Clinical trial NCT03796884: 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
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: 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
Lead sponsor: Thomas Jefferson University
Sponsor class: OTHER
Collaborators: name: United States Department of Defense
First posted: 2019-01-08
Enrollment: 230
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Pharmacodynamics effect on cGMP levels
timeFrame: Up to 2 years
Secondary outcomes:
measure: Incidence of adverse events (AEs)
timeFrame: From the time of first dose of linaclotide or placebo until resolution, if related to linaclotide, or through 30 days after occurrence
measure: Ki-67 expression
timeFrame: Up to 2 years
measure: GUCY2C expression
timeFrame: Up to 2 years
measure: Guanylin levels
timeFrame: Up to 2 years
Other outcomes:
measure: VASP serine 239 phosphorylation
timeFrame: Up to 2 years
measure: Beta-catenin levels
timeFrame: Up to 2 years
measure: Beta-catenin nuclear localization
timeFrame: Up to 2 years
measure: Axin and c-Myc messenger ribonucleic acid (mRNA) levels
timeFrame: Up to 2 years
measure: PCNA expression
timeFrame: Up to 2 years
Locations:
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Sidney Kimmel Cancer Center at Thomas Jefferson University
state: Pennsylvania
city: Seattle
country: United States
facility: VA Puget Sound Health Care Sysem
state: Washington
Study officials:
affiliation: Sidney Kimmel Cancer Center at Thomas Jefferson University
name: Scott Waldman, MD
role: PRINCIPAL_INVESTIGATOR
References: