Atorvastatin ± Aspirin in Lynch Syndrome Syndrome

Impact of Atorvastatin ± Aspirin on Colorectal Biomarkers in Patients With Lynch Syndrome: a Pilot Study

The goal of this study is to investigate that a common cholesterol lowering agent (atorvastatin) alone or combining with a nonsteroidal anti-inflammatory drug (aspirin) would reduce the risk of colorectal cancer (CRC) in high-risk individuals with Lynch syndrome.

Study Overview

• Status: Recruiting
• Conditions: Lynch Syndrome
• Intervention / Treatment: Drug: Atorvastatin 20mg; Drug: Atorvastatin 20mg AND Aspirin 325 mg

Detailed Description

This is an exploratory biomarker trial to assess the ability of atorvastatin (common cholesterol lowering agent) alone or combining with aspirin (a nonsteroidal anti-inflammatory drug) to reduce the risk of colorectal cancer in high-risk individuals with Lynch Syndrome. Subjects will be stratified based on their prior history of polyps/cancer to receive atorvastatin without or with aspirin for 6 weeks. Blood and normal colon biopsies will be obtained at Day 0 and at 6 weeks on study. Tissue endpoints for analysis include cell proliferation, apoptosis and changes in gene expression. Circulating lipid profiles and metabolic function, and post-treatment questionnaires will be used to assess the acceptability of the study.

• Study Type: Interventional
• Enrollment (Anticipated): 46
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Yana Chertock, MA; Phone Number: 215-214-3216; Email: yana.chertock@fccc.edu

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • Recruiting
      • Fox Chase Cancer Center
      • Contact: Yana Chertock, MA; Phone Number: 215-214-3216; Email: yana.chertock@fccc.edu
      • Contact: Michael Hall, MD, MS; Phone Number: 215-728-2791; Email: michael.hall@fccc.edu
      • Principal Investigator: Michael J Hall, MD, MS
      • Sub-Investigator: Margie L Clapper, PhD
      • Sub-Investigator: Minhhuyen T Nguyen, MD,AGAF,FACP
      • Sub-Investigator: Harry S Cooper, MD
      • Sub-Investigator: Wen-Chi L Chang, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subjects who are 18 years of age or older
• Able to read and sign an informed consent document in English
• Eligible subjects will have molecular evidence of Lynch Syndrome (mutation in MLH1, MSH2, MSH6, EPCAM or PMS2)
• History of colorectal cancer if surgically cured and > 1 year from completion of adjuvant chemotherapy

Exclusion Criteria:

• Are <18 years of age
• Unable to read and sign an informed consent document in English
• Have active cancer or are less than 3 years post hormonal maintenance therapy for cancer
• Have statin intolerance or contraindication for aspirin or atorvastatin use
• Are pregnant or are actively breast feeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Atorvastatin; Atorvastatin (LIPITOR) 20 milligram tablet daily for 6 weeks	Drug: Atorvastatin 20mg; No history of colorectal cancer and no colorectal adenomas within 5 years.; Other Names: Lipitor 20mg
Active Comparator: Atorvastatin and Aspirin; Atorvastatin (LIPITOR) 20 milligram tablet and Aspirin 325 mg tablet daily for 6 weeks	Drug: Atorvastatin 20mg AND Aspirin 325 mg; History of colorectal cancer and/or history of colorectal adenomas within 5 years.; Other Names: Lipitor 20mg AND Aspirin 325mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proliferation (Ki-67) and apoptosis (active caspase 3) by immunohistochemical staining	Effect of Atorvastatin or/and Aspirin on normal colonic proliferation and apoptosis will be evaluated by comparing of immunohistochemical staining of Ki-67 and active caspase 3 using formalin-fixed paraffin-embedded biopsies collected before and at the 6 weeks of drug treatments. Number of positive cells and total number of evaluated cells will be collected for both assays. Data of cells with positive Ki-67 or active caspase 3 will be expressed as % of positive cells (# positive cells/#total evaluated cells x 100). Statistical analyses will be performed to compare the difference between baseline and 6-weeks data.	Changes from baseline to 6 weeks
Genome-wide expression analyses using RNA-Seq	Effect of Atorvastatin or/and Aspirin on gene expressions in normal colonic epithelial cells will be analyzed using RNA-Seq. Total RNA will be extracted from frozen biopsies. RNASeq libraries will be generated and sequenced on an Illumina platform and analyzed. Differential expression between samples at baseline and 6-weeks of drug treatment will be assessed for statistical significance. Genes with false discovery rat ≤ 0.05 and a fold-change ≥ 2 will be considered significant.	Changes from baseline to 6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of adherence of healthy patients with Lynch Syndrome to a 6-week of the treatment regimen (atorvastatin ± aspirin).	Medication Adherence to the 6-week course of Atorvastatin or/and Aspirin preventive therapy will be assessed by one question in the follow -up survey which participants complete at the end of the study :"Over 6 weeks of preventive therapy, how many Atorvastatin/Aspirin pills did you forget to take?" In addition, participants will be asked to return medication bottle(s) with or without pills. RA will count pills and record number of missing pills in the system.	6 weeks
Frequency of adverse events among patients administered atorvastatin ± aspirin for 6 weeks	The adverse event assessment form is used to collect initial and follow-up information for non-serious and serious adverse events for patients participating in the study. Participants are contacted by RA every two weeks to assess side effects and toxicity. A grading scale from 1 to 5 (1-mild, 2-moderate, 3-severy, 4-life-threatining, 5- death related to AE) and causality (1-unrelated, 2-unlikly, 3-possible, 4-probable, 5-definite, NA- not assessed) are recorded for each adverse event (AE) term. Each AE is reviewed by principal investigator and entered into patient's electronic medical record (EMR)	6 weeks
Acceptability of the pilot study intervention and the willingness of the subject to participate in a similar larger study.	Acceptability of the study approach 6 Likert-type items (7 point scale) will assess participants' perceptions of various aspects of the study design as a measure of whether changes need to be made to the study methods or design prior to a larger multi-institutional trial. Participants' scores will be summed and a mean score generated. Mean scores > 4 will be considered in the acceptable range. Our threshold target is 75% of participants with a mean score in the acceptable range.	6 weeks

Collaborators and Investigators

• Sponsor: Fox Chase Cancer Center
• Investigators: Principal Investigator: Michael J Hall, MD, MS, Fox Chase Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): September 10, 2018
• Primary Completion (Anticipated): September 1, 2022
• Study Completion (Anticipated): September 10, 2023

Study Registration Dates

• First Submitted: January 3, 2020
• First Submitted That Met QC Criteria: May 6, 2020
• First Posted (Actual): May 8, 2020

Study Record Updates

• Last Update Posted (Actual): April 7, 2022
• Last Update Submitted That Met QC Criteria: April 6, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: HNPCC; MLH1; MSH2; MSH6; PMS2; EPCAM; LYNCH
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Metabolic Diseases; Neoplasms; Neoplasms by Site; Disease; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Genetic Diseases, Inborn; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Colorectal Neoplasms; Neoplastic Syndromes, Hereditary; DNA Repair-Deficiency Disorders; Syndrome; Colorectal Neoplasms, Hereditary Nonpolyposis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Aspirin; Atorvastatin
• Other Study ID Numbers: 18-1039

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Individual participant data that underline the results reported in the article , after de-identification
• IPD Sharing Time Frame: beginning 9 months and ending 3 years following article publication
• IPD Sharing Access Criteria: Investigators whose proposed use of data has been approved by a review committee identified for this purpose.Proposals should be directed to Michael.Hall@fccc.edu. To gain access, data requestors will need to sign a data access agreement.

Drug and device information, study documents

• 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