Linaclotide Acetate in Preventing Colorectal Cancer in Healthy Volunteers

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.

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 EXCLUSION CRITERIA

- Previous personal history of advanced adenomas (>= 1 cm in maximal diameter, >= 3 in
total number, villous morphology, or high‐grade dysplasia) or colorectal cancer

- Family history of polyposis syndrome (e.g., familial adenomatous polyposis [FAP],
hereditary non-polyposis colorectal cancer [HNPCC]) or colorectal cancer (first degree
relatives younger than 60 years old)

- History of gastroparesis

- History of surgery involving the luminal gastrointestinal (GI) tract, including
bariatric surgery

- History of celiac disease

- Inflammatory bowel disease (Crohn's disease, ulcerative colitis)

- Irritable bowel syndrome, chronic constipation, functional bowel disorders, or colonic
motility disorder

- Any malignancy within 3 years 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

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to linaclotide

- History of difficulty with colonoscopy or abnormal colorectal anatomy

- 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

- Use of laxatives more than 3 times per week

- Intestinal motility agents, histamine‐2 inverse agonists (H‐2 blockers), or proton
pump inhibitors

- Current use of >= 5 cigarettes/day

- Current use of >= 3 alcoholic drinks/day

- Use anti‐platelet agents within two weeks of anticipated colonoscopy

- Use of anti‐coagulants within two weeks of anticipated colonoscopy

- History of bleeding/coagulation problems

- Prior intolerance of or contraindications for the use of sedation or anesthetic
agents, which would prevent the safe use of sedation for colonoscopy; this includes
allergies to eggs and soy products

- Any medical condition judged by the investigator to constitute a risk to safe
participation

- REGISTRATION EXCLUSION CRITERIA

- Colonoscopic finding requiring clinical intervention

- Use of any illicit or illegal substances detected by urinary drug screen

- Inadequate pre‐intervention bowel preparation, as determined by the study physician