Trial of Statins for Chemoprevention in Hepatocellular Carcinoma

他汀类药物用于肝细胞癌化学预防的试验

基本信息

批准号：
10478274
负责人：
RAYMOND T CHUNG
金额：
$ 69.77万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10478274
关键词：
Adult Adverse event Affect Biological Markers Biopsy Cancer Etiology Cell Proliferation Cessation of life Chemoprevention Chemopreventive Agent Cirrhosis Clinical Clinical Chemoprevention Clinical Trials Companions Complication Conduct Clinical Trials Data Development Disease Progression Dose Drug Kinetics Etiology Fibrosis Future Gene Expression Hepatic Hepatology Human Immunohistochemistry Incidence Infrastructure International Intervention Length Liver Liver Cirrhosis Liver Fibrosis Liver diseases Malignant Neoplasms Measures Meta-Analysis Metabolic Molecular Monitor Observational Study Oncogenic Outcome Participant Pathway interactions Patient Selection Patients Pattern Persons Pharmacodynamics Phase Phase II Clinical Trials Placebo Control Placebos Positioning Attribute Predisposing Factor Prevention Prevention trial Primary carcinoma of the liver cells Prognosis Prognostic Marker Public Health Randomized Randomized Clinical Trials Randomized Controlled Trials Reporting Reproducibility Research Research Personnel Research Project Grants Resources Risk Risk Reduction Safety Sample Size Serious Adverse Event Serum Signal Pathway Signal Transduction Surrogate Markers Survival Rate Testing Therapeutic Time Tissue Sample Translating Translational Research Viral arm atorvastatin base cancer cell cancer chemoprevention cancer risk circulating biomarkers clinical center cohort design double-blind placebo controlled trial efficacy testing efficacy trial epidemiologic data follow-up genetic signature hazard high risk improved in vivo innovation intrahepatic lipophilicity liver biopsy liver inflammation liver transplantation mortality neoplastic novel novel strategies patient population pharmacodynamic biomarker population based pre-clinical prevent primary endpoint prognostic prospective randomized controlled design research clinical testing risk prediction screening secondary endpoint standard of care trend tumor two-arm study

项目摘要

PROJECT SUMMARY Worldwide, hepatocellular carcinoma (HCC) represents the fifth most common cancer and the second-leading cause of cancer-related mortality. In the U.S., both the HCC incidence and mortality are increasing at an alarming pace. Despite these concerning trends, treatment options for HCC remain limited, and the prognosis is grim, with a 5-year survival rate of just 15%. Thus, identifying effective strategies to prevent the development of incident HCC represents a critical public health need. A growing body of preclinical and population-based observational data now demonstrate that lipophilic statins, and in particular atorvastatin, reduces hepatic inflammation, cellular proliferation and cancer cell invasion, and reduces the incidence of HCC, in part by acting on relevant pathways, including the Hippo-YAP signaling pathway. However, despite these promising data, well-designed randomized controlled trials (RCTs) of atorvastatin for HCC prevention have not yet been reported. Historically, the feasibility of an HCC prevention trial has been limited by large sample size and long lengths of follow-up required to assess target endpoints. Recently, however, our group has derived and validated a 186-gene expression Prognostic Liver Signature (PLS), that represents an accurate, reproducible and highly reliable surrogate biomarker for HCC risk in multiple international cohorts of all major viral and non-viral etiologies of cirrhosis. Further, we have demonstrated that therapeutic modulation of the PLS accurately recapitulates future risk of developing incident HCC tumors, both in vivo and in confirmatory human studies. Finally, we and others have demonstrated in human liver tissue samples that atorvastatin modulates the PLS in part by acting on the Hippo-YAP pathway. Thus, the PLS represents a novel and highly tractable surrogate biomarker endpoint for an RCT of atorvastatin for the reduction of incident HCC risk. In this proposal, we will conduct a phase II RCT in 60 patients with compensated cirrhosis, designed to test the efficacy, safety and tolerability of 48 weeks of atorvastatin for the reduction of HCC risk, defined by our validated PLS profile. All subjects will have a high-risk PLS defined at screening liver biopsy, and subjects will be randomly assigned to 1 of 2 study arms for the 48-week study period: atorvastatin 20mg/day or placebo, with appropriate monitoring for the 48-week period, followed by a repeat biopsy at week 48 to assess for improvement in the PLS profile. We will also confirm whether atorvastatin has adequately engaged its targets by evaluating pharmacokinetics/pharmacodynamics, pre/neoplastic markers, and alteration in the Hippo-YAP pathway. We hypothesize that PLS-based HCC risk level decreases in the atorvastatin arm at the end of 48-week treatment. If atorvastatin treatment is effective, safe and well-tolerated, it could become the first chemopreventive agent designed to prevent the development of HCC, guided by PLS, in the growing population of patients in the U.S. who are affected by cirrhosis and are at high risk for this devastating complication.

项目概要在世界范围内，肝细胞癌 (HCC) 是第五大常见癌症，也是第二大癌症癌症相关死亡的原因。在美国，肝癌的发病率和死亡率都在以惊人的速度增长步伐。尽管有这些令人担忧的趋势，HCC 的治疗选择仍然有限，而且预后严峻， 5年生存率仅为15%。因此，确定有效的策略来防止事件的发展 HCC 代表了一项重要的公共卫生需求。越来越多的临床前和基于人群的观察现在的数据表明，亲脂性他汀类药物，特别是阿托伐他汀，可以减少肝脏炎症、细胞增殖和癌细胞侵袭，并降低 HCC 的发病率，部分是通过作用于相关途径，包括 Hippo-YAP 信号通路。然而，尽管有这些有希望的数据，精心设计的随机尚未报道阿托伐他汀预防 HCC 的对照试验 (RCT)。从历史上看，可行性 HCC 预防试验的开展受到大样本量和评估所需随访时间长的限制目标端点。然而，最近，我们的团队衍生并验证了 186 个基因的表达预测肝脏特征 (PLS)，代表 HCC 的准确、可重复且高度可靠的替代生物标志物肝硬化所有主要病毒和非病毒病因的多个国际队列中的风险。进一步，我们有证明 PLS 的治疗调节准确地概括了未来发生事件的风险 HCC 肿瘤，包括体内研究和验证性人体研究。最后，我们和其他人已经在人类身上证明了肝组织样本显示阿托伐他汀部分通过作用于 Hippo-YAP 通路来调节 PLS。因此， PLS 代表了阿托伐他汀随机对照试验的一种新颖且高度易于处理的替代生物标志物终点降低发生 HCC 的风险。在本提案中，我们将对 60 名代偿性肝硬化患者进行 II 期随机对照试验，旨在测试 48 周阿托伐他汀降低 HCC 风险的有效性、安全性和耐受性，由我们经过验证的定义 PLS 简介。所有受试者都将在筛选肝活检时确定高风险 PLS，并且受试者将被随机分配在为期 48 周的研究期间，分配至 2 个研究组中的 1 个：阿托伐他汀 20 毫克/天或安慰剂，并适当添加监测 48 周期间，然后在第 48 周重复活检以评估 PLS 的改善情况轮廓。我们还将通过评估来确认阿托伐他汀是否充分实现了其目标药代动力学/药效学、肿瘤前期/肿瘤标志物以及 Hippo-YAP 通路的改变。我们假设阿托伐他汀组基于 PLS 的 HCC 风险水平在 48 周治疗结束时降低。如果阿托伐他汀治疗有效、安全且耐受性良好，它可能成为第一个化学预防药物旨在以 PLS 为指导，预防美国不断增长的患者群体中 HCC 的发展。受肝硬化影响且发生这种毁灭性并发症的高风险人群。