Pravastatin Intervention to Delay Hepatocellular Carcinoma Recurrence

Study Overview
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Brief Summary
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Hepatocellular Carcinoma (HCC) is a major health concern in the United States, particularly among people with liver cirrhosis. Out of every 100 patients with liver cancer, only 18 will survive 5 years or more. While locoregional therapies are utilized in an effort to combat this disease, the recurrence rate of HCC after these therapies are high. Statins are widely used drugs that lower cholesterol levels. Some studies have suggested that statins lower risk of HCC recurrence, but this possibility has not been studied thoroughly in a clinical trial. This study will examine the effects of pravastatin, a type of statin, on time to HCC recurrence in patients with early stage HCC. It is possible that pravastatin in combination with locoregional therapies may delay or protect against HCC recurrence.

Detailed Description
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To date, there has been a scarcity of clinical trials evaluating the effectiveness of adjuvant therapies in patients with early stage HCC, although it is widely considered an area of highly unmet need. The objective of this randomized double-blinded, placebo-controlled Phase II trial is to examine the effects of pravastatin use versus placebo after 12 months of treatment on hepatocellular cancer (HCC) recurrence in 130 patients with liver cirrhosis, HCC meeting Milan Criteria or OPTN tumor downstaging criteria for tumor burden, and initial locoregional therapy (LRT) with adequate response.

Official Title
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Pravastatin Intervention to Delay Hepatocellular Carcinoma Recurrence

Conditions
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Hepatocellular Carcinoma, Liver Cirrhoses

Intervention / Treatment
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* Drug: Pravastatin Pill
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years Confirmed diagnosis of liver cirrhosis (Child-Pugh A or B) assessed by the presence of clinical signs, symptoms, body imaging, or liver biopsy Diagnosis of HCC falling within one of the following criteria prior to LRT. Criteria fulfillment will be confirmed by the Imaging Charter and MedQIA. One lesion ≤ 5 cm or two to three lesions, each ≤ 3 cm. One lesion > 5 cm and ≤ 8 cm. Two or three lesions, of which at least one is > 3 cm and all are ≤ 5 cm each. The sum of all diameters must be ≤ 8 cm. Four or five lesions, each < 3 cm. The sum of all diameters must be ≤ 8 cm. Initiation of LRT (according to clinical judgement) within 24 months prior to Screening Visit, with adequate response as determined by Imaging Charter and MedQIA. ECOG performance status ≤1 (Karnofsky ≥70%; see Appendix A) AST (SGOT) & ALT (SGPT) ≤5 × institutional ULN AFP < 400 ng/mL Ability to understand and the willingness to sign a written informed consent document and medical release Agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; for women who are able to become pregnant. Willing and able to comply with trial protocol and follow-up Exclusion Criteria: Current use of statin medication or statin use within 12 months of Screening visit. Current systemic use of medications known to interact with statins and potentially increase toxicity, including (e.g., gemfibrozil, cyclosporine, clarithromycin, colchicine, niacin and fibrates). History of adverse effects, intolerance, or allergic reactions attributed to compounds of similar chemical or biologic composition to pravastatin (i.e., other statin medications) Current use of any other investigational agents Women who are pregnant. Women who are able to become pregnant must have a confirmed negative pregnancy test prior to enrollment. Women who are breastfeeding. It is not known whether pravastatin 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 pravastatin, breastfeeding should be discontinued if the mother is treated with pravastatin. Prior liver transplant MELD score ≥30. History of chronic myopathy Active malignancy within the past 5 years (excluding HCC, basal/squamous cell skin cancer, or prostate cancer with a Gleason score 6 or less) Known HIV infection Hemophilia Concurrent illness which in the opinion of the investigators would compromise either the patient or the integrity of the data Concurrent excessive alcohol consumption (average alcohol consumption of more than 5 drinks per day)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 1:1 drug versus placebo
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pravastatin Pill<br>Daily pravastatin (40mg) | Drug: Pravastatin Pill<br>* statin<br>* Other names: statin;|
| Placebo Comparator: Placebo Oral Tablet<br>Placebo | Drug: Placebo Oral Tablet<br>* placebo<br>* Other names: placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Recurrence | Mean difference in time (in months) from baseline (study visit 1) to first hepatocellular cancer (HCC) recurrence or HCC death within 12 months following treatment initiation for subjects randomized to pravastatin versus subjects randomized to placebo. - HCC recurrence will be confirmed by central expert independent radiographic review. | 12 months from baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recurrence Free Survival | Mean difference in time (in months) from baseline (study visit 1) to first occurrence of a documented hepatocellular cancer (HCC) recurrence within 12 months following treatment initiation for subjects randomized to pravastatin versus subjects randomized to placebo. - HCC recurrence will be confirmed by central expert independent radiographic review. | 12 months from baseline | 
| Overall Survival | Mean difference in time (in months) from baseline (study visit 1) to death (for any reason) within 12 months following treatment initiation for subjects randomized to pravastatin versus subjects randomized to placebo. | 12 months from baseline | 
| Waitlist Drop-off | Mean difference in time from baseline (study visit 1) to liver transplant waitlist drop-off within 12 months following treatment initiation for subjects randomized to pravastatin versus subjects randomized to placebo. | 12 months from baseline | 
| Change in Liver Stiffness | Mean difference in mean change in liver stiffness (as measured by MRE or FibroScan) between baseline (study visit 1) and 12 months (study visit 6) for subjects randomized to pravastatin versus subjects randomized to placebo. | 12 months from baseline | 
| Change in Liver Fat Fraction | Mean difference in within-person change in liver fat fraction (as measured by MRE) between baseline (study visit 1) and 12 months (study visit 6) for subjects randomized to pravastatin versus subjects randomized to placebo. | 12 months from baseline | 
| Change in Serum Biomarkers of Monocyte/Macrophage and Stellate Cell Activation | Mean difference in serum biomarkers including cytokines, chemokines, soluble receptors, and proteins (eg. IL6, TNFα, sTNFRII, IL18BP, sCD163, IL10, IL17, IL-8, CCL17, TGFβ) from baseline (study visit 1) to 12 months (study visit 6) for subjects randomized to pravastatin versus subjects randomized to placebo. | 12 months from baseline | 
| Levels of Liver Tissue Markers Related to HCC | Mean difference in liver tissue markers related to HCC including those in the Wnt/β-catenin pathway (eg. β-catenin, glutamine synthetase) from baseline (study visit 1) to 12 months (study visit 6) for subjects randomized to pravastatin versus subjects randomized to placebo. | 12 months from baseline |