Colorectal Cancer, Healthy, no Evidence of Disease
Conditions
Brief summary
This randomized phase I trial studies the side effects and best dose of linaclotide acetate in preventing colorectal cancer in healthy volunteers. Chemoprevention is the use of certain drugs to keep cancer from forming. The use of linaclotide acetate may prevent colorectal cancer.
Detailed description
PRIMARY OBJECTIVES: I. To assess the pharmacodynamic effect (PD) of linaclotide (linaclotide acetate) (single daily dose x 7 days, stage I cohort dose= 0.870 mg/day) on cyclic guanosine monophosphate (cGMP) levels, based on biopsy samples obtained pre- and post-intervention from the rectum, until an effect is documented. SECONDARY OBJECTIVES: I. To confirm the safety and tolerability of linaclotide. II. To assess the pharmacodynamic effect of linaclotide on cGMP levels, analyzed sequentially from the transverse colon to the cecum, if no cGMP effect was observed in the rectum for the primary endpoint. III. To compare the change in the cGMP levels from baseline to day 7 between all the assigned doses of linaclotide (including placebo), analyzed sequentially from the rectum, transverse colon, and cecum. IV. If the study proceeds to stage II, the pharmacodynamic effect of linaclotide on cGMP levels will be assessed from day 6 rectal biopsies (un-prepped). TERTIARY OBJECTIVES: I. To assess the pharmacodynamic effect of linaclotide on an additional pathway-specific biomarkers relevant to guanylate cyclase C (GCC) signaling (i.e., vasodilator-stimulated phosphoprotein \[VASP\] phosphorylation) and a marker of general proliferation (Ki67 expression), based on intestinal mucosa biopsy samples obtained by colonoscopy pre- and post-exposure at the anatomical location (rectum, transverse colon, or cecum) in which cGMP is elevated following linaclotide exposure. OUTLINE: This is a dose-escalation study. Participants are randomized to 1 of 2 treatment arms. ARM I: Participants receive linaclotide acetate orally (PO) once daily (QD) on days 1-7. ARM II: Participants receive placebo PO QD on days 1-7. After completion of treatment, participants are followed up for 21-51 days.
Interventions
Given PO
OTHERplacebo
Given PO
OTHERpharmacological study
Correlative studies
OTHERlaboratory biomarker analysis
Correlative studies
Sponsors
National Cancer Institute (NCI)
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* PRE-REGISTRATION INCLUSION CRITERIA * Ability to understand and willingness to sign a written informed consent document and follow study procedures * Willingness to abstain from grapefruit juice, alcohol, and concomitant medications during study * Willingness to employ adequate contraception for men and women of childbearing potential; acceptable methods include double barrier methods, intrauterine device (IUD), postmenopausal status documented by serum follicle-stimulating hormone (FSH), and/or documentation of surgical sterilization * Body mass index \< 35 kg/m\^2 * Willingness to provide blood and tissue specimens for research purposes * REGISTRATION INCLUSION CRITERIA * Participants must have normal organ function and have normal laboratory findings without clinically significant findings * Satisfactory anesthesia and intestinal preparation, with no findings of advanced adenoma, chronic inflammation, or cancer
Exclusion criteria
* PRE-REGISTRATION
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose of linaclotide acetate that produces a 60% response rate for cGMP levels in rectal tissue by radioimmunoassay (RIA) | Baseline to 7 days | The pharmacological effect is measured by the arithmetic difference in mean cGMP levels before and after 7 days of linaclotide acetate in biopsies from the colonoscopy. The mean cGMP value will be calculated based on 2 biopsies from the rectum assessed at each time point. The PD response is measured by the difference in mean cGMP levels after 7 days. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of adverse events associated with linaclotide acetate assessed using the Common Terminology Criteria for Adverse Events version 4.0 | Up to 51 days | Summary statistics, frequency tables, and non-parametric tests will be used to describe the distributions of adverse events. |
| PD effect of linaclotide acetate on cGMP levels from the transverse colon to the cecum | Up to 7 days | — |
| Change in cGMP levels between all assigned doses, analyzed sequentially from the rectum, transverse colon, and cecum | Baseline to 7 days | Summary statistics and nonparametric tests will be used to compare the change in the cGMP levels between the different dose levels of linaclotide acetate and placebo. |
| PD effect on cGMP levels (Stage II) | Up to 6 days | Changes in cGMP levels from baseline to day 6 will also be assessed using summary statistics and nonparametric tests. |
Other
| Measure | Time frame | Description |
|---|---|---|
| PD effect of linaclotide acetate on GCC signaling (i.e., VASP phosphorylation) and general proliferation (Ki67 expression) | Up to 7 days | Summary statistics, frequency tables, non-parametric tests, and graphical methods will be used to describe the distributions of cGMP levels relative to linaclotide acetate dose levels and biomarkers. Linear and logistic regression models may also be used as appropriate. |
Countries
United States
Outcome results
None listed