 48 hours post-completion of blood
transfusion)

- Adequate hepatic function defined by:

- a total bilirubin level less than or equal to 1.5 (SqrRoot) ULN,

- an AST level <5(SqrRoot) ULN,

- an ALT level <5 (SqrRoot) ULN.

- Adequate renal function defined by:

- Creatinine clearance (CrCl) greater than or equal to 50 mL/min/1.73 m^2 by 24
hours urine collection or as predicted by the Cockcroft-Gault formula:

- CrCl = (140 age (y)) x (weight in kg) x (0.85, if female) x1.73 m^2/72 x Serum
Creatinine (mg/dL) x pt. s BSA (m^2) Or

- The effects of nivolumab on the developing human fetus are unknown. For this reason,
women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and for
the duration of study participation and up to 5 months (women) and 7 months (men)
after the last dose of the drug. Should a woman become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she should inform
her treating physician immediately.

- Patients with a history of cardiovascular disease may be enrolled per cardiology
consultation and approval with echocardiogram and troponin level in normal range at
the time of enrollment.

- Patient must be able to understand and willing to sign a written informed consent
document.

EXCLUSION CRITERIA:

- Patients who have had standard-of-care anti-cancer therapy or therapy with
investigational agents (e.g. chemotherapy, immunotherapy, endocrine therapy, targeted
therapy, biologic therapy, tumor embolization, monoclonal antibodies or other
investigation agents), large field radiotherapy, or major surgery within 4 weeks prior
to enrollment.

- Therapy with NSAIDs or antibiotics within 3 months prior to enrollment.

- Therapy with nitrates, alpha-blockers, or cytochrome P450 (CYP3A4) inhibitors within
7- days prior to enrollment and for whom stopping is unsafe and/or a safe substitute
is not medically recommended. Use of PDE5 inhibitors such as vardenafil (Levitra ),
tadalafil (Cialis ), and sildenafil citrate (Viagra ) less than or equal to 15-days
prior to enrollment.

- The patient must not be currently on a corticosteroid dose greater than physiologic
replacement dosing defined as 10 mg of cortisone per day or its equivalent.

- For PDAC patients with liver metastases, primary PDAC has not been resected (unless
the primary is in the tail of the pancreas).

- Patients with known brain metastases will be excluded from this clinical trial because
of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events.

- Have signs of liver failure, e.g. clinical significant ascites, encephalopathy, or
variceal bleeding within 6 months prior to enrollment.

- Prior major liver resection: remnant liver <50% of the initial liver volume. Patients
with a biliary stent can be included.

- Patients with active autoimmune disease or history of autoimmune disease that might
recur, which may affect vital organ function or require immune suppressive treatment
including systemic corticosteroids. These include but are not limited to patients with
a history of immune related neurologic disease, multiple sclerosis, autoimmune
(demyelinating) neuropathy, Guillain-Barre syndrome or CIDP, myasthenia gravis;
systemic autoimmune disease such as SLE, connective tissue diseases, scleroderma,
inflammatory bowel disease (IBD), Crohn s, ulcerative colitis, hepatitis; and patients
with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or
phospholipid syndrome. Such diseases should be excluded because of the risk of
recurrence or exacerbation of disease.

Of note, patients with vitiligo, endocrine deficiencies including thyroiditis managed with
replacement hormones including physiologic corticosteroids are eligible. Patients with
rheumatoid arthritis and other arthropathies, Sjogren s syndrome and psoriasis controlled
with topical medication and patients with positive serology, such as antinuclear antibodies
(ANA), anti-thyroid antibodies should be evaluated for the presence of target organ
involvement and potential need for systemic treatment but should otherwise be eligible.

- Have history of idiopathic pulmonary fibrosis (including bronchiolitis obliterans with
organizing pneumonia) or evidence of active pneumonitis on screening chest CT scan.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations (within timeframes identified in
the bullets below) that would limit compliance with study requirements.

- Patients with myocardial infarction or myocarditis within 12 months prior to
enrollment.

- History of severe or unstable cerebrovascular disease.

- Sustained hypotension (<90/50 mmHg) or uncontrolled hypertension (>160/100 mmHg)

- Stroke within 6 months prior to enrollment.

- HIV-positive patients are excluded because HIV causes complicated immune deficiency
and study treatment can possess more risks for these patients.

- Have had prior transplant of any kind.

- Have ascites.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to nivolumab, tadalafil or vancomycin.

- History of severe hypersensitivity reaction to any monoclonal antibody.

- Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free
for a minimum of 3 years prior to enrollment.

- Pregnant women are excluded from this study because nivolumab s potential for
teratogenic or abortifacient effects is unknown. Because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the
mother with nivolumab, breastfeeding should be discontinued if the mother is treated
with nivolumab