Hepatocellular Carcinoma, Liver Cirrhoses
Conditions
Brief summary
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
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.
Interventions
DRUGPravastatin Pill
statin
DRUGPlacebo Oral Tablet
placebo
Sponsors
National Institutes of Health (NIH)
National Cancer Institute (NCI)
Cedars-Sinai Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
double-blind
Intervention model description
1:1 drug versus placebo
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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. 1. One lesion ≤ 5 cm or two to three lesions, each ≤ 3 cm. 2. One lesion \> 5 cm and ≤ 8 cm. 3. 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. 4. 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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Recurrence | 12 months from baseline | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Waitlist Drop-off | 12 months from baseline | 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. |
| Recurrence Free Survival | 12 months from baseline | 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. |
| Change in Liver Stiffness | 12 months from baseline | 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. |
| Overall Survival | 12 months from baseline | 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. |
| Change in Serum Biomarkers of Monocyte/Macrophage and Stellate Cell Activation | 12 months from baseline | 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. |
| Levels of Liver Tissue Markers Related to HCC | 12 months from baseline | 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. |
| Change in Liver Fat Fraction | 12 months from baseline | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pravastatin Pill Pravastatin 40 mg, daily for 12 months
Pravastatin, a lipid-lowering agent, is a derivative of ML236B (compactin), which was identified in a fungus called Penicillium citrinum in the 1970s. It is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. | 1 |
| Placebo Oral Tablet Placebo identical in color, consistency, and appearance to pravastatin 40 mg, daily for 12 months
Placebo: A substance that has no therapeutic effect, and will be used as a control in testing the study agent. | 0 |
| Total | 1 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Pravastatin Pill | Total |
|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants |
| Region of Enrollment United States | 1 participants | 1 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 0 |
| other Total, other adverse events | 1 / 1 | 0 / 0 |
| serious Total, serious adverse events | 0 / 1 | 0 / 0 |
Outcome results
Primary
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.
Time frame: 12 months from baseline
Population: As accrual fell far below target, for associated privacy considerations related to the potential for participant re-identification, data are not reported.
Secondary
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.
Time frame: 12 months from baseline
Population: As accrual fell far below target, for associated privacy considerations related to the potential for participant re-identification, data are not reported.
Secondary
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.
Time frame: 12 months from baseline
Population: As accrual fell far below target, for associated privacy considerations related to the potential for participant re-identification, data are not reported.
Secondary
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.
Time frame: 12 months from baseline
Population: As accrual fell far below target, for associated privacy considerations related to the potential for participant re-identification, data are not reported.
Secondary
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.
Time frame: 12 months from baseline
Population: As accrual fell far below target, for associated privacy considerations related to the potential for participant re-identification, data are not reported.
Secondary
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.
Time frame: 12 months from baseline
Population: As accrual fell far below target, for associated privacy considerations related to the potential for participant re-identification, data are not reported.
Secondary
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.
Time frame: 12 months from baseline
Population: As accrual fell far below target, for associated privacy considerations related to the potential for participant re-identification, data are not reported.
Secondary
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.
Time frame: 12 months from baseline
Population: As accrual fell far below target, for associated privacy considerations related to the potential for participant re-identification, data are not reported.