Linaclotide in Treating Patients With Stages 0-3 Colorectal Cancer

Colorectal Adenoma Clinical Trial

Official title:

Phase II Randomized, Placebo-Controlled Trial of Linaclotide to Demonstrate Bioactivity in Patients With Sporadic Colorectal Adenomas and With Colorectal Cancer

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03796884
• Other study ID #: 18F.524
• Secondary ID: CDMRP-CA170223
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: October 30, 2019
• Est. completion date: June 30, 2025

Study information

• Verified date: May 2024
• Source: Thomas Jefferson University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 230
• Est. completion date: June 30, 2025
• Est. primary completion date: June 30, 2025
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Adenoma
• Colorectal Adenoma
• Colorectal Neoplasms
• 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

Intervention

Drug:
• Linaclotide
Given PO

Other:
• Placebo
Given PO

Locations

Country	Name	City	State
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	Sidney Kimmel Cancer Center at Thomas Jefferson University	Philadelphia	Pennsylvania
United States	VA Puget Sound Health Care Sysem	Seattle	Washington

Sponsors (2)

Lead Sponsor	Collaborator
Sidney Kimmel Cancer Center at Thomas Jefferson University	United States Department of Defense

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	VASP serine 239 phosphorylation	Assessed by immunoblot analysis. Wilcoxon rank sum and Fisher's exact tests will be used to compare VASP phosphorylation between study arms.	Up to 2 years
Other	Beta-catenin levels	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.	Up to 2 years
Other	Beta-catenin nuclear localization	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	Up to 2 years
Other	Axin and c-Myc messenger ribonucleic acid (mRNA) levels	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.	Up to 2 years
Other	PCNA expression	Assessed by immunofluorescence.	Up to 2 years
Primary	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.	Up to 2 years
Secondary	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.	From the time of first dose of linaclotide or placebo until resolution, if related to linaclotide, or through 30 days after occurrence
Secondary	Ki-67 expression	Wilcoxon rank sum test will be used to compare Ki-67 expression in adenomas across arms.	Up to 2 years
Secondary	GUCY2C expression	Wilcoxon rank sum and Fisher's exact tests will be used to compare GUCY2C expression between study arms.	Up to 2 years
Secondary	Guanylin levels	Wilcoxon rank sum and Fisher's exact tests will be used to compare guanylin levels between study arms.	Up to 2 years

External Links

•   Thomas Jefferson University Hospital