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.
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. III. Examination of the effect of atorvastatin on the plasma concentration of cholesterol, high density lipoprotein (HDL) and low density lipoprotein (LDL) for monitoring atorvastatin effect on lowering cholesterol and its correlation with the levels of biomarkers in the colorectal biopsies. IV. Examination of the effect of atorvastatin on the clinical efficacy on ulcerative colitis (UC) related symptoms using the Ulcerative Colitis Disease Activity Index (i.e. the Mayo score). EXPLORATORY OBJECTIVES I. Examination of the effect of atorvastatin on the spectrum, hotspot and load of TP53 gene mutations using next generation sequencing and droplet digital polymerase chain reaction (PCR). II. Will bank colorectal biopsies and blood samples and ribonucleic acid (RNA) and germline deoxyribonucleic acid (DNA) for future analyses, particularly on proteomics/prenylated protein profile, cytokine/chemokine profile, inflammatory lipid-mediator profile, RNA sequencing (RNAseq) and Chaperon/Co-chaperon proteins, etc. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients receive atorvastatin orally (PO) once daily (QD) for 12 months. Patients also undergo colonoscopy with biopsy, and collection of blood on the trial. ARM II: Patients receive placebo PO QD for 12 months. Patients also undergo colonoscopy with biopsy, and collection of blood on the trial. After completion of study treatment, patients are followed up at 2 weeks.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
QUADRUPLE
Enrollment
42
Given PO
Undergo colonoscopy with biopsy
Undergo collection of blood samples
Given PO
Ancillary studies
Northwestern University
Chicago, Illinois, United States
University of Chicago Comprehensive Cancer Center
Chicago, Illinois, United States
University of Kansas Cancer Center
Kansas City, Kansas, United States
Reduction in mutant p53 staining in biopsy samples obtained during colonoscopies done before and after intervention
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.
Time frame: Up to 2 years
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)
Using IHC approach for colorectal biopsy specimens.
Time frame: Up to 2 years
Histological analysis for grading the severity of histologic inflammation in colorectal biopsies
Using the Geboes grading system (grading score: 0 - 4). Highest grade histology and extent of UC (pancolitis vs localized UC) across multiple samples will be used at each time point. Changes in scores from baseline to post-treatment will be calculated, and compared between arms using the Wilcoxon rank sum test.
Time frame: Up to 2 years
Plasma concentration of cholesterol, high density lipoprotein (HDL) and low density lipoprotein (LDL)
Will monitor atorvastatin effect on lowering cholesterol and its correlation with the levels of biomarkers in the colorectal biopsies. Changes in plasma concentration of cholesterol, HDL and LDL (for monitoring atorvastatin effect on lowering cholesterol) will be compared between treatment arms using similar approaches as the primary analysis of %TP53 described above. The association of plasma concentration of cholesterol, HDL and LDL with the levels of biomarkers in the colorectal biopsies will be analyzed using linear mixed models as described above with plasma level added to the model as a fixed effect. Separate models will be fitted for each type of cholesterol (total, HDL and LDL).
Time frame: Up to 2 years
Clinical efficacy on UC related symptoms
Using the Ulcerative Colitis Disease Activity Index (activity score: 0 - 4) (i.e. the Mayo score).
Time frame: Up to 2 years
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