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Linaclotide Acetate in Preventing Colorectal Cancer in Healthy Volunteers

Trial Status: Complete

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.

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
  • Screening laboratory values (comprehensive metabolic panel, complete blood count [CBC], complete urinalysis, a urinary drug screen, and, if applicable, FSH) within institutional normal range or judged to be not clinically significant by the site principal investigator (PI) and medical monitor
  • No findings in the rectum of advanced adenoma, chronic inflammation, or cancer

Exclusion Criteria

  • PRE-REGISTRATION EXCLUSION CRITERIA
  • Documented 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; exception: prior appendectomy is not an exclusion criterion
  • 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 sigmoidoscopy 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 sigmoidoscopy
  • Use of anti‐coagulants within two weeks of anticipated sigmoidoscopy
  • History of bleeding/coagulation problems
  • Any medical condition judged by the investigator to constitute a risk to safe participation
  • REGISTRATION EXCLUSION CRITERIA
  • Sigmoidoscopy finding requiring clinical intervention
  • Use of any illicit or illegal substances detected by urinary drug screen

Minnesota

Rochester
Mayo Clinic in Rochester
Status: COMPLETED
Contact: Paul John Limburg
Phone: 507-284-2511

Pennsylvania

Philadelphia
Fox Chase Cancer Center
Status: COMPLETED
Contact: David S. Weinberg
Phone: 215-214-1424
Thomas Jefferson University Hospital
Status: COMPLETED
Contact: Scott Arthur Waldman
Phone: 215-955-6086

PRIMARY OBJECTIVES:

I. To identify the minimum effective dose of linaclotide (linaclotide acetate), when administered as a single daily dose x 7 days, that induces a pharmacodynamic (PD) effect on cyclic guanosine monophosphate (cGMP) levels, based on biopsy samples from the rectum obtained pre‐ and post‐intervention.

SECONDARY OBJECTIVES:

I. To confirm the safety and tolerability of linaclotide.

II. To determine if linaclotide can induce a PD effect on cGMP levels when administered as a single daily dose for 7 days without the concurrent bowel preparation utilized in Stages I and III of this study, based on biopsy samples from the rectum obtained pre‐ and post‐intervention.

III. To validate the efficacy of the minimum effective daily dose of linaclotide to produce a PD effect on cGMP levels based on biopsy samples from the rectum obtained pre‐ and post‐intervention in an expansion cohort of 6 healthy volunteers.

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 at 21, 30, and 51 days.

Trial Phase Phase I

Trial Type Prevention

Lead Organization
Mayo Clinic in Rochester

Principal Investigator
David S. Weinberg

  • Primary ID MAY2012-00-01
  • Secondary IDs NCI-2013-01788, NCT01912079, 13-829, HHSN2512012000042I, HHSN261201200042I, N01-CN-2012-00042
  • Clinicaltrials.gov ID NCT01950403