Atorvastatin ± Aspirin in Lynch Syndrome Syndrome

• ClinicalTrials.gov Identifier: NCT04379999
• Recruitment Status: Recruiting
• First Posted: May 8, 2020
• Last Update Posted: April 5, 2021
• Sponsor: Fox Chase Cancer Center
• Information provided by (Responsible Party): Fox Chase Cancer Center

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Lynch Syndrome	Drug: Atorvastatin 20mg; Drug: Atorvastatin 20mg AND Aspirin 325 mg	Early Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 46 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: One group receives atorvastatin 20 mg, and the other group receives atorvastatin 20 mg+ aspirin 325mg
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Impact of Atorvastatin ± Aspirin on Colorectal Biomarkers in Patients With Lynch Syndrome: a Pilot Study
• Actual Study Start Date: September 10, 2018
• Estimated Primary Completion Date: September 1, 2022
• Estimated Study Completion Date: September 10, 2023

Arms and Interventions

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 Name: 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 Name: Lipitor 20mg AND Aspirin 325mg

Outcome Measures

Primary Outcome Measures :

1. Proliferation (Ki-67) and apoptosis (active caspase 3) by immunohistochemical staining [ Time Frame: Changes from baseline to 6 weeks ]
   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.
2. Genome-wide expression analyses using RNA-Seq [ Time Frame: Changes from baseline to 6 weeks ]
   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.

Secondary Outcome Measures :

1. Rate of adherence of healthy patients with Lynch Syndrome to a 6-week of the treatment regimen (atorvastatin ± aspirin). [ Time Frame: 6 weeks ]
   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.
2. Frequency of adverse events among patients administered atorvastatin ± aspirin for 6 weeks [ Time Frame: 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)
3. Acceptability of the pilot study intervention and the willingness of the subject to participate in a similar larger study. [ Time Frame: 6 weeks ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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

Contacts and Locations

Contacts

Contact: Yana Chertock, MA; 215-214-3216; yana.chertock@fccc.edu

Locations

United States, Pennsylvania

Fox Chase Cancer Center; Recruiting

Philadelphia, Pennsylvania, United States, 19111

Contact: Yana Chertock, MA 215-214-3216 yana.chertock@fccc.edu

Contact: Michael Hall, MD, MS 215-728-2791 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

Sponsors and Collaborators

Fox Chase Cancer Center

Investigators

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

More Information

• Responsible Party: Fox Chase Cancer Center
• ClinicalTrials.gov Identifier: NCT04379999
• Other Study ID Numbers: 18-1039
• First Posted: May 8, 2020
• Last Update Posted: April 5, 2021
• Last Verified: April 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Individual participant data that underline the results reported in the article , after de-identification
• Time Frame: beginning 9 months and ending 3 years following article publication
• 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.

• 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

Keywords provided by Fox Chase Cancer Center:

HNPCC; MLH1; MSH2; MSH6; PMS2; EPCAM; LYNCH

Additional relevant MeSH terms:

Syndrome; Neoplastic Syndromes, Hereditary; Colorectal Neoplasms, Hereditary Nonpolyposis; Disease; Pathologic Processes; Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Genetic Diseases, Inborn; DNA Repair-Deficiency Disorders; Metabolic Diseases; Aspirin; Atorvastatin; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents