Simvastatin in Preventing Liver Cancer in Patients With Liver Cirrhosis

Phase 2

Active, not recruiting

Conditions: Hepatocellular Carcinoma
Cirrhosis

Interventions: Procedure: Biospecimen Collection
Procedure: Computed Tomography
Procedure: Magnetic Resonance Imaging
Other: Questionnaire Administration
Other: Placebo Administration
Drug: Simvastatin

Registration Number: NCT02968810

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This phase II trial studies how well simvastatin works in preventing liver cancer in patients with liver cirrhosis. Simvastatin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed Description: PRIMARY OBJECTIVE:

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:

Ia. Serum AFP; Ib. Serum IL-6; Ic. Serum deoxycholic acid; Id. Liver stiffness; Ie. Fibrosis 4 index (FIB-4) score; If. MELD score.

EXPLORATORY OBJECTIVES:

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

Ia. serum bile acid levels; Ib. serum immune markers.

OUTLINE: Patients are randomized to 1 of 2 groups.

GROUP I: Patients receive simvastatin orally (PO) once daily (QD). Patients also undergo collection of blood on study and computed tomography (CT) scans/magnetic resonance imaging (MRI) throughout the trial.

GROUP II: Patients receive placebo PO QD. Patients also undergo collection of blood on study and CT/MRI throughout the trial.

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.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 52

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
Age >= 18 years
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 >= 8 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
The effects of simvastatin on the developing human fetus at the recommended therapeutic dose are unknown; for this reason, 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 18 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; pregnant women are excluded from this study because simvastatin is a lipid-lowering agent with the potential for teratogenic or abortifacient effects; it is not known whether simvastatin is excreted into human milk; however, a small amount of another drug in this class does pass into breast milk; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with simvastatin, 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)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group I (simvastatin)	Biospecimen Collection	Patients receive simvastatin PO QD. Treatment continues for up to 6 months in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood on study and CT/MRI throughout the trial.
Group I (simvastatin)	Computed Tomography	Patients receive simvastatin PO QD. Treatment continues for up to 6 months in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood on study and CT/MRI throughout the trial.
Group I (simvastatin)	Magnetic Resonance Imaging	Patients receive simvastatin PO QD. Treatment continues for up to 6 months in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood on study and CT/MRI throughout the trial.
Group I (simvastatin)	Questionnaire Administration	Patients receive simvastatin PO QD. Treatment continues for up to 6 months in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood on study and CT/MRI throughout the trial.
Group II (placebo)	Biospecimen Collection	Patients receive placebo PO QD. Treatment continues for up to 6 months in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood on study and CT/MRI throughout the trial.
Group II (placebo)	Computed Tomography	Patients receive placebo PO QD. Treatment continues for up to 6 months in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood on study and CT/MRI throughout the trial.
Group II (placebo)	Magnetic Resonance Imaging	Patients receive placebo PO QD. Treatment continues for up to 6 months in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood on study and CT/MRI throughout the trial.
Group II (placebo)	Placebo Administration	Patients receive placebo PO QD. Treatment continues for up to 6 months in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood on study and CT/MRI throughout the trial.
Group II (placebo)	Questionnaire Administration	Patients receive placebo PO QD. Treatment continues for up to 6 months in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood on study and CT/MRI throughout the trial.
Group I (simvastatin)	Simvastatin	Patients receive simvastatin PO QD. Treatment continues for up to 6 months in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood on study and CT/MRI throughout the trial.

Primary Outcome Measures

Name	Time	Method
Change in Serum AFP-L3%	Baseline to 6 months	Assessed by liquid-phase binding assay. Mean AFP-L3% difference calculated including all participants imputing undetectable values with 0.5%

Secondary Outcome Measures

Name	Time	Method
Change in Serum AFP	Baseline to 6 months	Assessed by liquid-phase binding assay. Mean difference in AFP, a glycoform produced by malignant liver cells.
Change in Serum IL-6	Baseline to 6 months	Mean difference in IL-6 (interleukin-6) NPX (normalized protein expression).
Change in Serum Deoxycholic Acid	Baseline to 6 months	Assessed by liquid chromatography coupled with mass spectrometry. Median difference in serum DCA (deoxycholic acid), a secondary bile acid.
Change in Liver Stiffness	Baseline to 6 months	Assessed by liver elastography. Fibroscan score from a fibroscan examination (a non-invasive measurement of liver fibrosis). A test result of greater than 20kPa is generally associated with an increased HCC risk. Mean difference in liver stiffness.
Change in Fibrosis 4 Index Score	Baseline to 6 months	The Fib-4 index is a non-invasive measure of liver stiffness. A high score (FIB4 ≥ 3.25) and low score is (FIB4 \< 1.3) The FIB-4 index is calculated as follows: FIB-4 = (Age × AST (U/L)) ÷ (PLT (109/L) × (√ ALT (U/L)). Change in mean difference.
Change in Model for End-Stage Liver Disease Score	Baseline to 6 months	The Model for End-Stage Liver Disease (MELD) is a validated predictor of survival among different populations of patients with advanced liver disease. MELD = 9.57 x ln(creatinine \[mg/dL\]) + 3.78 x ln(total bilirubin \[mg/dL\]) + 11.2 x ln(INR) + 6.43. Scores range from 6 (low/ less liver disease) to 40 (high/severe liver disease). Change in mean difference.

Trial Locations

Locations (5): Centro Comprensivo de Cancer de UPR
🇵🇷
San Juan, Puerto Rico
Northwestern University
🇺🇸
Chicago, Illinois, United States
MedStar Georgetown University Hospital
🇺🇸
Washington, District of Columbia, United States
Cedars Sinai Medical Center
🇺🇸
Los Angeles, California, United States
University of Puerto Rico
🇵🇷
San Juan, Puerto Rico