Simvastatin in Preventing Liver Cancer in Patients With Liver Cirrhosis

PRIMARY OBJECTIVES:

I. To evaluate the effect of a simvastatin intervention versus placebo on the change in serum
AFP-L3% from baseline to 6 months following treatment initiation in patients with liver
cirrhosis who have a current model for end-stage liver disease (MELD) =< 20.

SECONDARY OBJECTIVES:

I. To evaluate the effect of a simvastatin intervention versus placebo at 6 months from
baseline on the change in serum AFP.

II. To evaluate the effect of a simvastatin intervention versus placebo at 6 months from
baseline on the change in serum IL-6.

III. To evaluate the effect of a simvastatin intervention versus placebo at 6 months from
baseline on the change in serum bile acid levels.

IV. To evaluate the effect of a simvastatin intervention versus placebo at 6 months from
baseline on the change in liver stiffness.

V. To evaluate the effect of a simvastatin intervention versus placebo at 6 months from
baseline on the change in fibrosis 4 index (FIB-4) score.

VI. To evaluate the effect of a simvastatin intervention versus placebo at 6 months from
baseline on the change in MELD score.

OUTLINE: Patients are randomized to 1 of 2 groups.

GROUP I: Patients receive simvastatin orally (PO) once daily (QD).

GROUP II: Patients receive placebo PO QD.

In both groups, treatment continues for up to 6 months in the absence of disease progression
or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30, 60, and 90 days.

Inclusion Criteria:

- Confirmed diagnosis of liver cirrhosis assessed by the presence of clinical signs,
symptoms, body imaging (ultrasound, computed tomography [CT], or magnetic resonance
imaging [MRI]), or liver biopsy

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

- Leukocytes >= 2,500/microliter

- Absolute neutrophil count >= 1,500/microliter

- Platelets >= 50,000/microliter

- Hemoglobin >= 10 g/dL

- Total bilirubin =< 3 x institutional upper limit of normal (ULN)

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

- Creatinine =< 1.5 x institutional ULN

- Women who are able to become pregnant must have a confirmed negative pregnancy test
result prior to enrollment; women >= 50 years of age who have not had a menstrual
period in the past year; and women who have had a hysterectomy, both ovaries removed,
or a tubal ligation; will not be required to have a pregnancy test

- Women who are able to become pregnant 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; should a woman become pregnant or suspect she is
pregnant while participating in this study, she should inform her study physician
immediately

- Ability to understand and the willingness to sign a written informed consent document
and medical release

- Willing and able to comply with trial protocol and follow-up

- Have had an abdominal imaging test (CT, MRI, or ultrasound) within the past 7 months

Exclusion Criteria:

- Prior or current use of statin medication

- Current systemic use of medications known to interact with statins and potentially
increase toxicity, including gemfibrozil, cyclosporine, danazol, lomitapide,
verapamil, diltiazem, dronedarone, amiodarone, amlodipine, ranolazine, strong CYP3A4
inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, human
immunodeficiency virus [HIV] protease inhibitors, boceprevir, telaprevir,
erythromycin, clarithromycin, telithromycin, nefazodone, or cobicistat-containing
products), or strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St.
John's wort, bosentan, efavirenz, etravirine, modafinil, nafcillin)

- History of adverse effects, intolerance, or allergic reactions attributed to compounds
of similar chemical or biologic composition to simvastatin (i.e., other statin
medications)

- Current use of any other investigational agents

- Women who are pregnant or breastfeeding; breastfeeding should be discontinued if the
mother is treated with simvastatin

- Prior liver transplant

- Prior known or suspected hepatocellular carcinoma

- Prior cholangiocarcinoma

- Model for end-stage liver disease (MELD) > 20

- Any lab results that do not meet inclusion criteria after the Screen 1 blood tests

- 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 that would limit compliance with
study requirements

- History of chronic myopathy

- Prior germ cell cancer

- History of active malignancy within the past 5 years (excluding basal/squamous cell
skin cancer or prostate cancer with a Gleason score 6 or less)

- Known active infection with HIV

- Medical contraindications to blood draw (e.g., hemophilia)

- Concurrent illness which in the opinion of the investigators would compromise either
the patient or the integrity of the data

- Current excessive alcohol consumption (average alcohol consumption of more than 5
drinks per day)