Testing Atorvastatin to Lower Colon Cancer Risk in Longstanding Ulcerative Colitis

• ClinicalTrials.gov Identifier: NCT04767984
• Recruitment Status: Recruiting
• First Posted: February 24, 2021
• Last Update Posted: February 11, 2022
• Sponsor: National Cancer Institute (NCI)
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Colorectal Carcinoma; Ulcerative Colitis	Drug: Atorvastatin Calcium; Procedure: Biospecimen Collection; Drug: Placebo Administration	Phase 2

Detailed Description:

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 spectrum, hotspot and load of TP53 gene mutations using next generation sequencing and droplet digital polymerase chain reaction (PCR).

III. Examination of the effect of atorvastatin on the severity of histologic inflammation in colorectal biopsies using the Geboes grading system.

IV. 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.

V. 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).

VI. 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.

ARM II: Patients receive placebo PO QD for 12 months.

In both arms, patients also undergo collection of blood samples at each study visit to analyze the inflammation from the blood.

After completion of study treatment, patients are followed up at 2 weeks.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 70 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: 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
• Actual Study Start Date: September 24, 2021
• Estimated Primary Completion Date: March 31, 2024
• Estimated Study Completion Date: March 31, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm I (atorvastatin, biospecimen collection); Patients receive atorvastatin PO QD for 12 months.	Drug: Atorvastatin Calcium; Given PO; Other Names: ATORVASTATIN CALCIUM TRIHYDRATE; CI-981; Lipitor; Procedure: Biospecimen Collection; Undergo collection of blood samples; Other Names: Biological Sample Collection; Biospecimen Collected
Placebo Comparator: Arm II (placebo, biospecimen collection); Patients receive placebo PO QD for 12 months.	Procedure: Biospecimen Collection; Undergo collection of blood samples; Other Names: Biological Sample Collection; Biospecimen Collected; Drug: Placebo Administration; Given PO

Outcome Measures

Primary Outcome Measures :

1. Reduction in mutant p53 staining in biopsy samples obtained during colonoscopies done before and after intervention [ Time Frame: 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.

Secondary Outcome Measures :

1. 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) [ Time Frame: Up to 2 years ]
   Using IHC approach for colorectal biopsy specimens.
2. Analysis of spectrum, hotspot and load of TP53 gene mutations [ Time Frame: Up to 2 years ]
   Using next generation sequencing and droplet digital polymerase chain reaction (PCR) technologies. The spectrum of TP53 mutations will be analyzed for frequency of each hotspot mutation in each group. For analyzing binary variables (presence or absence of each hot spot mutation), a Pearson's chi-squared test will be used. Frequency of each hotspot mutation for each noted group will be provided as descriptive measures of location and variance. The load of TP53 mutations in the biopsy specimens will be quantified as the ratio of mutant allele to wild-type allele using droplet digital PCR and allele-specific primers. Descriptive statistics will be used to summarize these at each time point for each treatment arm. Changes in TP53 mutation load, a continuous biomarker, will be compared between treatment arms using similar approaches as the primary analysis of %TP53 described above.
3. Histological analysis for grading the severity of histologic inflammation in colorectal biopsies [ Time Frame: Up to 2 years ]
   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.
4. Plasma concentration of cholesterol, high density lipoprotein (HDL) and low density lipoprotein (LDL) [ Time Frame: Up to 2 years ]
   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).
5. Clinical efficacy on UC related symptoms [ Time Frame: Up to 2 years ]
   Using the Ulcerative Colitis Disease Activity Index (activity score: 0 - 4) (i.e. the Mayo score).
6. Banking of colorectal specimens [ Time Frame: Up to 2 years ]
   To bank the colorectal biopsies, blood, ribonucleic acid, and germline deoxyribonucleic acid for future pooled analyses of inflammatory biomarkers, prenylated proteins and gene expression profile, statistical analysis will be used as needed.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• 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 0 or 1)
• 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 =< 1 (Karnofsky >= 70%)
• 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
• International normalized ratio (INR) =< 1.5
• 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)
• 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

Exclusion Criteria:

• 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)
• Subjects with medical conditions that, in the opinion of the investigator, would preclude the treatment intervention and colonoscopy, or limit ability to comply with therapy
• Subjects with pancolitis or localized UC with Mayo grading >= 2 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 and severe liver functional alteration
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant or lactating subjects are excluded
• Human immunodeficiency virus (HIV)-positive subjects 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)

Contacts and Locations

Locations

United States, Illinois

Northwestern University; Recruiting

Chicago, Illinois, United States, 60611

Contact: Guang-Yu Yang 312-503-0645 g-yang@northwestern.edu

Principal Investigator: Guang-Yu Yang

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Seema A Khan; Northwestern University

More Information

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT04767984
• Other Study ID Numbers: NCI-2021-01261; NCI-2021-01261 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); NCI20-02-02 ( Other Identifier: Northwestern University ); NWU20-02-02 ( Other Identifier: DCP ); P30CA060553 ( U.S. NIH Grant/Contract ); UG1CA242643 ( U.S. NIH Grant/Contract )
• First Posted: February 24, 2021
• Last Update Posted: February 11, 2022
• Last Verified: October 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
• URL: https://grants.nih.gov/policy/sharing.htm

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Colorectal Neoplasms; Colitis; Colitis, Ulcerative; Ulcer; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Colonic Diseases; Intestinal Diseases; Pathologic Processes; Inflammatory Bowel Diseases; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Rectal Diseases; Calcium, Dietary; Atorvastatin; Calcium; Calcium-Regulating Hormones and Agents; Physiological Effects of Drugs; Bone Density Conservation Agents; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Enzyme Inhibitors