Dolcanatide in Preventing Colorectal Cancer in Healthy Volunteers

Study Overview
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Brief Summary
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This phase I trial studies how well dolcanatide works in preventing colorectal cancer in healthy participants. Dolcanatide is similar to a natural hormone released into the intestine. It is thought that people who have low levels of the hormone are more likely to get colon cancer. It may be possible to prevent colon cancer by giving a drug that is similar to the hormone, such as dolcanatide.

Detailed Description
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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.

Official Title
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Phase I Double-Blind, Placebo-Controlled Trial of 27 mg Dolcanatide (SP-333) to Demonstrate Colorectal Bioactivity in Healthy Volunteers

Conditions
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Colorectal Carcinoma

Intervention / Treatment
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* Drug: Dolcanatide
* Other: Laboratory Biomarker Analysis
* Other: Placebo Administration
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (dolcanatide)<br>Participants receive dolcanatide PO QD for 7 days. | Drug: Dolcanatide<br>* Given PO<br>* Other names: SP333;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Placebo Comparator: Arm B (placebo)<br>Participants receive placebo PO QD for 7 days. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Placebo Administration<br>* Given PO<br>Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacological Effect on Cyclic Guanosine Monophosphate (cGMP) Levels for Dolcanatide Arm Versus (vs.) Placebo, as Measured by the Differences in Mean cGMP Levels After 7 Days of Intervention | Pharmacological effect on cyclic guanosine monophosphate (cGMP) levels for dolcanatide arm versus (vs.) placebo, where this effect is defined as the arithmetic difference in mean cGMP levels before and after 7 days of dolcanatide from subject biopsies. This represents the increase in cGMP stimulated by 7 days of dolcanatide in an individual subject. The mean cGMP value will be calculated based on 6 biopsies collected from the rectum during a flexible sigmoidoscopy procedure. Each biopsy was analyzed in triplicate using a commercially available EIA kit. | Baseline to 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacodynamic (PD) Response Rate | Each participant will be assessed for PD response. The calculation is based on the standardized difference in means for the pharmacological effect on cGMP levels at the participant level, where a subject with a z >= 1.645 will be considered a PD responder. A participant with a z < 1.645 will be considered a non-responder. The PD response rate (percentage) of patients are summarized below by arm. | Baseline to 7 days | 
| Percentage of Participants With Grade 3 or Higher Diarrhea Per National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 | The overall adverse event rates (percentages) for grade 3 or higher adverse events regardless of attribution to treatment are reported below. The percentages below are summarized for Diarrhea. | Up to 21 days |