Study of Sorafenib With or Without VT-122 in Patients With Hepatocellular Carcinoma (HCC)

The most common clinical course of the patient with cancer is local tumor progression
leading to the development of metastases, systemic inflammation and the ensuing symptom
cluster known as anorexia-cachexia syndrome. This syndrome includes cachexia (anorexia,
weight loss and muscle wasting), fatigue, weakness, pain, dyspnea, nausea, malaise,
depression and poor performance status. Patients suffering from this syndrome also have poor
tolerance, adherence and response to anti-cancer therapy, resulting in disease progression
and reduced life expectancy. In spite of the dire need, no proven options for treating
inflammatory cancer cachexia are currently available.

VT-122 is the co-administration of the cyclo-oxygenase 2 (COX-2) inhibitor, etodolac and the
beta-adrenergic antagonist, propranolol.

It is proposed that these drugs can attenuate systemic inflammation and ameliorate the
symptoms of inflammatory cachexia in patients with advanced cancer. As a result, this
treatment may improve tolerability and adherence to anti-cancer therapy, thereby yielding
direct and indirect benefits in reducing disease progression and improving both the life
expectancy and quality of life for patients with advanced cancer.

The potentially synergistic activities of beta blockers and COX-2 inhibitors, their
offsetting side effects and their known beneficial impact on co-morbidities associated with
liver failure may make them well-suited for use with sorafenib, the standard of care for
patients with advanced HCC.

The purpose of this study is to assess whether use of VT-122 is safe and effective in
cachectic patients with advanced HCC. In addition to assessing cachexia-related symptoms,
the ability of the VT-122 regimen to improve tolerability to sorafenib and thereby to
improve both survival and quality of life will also be assessed.

Inclusion Criteria:

Participants will be required to meet all of the following criteria to be considered
eligible for the study:

- Have a confirmed diagnosis of HCC. Biopsy is preferred but is not required.

- Male and female participants who are ≥18 years of age.

- In the opinion of the investigator, the participants have a life expectancy of at
least 12 weeks.

- Able to take food or nutritional support orally.

- On sorafenib for at least 4 weeks prior to randomization. Dose adjustments are
allowed prior to randomization.

- Have a Karnofsky Performance Score (KPS) equal to or greater than 50.

- Have a cirrhotic status of Child-Pugh Class A or B7.

- Have the following laboratory parameters:

- a. Platelet count ≥50 x 10E9/L.

- b. Total bilirubin ≤1.5 mg/dL (≤1.0 mg/dL for primary biliary cirrhosis). If
total bilirubin >1.5 mg/dL but <3.0 mg/dL, a patient could be enrolled after
consultation with the Medical Monitor. If total bilirubin is >3.0 mg/dL, but the
value has been constant for a period of greater than 3 months, a patient could
be enrolled after consultation with the Medical Monitor.

- c. Serum creatinine ≤1.5 x upper limit of normal (ULN) or creatinine clearance
>60 mL/min calculated using Cockcroft-Gault.

- d. Serum albumin ≤3.5 g/dL and/or C-reactive protein (CRP) ≥3 mg/L

- Able to provide written informed consent prior to any study specific screening
procedures with the understanding that the patient has the right to withdraw from the
study at any time, for any reason without prejudice.

Exclusion Criteria:

Participants must not have any of the following criteria to be considered eligible for
inclusion in the study:

- The patient has a history of another primary cancer, with the exception of: a)
curatively resected non-melanomatous skin cancer; b) curatively treated cervical
carcinoma in-situ; or c) other primary solid tumor with no known active disease
present that in the opinion of the investigator will not affect patient outcome in
the setting of current HCC diagnosis.

- Contraindication to sorafenib, propranolol, etodolac, or placebo.

- Patient currently on beta-blockers for the treatment of portal hypertension or
arrhythmia. [Patients on beta blockers for the treatment of hypertension are allowed
if they change to a different drug class, e.g. some classes of angiotensin-converting
enzyme (ACE) inhibitors, for controlling hypertension at least one week before
randomization].

- Body mass index (BMI) <17.5 kg/m2.

- History or evidence of cardiac disease: congestive heart failure; New York Heart
Association class 2 or greater; active coronary artery disease; unstable angina,
cardiac arrhythmias requiring anti-arrhythmic therapy, atrioventricular block of
second or third degree, or uncontrolled hypertension. Patients with recent (less than
6 months) myocardial infarction (MI) or coronary revascularization.

- Hypotension at the time of screening (i.e., systolic blood pressure <90 mmHg,
diastolic blood pressure <60 mmHg).

- Resting heart rate <60 bpm at time of screening.

- Participants with a recent diagnosis of bleeding varices that has not been resolved
for a minimum period of 4 weeks.

- Any uncontrolled intercurrent illness that, in the opinion of the Investigator, may
interfere with study evaluation.

- On chronotropic drugs (acetylcholine, digoxin, diltiazem, verapamil, atropine,
dopamine, dobutamine, epinephrine, isoproterenol).

- Active clinically serious infections [>Grade 2 National Cancer Institute (NCI)-Common
Terminology Criteria for Adverse Events (CTCAE) version 4.0].

- Known history of human immunodeficiency virus (HIV) infection.

- Known central nervous system tumors including metastatic brain disease.

- Clinically significant gastrointestinal (GI) bleeding within 30 days prior to
Screening.

- Substance abuse, medical, psychological or social conditions that may, in the in the
opinion of the investigator, interfere with the patient's participation in the study
or evaluation of the study results.

- Known or suspected allergy to the investigational agents or any agent given in
association with this trial (hypersensitivity reaction, hives, rash, difficulty
breathing swelling of face, lips, tongue, or throat).

- Inability to swallow oral medications.

- Any condition that is unstable or which in the opinion of the Investigator could
jeopardize the safety of the patient and his/her compliance in the study.

- Pregnant or breastfeeding participants. Women of childbearing potential
(non-childbearing potential is defined as menopausal for at least 2 years,
post-bilateral tubal ligation for at least 1 year, post-bilateral oophorectomy or
post-hysterectomy) must have a negative urine pregnancy test performed within 10 days
prior to the start of study drug. Both men and women enrolled in this trial must use
adequate double-barrier birth control measures [2 types of an acceptable form of
FDA-approved contraception (e.g., barrier method, Depo-Provera™, Norplant™, Ortho
Evra® [birth control patch], oral contraceptives)] during the course of the trial.

- Participation in any other investigational trial in which receipt of investigational
drug or device occurred within 30 days prior to screening for this study.