Dolcanatide in Preventing Colorectal Cancer in Healthy Volunteers

PRIMARY OBJECTIVES:

I. To identify the ability of dolcanatide (SP333), when administered as a single daily dose of 27 mg x 7 days, to induce a direct pharmacological effect on cGMP levels, based on biopsy samples from the rectum obtained pre- and post-intervention, as compared to placebo.

SECONDARY OBJECTIVES:

I. To assess the pharmacodynamic (PD) response rate between arms (dolcanatide versus placebo).

II. To confirm the safety and tolerability of dolcanatide, as compared to placebo.

OUTLINE: Participants are randomized to 1 of 2 arms.

ARM A: Participants receive dolcanatide orally (PO) once daily (QD) for 7 days.

ARM B: Participants receive placebo PO QD for 7 days.

After completion of study, participants are followed up at 21 and 51 days.

Inclusion criteria

• PRE-REGISTRATION INCLUSION
• Able to understand and willingness to sign a written informed consent document and follow study procedures
• Willing to abstain from grapefruit juice during study
• Willing to employ adequate contraception for men and women of childbearing potential; Note: acceptable methods include double barrier methods, intrauterine device (IUD), postmenopausal status documented by serum follicle stimulating hormone (FSH), and/or documentation of surgical sterilization
• Willing to provide blood and tissue specimens for research purposes
• REGISTRATION INCLUSION
• Normal organ function and have normal laboratory findings without clinically significant findings
• Leukocytes >= 3 x 10^3/microliter (B/L)
• Absolute neutrophil count >= 1.5 x 10^3/microliter (B/L)
• Platelets >= 100 x 10^3/microliter (B/L)
• Total bilirubin within normal institutional limits
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/ alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 1.5 x institutional upper limit of normal (ULN)
• Creatinine =< institutional upper limit of normal
• Body mass index < 35 kg/m^2
• No findings in the rectum of advanced adenoma, chronic inflammation, or cancer

Exclusion criteria

• PRE-REGISTRATION EXCLUSION
• 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 nonpolyposis 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 >= 60 days prior to pre-registration is not an exclusion criterion
• History of celiac disease
• Inflammatory bowel disease (Crohn's disease, ulcerative colitis)
• Previous diagnosis of irritable bowel syndrome, chronic constipation, functional bowel disorders, colonic motility disorder, or opioid-induced constipation
• Any malignancy within 3 years of baseline; exception: participants with a history of basal cell or squamous cell skin cancer may be enrolled at the discretion of the investigator
• Currently receiving any other investigational agents
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to dolcanatide or to any of the excipients
• 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
• Current use of laxatives more than 3 times per week
• Current use of >= 5 cigarettes/day
• Current use of >= 3 alcoholic drinks/day
• Use of anti-coagulants or anti-platelet agents within 5 days prior to anticipated sigmoidoscopy; exception: individuals taking aspirin will not be excluded and will not be subject to a wash-out period
• History of bleeding/coagulation problems
• Any medical condition reported by the participant or documented in the medical record that is judged by the investigator to constitute a risk to safe participation
• Known or suspected mechanical gastrointestinal obstruction
• REGISTRATION EXCLUSION
• Sigmoidoscopy finding requiring clinical intervention
• Use of any illicit or illegal substances detected by urinary drug screen