IRX-2, Cyclophosphamide, and Nivolumab in Treating Participants With Recurrent or Metastatic and Refractory Liver Cancer

PRIMARY OBJECTIVES:

I. To determine the safety profile of combination IRX-2 regimen and nivolumab in
anti-PD-1/PD-L1 naive patients who have progressed or were intolerant to sorafenib.

SECONDARY OBJECTIVES:

I. To evaluate the overall response rate of IRX-2 regimen combined with nivolumab using
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and immune modified RECIST
criteria.

II. To evaluate the rate of 6-month progression-free survival in patients treated with
combination IRX-2 regimen with nivolumab.

III. To evaluate median progression-free survival and overall survival.

EXPLORATORY OBJECTIVES:

I. To evaluate the circulating T cell profiles in patients before and after therapy with the
combination IRX-2 regimen and nivolumab.

II. To explore identification of tumor tissue neoantigens through a multiplex proteomic assay
(MHC-PepSeq) paired with tumor genomic and transcriptomic sequencing.

III. To explore putative biomarkers (including circulating tumor deoxyribonucleic acid [DNA]
and immune cell profiles) in peripheral blood to generate hypotheses for response to
treatment with combination IRX-2 regimen and nivolumab.

OUTLINE: This is a dose-escalation study of IRX-2.

Participants receive nivolumab intravenously (IV) over 30 minutes on day 1, cyclophosphamide
IV on day 1, and IRX-2 subcutaneously (SC) for 10 days between days 4 and 15. Courses repeat
every 28 days in the absence of disease progression or unacceptable toxicity. Participants
receive booster IRX-2 SC at 3, 6, 9, 12, and 15 months.

After completion of study treatment, participants are followed up every 12 weeks.

Inclusion Criteria:

- Patients with histologically or cytologically confirmed recurrent or metastatic
hepatocellular carcinoma (HCC) and refractory or intolerant to sorafenib.

- Patients must have recurrent or metastatic HCC that are not amenable to local therapy
with curative intent (surgery or radiation therapy with or without chemotherapy).

- Willing and able to give informed consent and adhere to protocol therapy; written
informed consent and any locally required authorization must be obtained from the
patient prior to performing any protocol-related procedures, including screening
evaluations.

- Up to three prior systemic therapy regimens for recurrent and/or metastatic disease.

- Eastern Cooperative Oncology Group (ECOG) 0-1.

- Have a Child-Pugh class A liver score within 7 days of first dose of study drug.

- Hemoglobin > 8 g/dL.

- Absolute neutrophil count (ANC) > 1,200 x 10^9/mL.

- Platelet count > 60 x 10^9/mL.

- Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN).

- Aspartate aminotransferase (AST/serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT/serum glutamate pyruvate transaminase [SGPT]) =< 5 x
ULN.

- Serum albumin > 3.0 g/dL.

- Prothrombin time (PT) and partial thromboplastin time (PTT) < 1.5 x the ULN.

- Measured creatinine clearance (CL) > 40 mL/min or calculated creatinine clearance CL >
40 mL/min by the Cockcroft-Gault formula 10 or by 24-hour urine collection for
determination of creatinine clearance.

- Palliative radiation therapy is allowed to non-target lesions at the discretion of the
treating physician.

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded) as
outlined in RECIST version 1.1.

- Life expectancy of greater than 3 months.

- Subjects with chronic infection by hepatitis C virus (HCV) who are untreated are
allowed on study. In addition, subjects with successful HCV treatment (defined as
sustained virologic response [SVR] 12 or SVR 24) are allowed as long as 4 weeks have
passed between completion of HCV therapy and start of study drug.

- Subjects with hepatitis B virus (HBV) may only be enrolled if their hepatitis is
judged clinically stable by the investigator.

- Female patients of childbearing potential must have a negative serum pregnancy test
within 7 days prior to enrollment.

- Body weight > 30 Kg.

Exclusion Criteria:

- Prior exposure to PD-1/PD-L1 inhibitors.

- Prior exposure to IRX-2 regimen.

- Radiation therapy with a curable intent within 30 days of first dose of study
treatment is excluded. However, radiation therapy with a palliative intent is allowed
as long as treatment with study medication occurs >= 14 days after last dose of
radiation and as long as there is at least 1 evaluable non-treated target lesion
remaining.

- Any medical contraindications or previous therapy that would preclude treatment with
the IRX 2 regimen or nivolumab including the following:

- Patients with allergies to ciprofloxacin or phytohemagglutinin (PHA)

- Patients with evidence of pre-existing myelosuppression, myelodysplasia or
hemorrhagic cystitis.

- Any unresolved toxicity National Cancer Institute (NCI) Common Terminology Criteria
for Adverse Events (CTCAE) grade >= 2 from previous anticancer therapy with the
exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
criteria.

- Patients with grade >= 2 neuropathy will be evaluated on a case-by-case basis after
consultation with the study physician.

- Patients with irreversible toxicity not reasonably expected to be exacerbated by
treatment with IRX-2, nivolumab may be included only after consultation with the study
physician.

- Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with
the exception of diverticulosis], systemic lupus erythematosus, sarcoidosis syndrome,
or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this
criterion:

- Patients with vitiligo or alopecia.

- Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on
hormone replacement. Any chronic skin condition that does not require systemic
therapy.

- Patients without active disease in the last 2 years may be included but only
after consultation with the study physician.

- Patients with celiac disease controlled by diet alone.

- Current or prior use of immunosuppressive medication within 14 days before the first
dose of nivolumab. The following are exceptions to this criterion:

- Intranasal, inhaled, topical steroid or local steroid injections (e.g., intra
articular injection).

- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or its equivalent.

- Steroids as premedication for hypersensitivity reactions (e.g., computed
tomography [CT] scan premedication).

- Major surgical procedure (as defined by the investigator) within 28 days prior to the
first dose of nivolumab.

- Note: Local surgery of isolated lesions for palliative intent is acceptable.

- History of allogenic organ transplantation.

- Symptomatic cardiopulmonary disease (including congestive heart failure and
hypertension), coronary artery disease, serious arrhythmia or chronic lung disease.
Patients with these conditions who are stable with relatively minor symptoms and who
are appropriate candidates for systemic treatments need not be excluded.

- Myocardial infarction within the last 3 months.

- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).

- Has untreated active Hepatitis B.

- Note: To qualify for enrollment, antiviral therapy for HBV must be given for at
least 3 months, and HBV viral load must be less than 100 IU/mL prior to first
dose of study drug. Those on active HBV therapy with viral loads under 100 IU/mL
should stay on the same therapy throughout trial treatment. Those subjects who
are anti-HBc (+), and negative for hepatitis B surface antigen (HBsAg), and
negative for anti- HBs, and have an HBV viral load under 100 IU/mL do not require
HBV anti-viral prophylaxis, but need close monitoring.

- Has dual infection with HBV/HCV or other hepatitis combinations at study entry.

- Receipt of live attenuated vaccine within 4 months prior to the first dose of study
treatment.

- Note: Patients, if enrolled, should not receive live vaccine whilst receiving
study treatment and up to 4 months after the last dose of study treatment.
Inactivated vaccines should not be administered within 2 weeks prior to or after
study regimen (ideally 4 weeks).

- Signs or symptoms of systemic infection (use of antibiotics to treat superficial
infection or contamination of tumor shall not, by itself, be considered evidence of
infection).

- Stroke or other symptoms of cerebral vascular insufficiency within the last 3 months.

- Previous diagnosis of invasive cancer from which the individual is not disease-free
AND that has required treatment within the past 3 years, except for superficial skin,
cervical cancer in-situ, or early stage prostate or bladder cancer (i.e. treatment
with curative intent and long term disease-free expectations).

- History of leptomeningeal carcinomatosis.

- Known allergy or hypersensitivity to any of the study drugs or any of the study drug
excipients.

- Female patients who are pregnant or breastfeeding or male or female patients of
reproductive potential who are not willing to employ effective birth control from
screening to one year after last dose of cyclophosphamide or 180 days after the last
dose of nivolumab therapy, whichever is longer.