A Randomized and Placebo-Controlled Phase II Trial Targeting Dominant-Negative Missense Mutant P53 by Atorvastatin for Reducing the Risk of Longstanding Ulcerative Colitis-Associated Cancer
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 42
- 试验地点
- 3
- 主要终点
- Reduction in mutant p53 staining in biopsy samples obtained during colonoscopies done before and after intervention
研究概览
简要总结
This phase II trial studies the effect of atorvastatin in treating patients with ulcerative colitis who have a dominant-negative missense P53 mutation and are at risk of developing large intestinal cancer. Patients with ulcerative colitis are known to have an increased risk of developing large intestinal cancer. Better ways to control ulcerative colitis and more knowledge about how to prevent colon cancer are needed. Atorvastatin is a drug used to lower the amount of cholesterol in the blood and to prevent stroke, heart attack, and angina (chest pain). It blocks an enzyme that helps make cholesterol in the body. It also causes an increase in the breakdown of cholesterol. The information gained from this study may help doctors learn more about atorvastatin as an agent in cancer prevention, and may help to improve public health.
详细描述
PRIMARY OBJECTIVE:
I. To determine the effect of atorvastatin calcium (atorvastatin) treatment on reducing the fraction of colonic epithelial cells expressing mutant p53 protein detected via immunohistochemical staining in biopsy samples of colorectal mucosa obtained during colonoscopies done before and after atorvastatin intervention and compared to placebo control.
SECONDARY OBJECTIVES:
I. Examination of the effect of atorvastatin on the levels of biomarkers including Ki-67 (cell proliferation), Waf1p21 (wild type p53 allele reactivated signal), and cleaved caspase-3 (wild type p53-induced cell apoptosis) using immunohistochemistry (IHC) approach for colorectal biopsy specimens.
II. Examination of the effect of atorvastatin on the severity of histologic inflammation in colorectal biopsies using the Geboes grading system.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants must have ulcerative colitis with > 8 years history and clinical remission (including the clinical remission for an extraintestinal manifestation/complication) confirmed by yearly surveillance endoscopy examination (Mayo grading < 3)
- •They must be stable on maintenance therapy with mesalamine, thiopurines or biologics for over 3 months (Ulcerative Colitis Disease Activity Index [UCDAI] =< 1)
- •A history of segmental colon resection is allowed
- •UC in clinical remission, but with dysplasia-associated lesion or mass (DALM) at entry endoscope examination and DALM was completely resected by endoscopic mucosa resection, is allowed
- •Participants 18-70 years old (both men and women). This is the standard age range for routine ulcerative colitis surveillance in adults
- •Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
- •White blood cell count within normal institutional limits or absolute neutrophil count >= 1,500/uL
- •Platelets >= 100,000/uL
- •Total bilirubin within normal institutional limits, unless known to have Gilberts syndrome
- •Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (SGPT) =< 1.5 X institutional upper limit of normal (ULN)
- •Creatinine =< 1.5 X institutional ULN
- •Plasma level of cholesterol < 240 mg/dl or LDL-C < 190 mg/dl (since cholesterol > 240 mg/dl and LDL-C > 190 mg/dl need high dose (40 - 80 mg) atorvastatin per day to control hypercholesterolemia)
- •For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
- •Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
- •Participants on chronic suppressive antiviral therapy for herpes simplex virus (HSV) are eligible
- •Atorvastatin is contraindicated in pregnancy since it affects cholesterol synthesis pathway. For this reason, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) from the time of baseline pregnancy test, throughout the duration of the study, and for 1 month following cessation of study drug. Females must begin adequate contraception immediately following screening pregnancy test. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately. If she is pregnant, she will be immediately withdrawn from the study and followed until the birth of the child
- •Ability to understand and the willingness to sign a written informed consent document
排除标准
- •Ulcerative proctitis (since patients with ulcerative proctitis have a significantly lower risk of developing colorectal cancer [CRC] than those with pancolitis or localized UC in left colon)
- •Participants with medical conditions that, in the opinion of the investigator, would preclude the treatment intervention and colonoscopy, or limit ability to comply with therapy
- •Participants with pancolitis or localized UC with total Mayo score >= 3 including Mayo endoscopic sub-score < 3 are excluded
- •Use of corticosteroid therapy in the past 3 months due to high potential of relapse of active disease
- •Use of statins in the last 12 months
- •Use of any investigational drugs within the past 3 months
- •A history of high-grade dysplasia or CRC or pan/severe colitis with total proctocolectomy
- •History of chemotherapy within 2 years of screening
- •History of allergic reactions attributed to atorvastatin
- •Concomitant primary sclerosing cholangitis (PSC) with stage 4 liver fibrosis (biliary cirrhosis) and severe liver functional alteration
- •Uncontrolled intercurrent illness or psychiatric illness/social situations that would limit compliance with study requirements
- •Pregnant or breastfeeding participants are excluded
- •Human immunodeficiency virus (HIV)-positive participants are excluded due to anti-retroviral therapy that affect atorvastatin effect
- •Children are excluded from this study since disease duration is usually < 8 years and there is no data about p53 mutation in this patient population
- •Current use of cyclosporine, fibrates (e.g., gemfibrozil, fenofibrate), 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)
研究组 & 干预措施
Arm I (atorvastatin, biospecimen collection)
Patients receive atorvastatin PO QD for 12 months. Patients also undergo colonoscopy with biopsy, and collection of blood on the trial.
干预措施: Atorvastatin Calcium (Drug)
Arm I (atorvastatin, biospecimen collection)
Patients receive atorvastatin PO QD for 12 months. Patients also undergo colonoscopy with biopsy, and collection of blood on the trial.
干预措施: Biopsy of Colon (Procedure)
Arm I (atorvastatin, biospecimen collection)
Patients receive atorvastatin PO QD for 12 months. Patients also undergo colonoscopy with biopsy, and collection of blood on the trial.
干预措施: Biospecimen Collection (Procedure)
Arm I (atorvastatin, biospecimen collection)
Patients receive atorvastatin PO QD for 12 months. Patients also undergo colonoscopy with biopsy, and collection of blood on the trial.
干预措施: Questionnaire Administration (Other)
Arm II (placebo, biospecimen collection)
Patients receive placebo PO QD for 12 months. Patients also undergo colonoscopy with biopsy, and collection of blood on the trial.
干预措施: Biopsy of Colon (Procedure)
Arm II (placebo, biospecimen collection)
Patients receive placebo PO QD for 12 months. Patients also undergo colonoscopy with biopsy, and collection of blood on the trial.
干预措施: Biospecimen Collection (Procedure)
Arm II (placebo, biospecimen collection)
Patients receive placebo PO QD for 12 months. Patients also undergo colonoscopy with biopsy, and collection of blood on the trial.
干预措施: Placebo Administration (Drug)
Arm II (placebo, biospecimen collection)
Patients receive placebo PO QD for 12 months. Patients also undergo colonoscopy with biopsy, and collection of blood on the trial.
干预措施: Questionnaire Administration (Other)
结局指标
主要结局
Reduction in mutant p53 staining in biopsy samples obtained during colonoscopies done before and after intervention
时间窗: Up to 2 years
Counted as p53 positive cells/100 epithelial cells under at least 5 high powered fields per slide or 100 crypts or 2000 cells/slide per biopsy, measured by immunohistochemistry (IHC) staining. The level of biomarker expression will be determined by chromogenic staining. Because multiple samples will be obtained per participant, participant-level %p53 mutation will be summarized as the average %p53 across these samples. Descriptive statistics will be used to summarize changes in each arm, as well as the difference in change between arms. Analysis will be conducted using a two-sample t-test comparing within-subject changes in average percentage (%) p53 between treatment arms. A more comprehensive analysis will be done using a linear mixed effects model, where the outcome variable will be %p53 staining in each sample evaluated at baseline and post-treatment.
次要结局
- Levels of biomarkers of Ki-67 (cell proliferation), Waf1p21 (wild type p53 allele reactivated signal), and cleaved caspase-3 (wild type p53-induced cell apoptosis)(Up to 2 years)
- Histological analysis for grading the severity of histologic inflammation in colorectal biopsies(Up to 2 years)
- Plasma concentration of cholesterol, high density lipoprotein (HDL) and low density lipoprotein (LDL)(Up to 2 years)
- Clinical efficacy on UC related symptoms(Up to 2 years)