Linaclotide in Treating Patients With Stages 0-3 Colorectal Cancer
Primary Purpose
Colorectal Adenoma, Stage 0 Colorectal Cancer AJCC v8, Stage I Colorectal Cancer AJCC v8
Status
Active
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Linaclotide
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Colorectal Adenoma
Eligibility Criteria
Inclusion Criteria:
- History of 1 or more sporadic colorectal adenoma on previous endoscopy (adenoma cohort) or stage 0-3 biopsy proven colorectal cancer (CRC) (colorectal cancer cohort) who are scheduled for a surgical procedure
- Ability to understand and willingness to sign a written informed consent document and follow study procedures
- Ability to swallow capsules without difficulty
- Ability to maintain pill diaries
- Willingness to employ adequate contraception for men and women of childbearing potential for the duration of the study. Acceptable methods include double barrier methods, intrauterine device (IUD), postmenopausal status, and/or documentation of surgical sterilization
- Participants must have no chronic, clinically severe health issues which, in the opinion of their physician or the research team, could preclude trial activities including the one week drug exposure phase
Exclusion Criteria:
- History of gastroparesis
- History of celiac disease
- Inflammatory bowel disease (Crohn's disease, ulcerative colitis)
- Microscopic colitis, including collagenous colitis
- Has taken linaclotide within 30 days prior to consent
- Any malignancy except colorectal cancer or any active radiotherapy or cytotoxic chemotherapy within the last 6 months of baseline. Participants with a history of basal cell or squamous cell skin cancer may be enrolled at the discretion of the investigator
- Participants may not be receiving any other investigational agents, or be active participants in any clinical trials. If participants previously participated in a clinical trial, a 30 day washout period for the investigational drug is needed before the participant can be considered for this study
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to linaclotide
- Uncontrolled current 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 women
- History of bleeding/coagulation problems. Concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin is acceptable
- Any medical condition judged by the investigator to constitute a risk to safe participation
- At risk for obstructing or near-obstructing mechanical gastrointestinal obstruction
- Chronic use of anti-coagulants or non-NSAID anti-platelet agents will serve as an exclusion only when such medications cannot be safely discontinued before study related endoscopy or surgery
Sites / Locations
- Fox Chase Cancer Center
- Sidney Kimmel Cancer Center at Thomas Jefferson University
- VA Puget Sound Health Care Sysem
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Arm I (linaclotide)
Arm II (placebo)
Arm Description
Patients receive linaclotide PO daily on days 1-7 and undergo standard of care colonoscopy or surgery on day 7.
Patients receive placebo PO QD on days 1-7 and undergo standard of care colonoscopy or surgery on day 7.
Outcomes
Primary Outcome Measures
Pharmacodynamics effect on cGMP levels
Will compare cGMP levels in adenomas between study arms using a two-sample t-test (alpha=.05; two-sided) or Wilcoxon rank sum test.
Secondary Outcome Measures
Incidence of adverse events (AEs)
All participants will be evaluated for toxicity. Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be used to summarize adverse events associated with linaclotide.
Ki-67 expression
Wilcoxon rank sum test will be used to compare Ki-67 expression in adenomas across arms.
GUCY2C expression
Wilcoxon rank sum and Fisher's exact tests will be used to compare GUCY2C expression between study arms.
Guanylin levels
Wilcoxon rank sum and Fisher's exact tests will be used to compare guanylin levels between study arms.
Full Information
NCT ID
NCT03796884
First Posted
January 7, 2019
Last Updated
March 20, 2023
Sponsor
Sidney Kimmel Cancer Center at Thomas Jefferson University
Collaborators
United States Department of Defense
1. Study Identification
Unique Protocol Identification Number
NCT03796884
Brief Title
Linaclotide in Treating Patients With Stages 0-3 Colorectal Cancer
Official Title
Phase II Randomized, Placebo-Controlled Trial of Linaclotide to Demonstrate Bioactivity in Patients With Sporadic Colorectal Adenomas and With Colorectal Cancer
Study Type
Interventional
2. Study Status
Record Verification Date
March 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
October 30, 2019 (Actual)
Primary Completion Date
October 2023 (Anticipated)
Study Completion Date
October 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Sidney Kimmel Cancer Center at Thomas Jefferson University
Collaborators
United States Department of Defense
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This phase II trial studies the how well linaclotide works in treating patients with stages 0-3 colorectal cancer. Linaclotide is a very small protein that binds to receptors on intestinal cells and makes them secrete water and salt.
Detailed Description
PRIMARY OBJECTIVES:
I. To determine whether, compared to placebo, linaclotide administered as a single oral daily dose x 7 days, induces a pharmacodynamics (PD) effect on cGMP levels, based on biopsy samples of adenomas or resected colorectal adenocarcinomas.
SECONDARY OBJECTIVES:
I. To compare Ki-67, guanylin levels and GUCY2C expression in adenomas and cancers versus normal tissue after exposure to linaclotide or placebo.
II. To confirm the safety and tolerability of linaclotide in sporadic adenoma and cancer patients.
TRANSLATIONAL OBJECTIVE:
I. To assess the pharmacodynamic effect of linaclotide on pathway-specific biomarkers relevant to GUCY2C signaling (i.e. VASP phosphorylation), markers of mutant APC-beta-catenin signaling (beta-catenin levels, beta-catenin nuclear localization, axin levels, c-Myc levels, guanylin levels, PCNA expression), based on adenoma/cancer and normal mucosa biopsy samples obtained by endoscopy following linaclotide or placebo exposure.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive linaclotide orally (PO) daily on days 1-7 and undergo standard of care colonoscopy or surgery on day 7.
ARM II. Patients receive placebo PO QD on days 1-7 and undergo standard of care colonoscopy or surgery on day 7.
After completion of study treatment, patients are followed up at day 14.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Colorectal Adenoma, Stage 0 Colorectal Cancer AJCC v8, Stage I Colorectal Cancer AJCC v8, Stage II Colorectal Cancer AJCC v8, Stage IIA Colorectal Cancer AJCC v8, Stage IIB Colorectal Cancer AJCC v8, Stage IIC Colorectal Cancer AJCC v8, Stage III Colorectal Cancer AJCC v8, Stage IIIA Colorectal Cancer AJCC v8, Stage IIIB Colorectal Cancer AJCC v8, Stage IIIC Colorectal Cancer AJCC v8
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
230 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Arm I (linaclotide)
Arm Type
Experimental
Arm Description
Patients receive linaclotide PO daily on days 1-7 and undergo standard of care colonoscopy or surgery on day 7.
Arm Title
Arm II (placebo)
Arm Type
Placebo Comparator
Arm Description
Patients receive placebo PO QD on days 1-7 and undergo standard of care colonoscopy or surgery on day 7.
Intervention Type
Drug
Intervention Name(s)
Linaclotide
Other Intervention Name(s)
851199-59-2, Linzess, [9-L-tyrosine]heat-stable enterotoxin (Escherichia coli)-(6-19)-peptide, L-Tyrosine, L-cysteinyl-L-cysteinyl-L-alpha-glutamyl-L-tyrosyl-L-cysteinyl-L-cysteinyl-L- asparaginyl-L-prolyl-L-alanyl-L-cysteinyl-L-threonylglycyl-L-cysteiny, cyclic (1->6), (2->10), (5->13)-tris(disulfide), MD-1100
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Given PO
Primary Outcome Measure Information:
Title
Pharmacodynamics effect on cGMP levels
Description
Will compare cGMP levels in adenomas between study arms using a two-sample t-test (alpha=.05; two-sided) or Wilcoxon rank sum test.
Time Frame
Up to 2 years
Secondary Outcome Measure Information:
Title
Incidence of adverse events (AEs)
Description
All participants will be evaluated for toxicity. Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be used to summarize adverse events associated with linaclotide.
Time Frame
From the time of first dose of linaclotide or placebo until resolution, if related to linaclotide, or through 30 days after occurrence
Title
Ki-67 expression
Description
Wilcoxon rank sum test will be used to compare Ki-67 expression in adenomas across arms.
Time Frame
Up to 2 years
Title
GUCY2C expression
Description
Wilcoxon rank sum and Fisher's exact tests will be used to compare GUCY2C expression between study arms.
Time Frame
Up to 2 years
Title
Guanylin levels
Description
Wilcoxon rank sum and Fisher's exact tests will be used to compare guanylin levels between study arms.
Time Frame
Up to 2 years
Other Pre-specified Outcome Measures:
Title
VASP serine 239 phosphorylation
Description
Assessed by immunoblot analysis. Wilcoxon rank sum and Fisher's exact tests will be used to compare VASP phosphorylation between study arms.
Time Frame
Up to 2 years
Title
Beta-catenin levels
Description
Assessed by immunoblot analysis. Wilcoxon rank sum and Fisher's exact tests will be used to compare beta-catenin accumulation and downstream signaling between study arms.
Time Frame
Up to 2 years
Title
Beta-catenin nuclear localization
Description
Assessed by immunofluorescence. Wilcoxon rank sum and Fisher's exact tests will be used to compare beta-catenin accumulation and downstream signaling between study arms
Time Frame
Up to 2 years
Title
Axin and c-Myc messenger ribonucleic acid (mRNA) levels
Description
Assessed by quantitative reverse transcriptase-polymerase chain reaction. Wilcoxon rank sum and Fisher's exact tests will be used to compare axin and c-Myc mRNA levels between study arms.
Time Frame
Up to 2 years
Title
PCNA expression
Description
Assessed by immunofluorescence.
Time Frame
Up to 2 years
10. Eligibility
Sex
Female
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
History of 1 or more sporadic colorectal adenoma on previous endoscopy (adenoma cohort) or stage 0-3 biopsy proven colorectal cancer (CRC) (colorectal cancer cohort) who are scheduled for a surgical procedure
Ability to understand and willingness to sign a written informed consent document and follow study procedures
Ability to swallow capsules without difficulty
Ability to maintain pill diaries
Willingness to employ adequate contraception for men and women of childbearing potential for the duration of the study. Acceptable methods include double barrier methods, intrauterine device (IUD), postmenopausal status, and/or documentation of surgical sterilization
Participants must have no chronic, clinically severe health issues which, in the opinion of their physician or the research team, could preclude trial activities including the one week drug exposure phase
Exclusion Criteria:
History of gastroparesis
History of celiac disease
Inflammatory bowel disease (Crohn's disease, ulcerative colitis)
Microscopic colitis, including collagenous colitis
Has taken linaclotide within 30 days prior to consent
Any malignancy except colorectal cancer or any active radiotherapy or cytotoxic chemotherapy within the last 6 months of baseline. Participants with a history of basal cell or squamous cell skin cancer may be enrolled at the discretion of the investigator
Participants may not be receiving any other investigational agents, or be active participants in any clinical trials. If participants previously participated in a clinical trial, a 30 day washout period for the investigational drug is needed before the participant can be considered for this study
History of allergic reactions attributed to compounds of similar chemical or biologic composition to linaclotide
Uncontrolled current 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 women
History of bleeding/coagulation problems. Concurrent use of nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin is acceptable
Any medical condition judged by the investigator to constitute a risk to safe participation
At risk for obstructing or near-obstructing mechanical gastrointestinal obstruction
Chronic use of anti-coagulants or non-NSAID anti-platelet agents will serve as an exclusion only when such medications cannot be safely discontinued before study related endoscopy or surgery
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Scott Waldman, MD
Organizational Affiliation
Sidney Kimmel Cancer Center at Thomas Jefferson University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Fox Chase Cancer Center
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19111
Country
United States
Facility Name
Sidney Kimmel Cancer Center at Thomas Jefferson University
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19126
Country
United States
Facility Name
VA Puget Sound Health Care Sysem
City
Seattle
State/Province
Washington
ZIP/Postal Code
98108
Country
United States
12. IPD Sharing Statement
Links:
URL
http://hospitals.jefferson.edu/
Description
Thomas Jefferson University Hospital
Learn more about this trial
Linaclotide in Treating Patients With Stages 0-3 Colorectal Cancer
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