Pravastatin Intervention to Delay Hepatocellular Carcinoma Recurrence

• ClinicalTrials.gov Identifier: NCT03219372
• Recruitment Status: Recruiting
• First Posted: July 17, 2017
• Last Update Posted: May 29, 2020
• Sponsor: Cedars-Sinai Medical Center
• Collaborators: National Institutes of Health (NIH); National Cancer Institute (NCI)
• Information provided by (Responsible Party): Shehnaz Hussain, Cedars-Sinai Medical Center

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Hepatocellular Carcinoma; Liver Cirrhoses	Drug: Pravastatin Pill; Drug: Placebo Oral Tablet	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 130 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: 1:1 drug versus placebo
• Masking: Triple (Participant, Care Provider, Investigator)
• Masking Description: double-blind
• Primary Purpose: Prevention
• Official Title: Pravastatin Intervention to Delay Hepatocellular Carcinoma Recurrence
• Actual Study Start Date: September 27, 2018
• Estimated Primary Completion Date: June 1, 2021
• Estimated Study Completion Date: June 1, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Pravastatin Pill; Daily pravastatin (40mg)	Drug: Pravastatin Pill; statin; Other Name: statin
Placebo Comparator: Placebo Oral Tablet; Placebo	Drug: Placebo Oral Tablet; placebo; Other Name: placebo

Outcome Measures

Primary Outcome Measures :

1. Time to Recurrence [ Time Frame: 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 Outcome Measures :

1. Recurrence Free Survival [ Time Frame: 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.

2. Overall Survival [ Time Frame: 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.
3. Waitlist drop-off [ Time Frame: 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.
4. Change in liver stiffness [ Time Frame: 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.
5. Change in liver fat fraction [ Time Frame: 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.
6. Change in Inflammatory Biomarkers [ Time Frame: 12 months from baseline ]
   Mean difference in biomarkers (eg. IL6, TNFα, sTNFRII, IL18BP, sCD163, IL10, IL17, IL-8, CCL17, TGFβ, 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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)

Contacts and Locations

Contacts

Contact: Sandra Conteras; 424-315-2216; Sandra.Contreras@cshs.org

Contact: Shehnaz Hussain, PhD; 310-423-6401; Shehnaz.Hussain@cshs.org

Locations

United States, California

Cedars-Sinai Medical Center; Recruiting

Los Angeles, California, United States, 90048

Contact: Shehnaz Hussain, PhD 310-423-6401 Shehnaz.Hussain@cshs.org

Contact: Sandra Contreras 424-315-2216 sandra.contreras@cshs.org

Sub-Investigator: Walid S Ayoub, MD

Sub-Investigator: Marc T Goodman, PhD

Sub-Investigator: Mazen Noureddin, MD

Sub-Investigator: Laura M Kulik, MD

Sub-Investigator: Vatche Agopian, MD

Sub-Investigator: Richard Finn, MD

Sub-Investigator: David Lu, MD

Sub-Investigator: Otoniel Martinez-Maza, PhD

Sub-Investigator: Saeed Sadeghi, MD

Sub-Investigator: Vinay Sundaram, MD

Sub-Investigator: Marc L Friedman, MD

Sub-Investigator: H G Lipshutz, MD

Sub-Investigator: Jonathan Steinberger, MD

Sub-Investigator: Ju Dong Yang, MD

Sponsors and Collaborators

Cedars-Sinai Medical Center

National Institutes of Health (NIH)

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Shehnaz Hussain, PhD; Cedars-Sinai Medical Center

More Information

• Responsible Party: Shehnaz Hussain, Associate Professor, Cedars-Sinai Medical Center
• ClinicalTrials.gov Identifier: NCT03219372
• Other Study ID Numbers: IIT2017-08-HUSSAIN-STATLV; 1R01CA218486-01 ( U.S. NIH Grant/Contract )
• First Posted: July 17, 2017
• Last Update Posted: May 29, 2020
• Last Verified: May 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:

Carcinoma; Carcinoma, Hepatocellular; Liver Cirrhosis; Recurrence; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases; Pathologic Processes; Disease Attributes; Pravastatin; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Enzyme Inhibitors