Macrogol 3350-based Oral Osmotic Laxative in Preventing Cancer in Patients at Risk of Colorectal Cancer

Study Overview
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Brief Summary
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This randomized phase II trial studies how well macrogol 3350-based oral osmotic laxative (polyethylene glycol 3350) works in preventing cancer in patients at risk of colorectal cancer. Chemoprevention is the use of certain drugs to keep cancer from forming. The use of macrogol 3350-based oral osmotic laxative may stop cancer from growing in patients who are at risk of colorectal cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the effect of polyethylene glycol (PEG) 3350 (administered at 8 g or 17 g/day for six months) versus placebo on epidermal growth factor receptor (EGFR) expression. SECONDARY OBJECTIVES: I. To determine the effect of PEG 3350 on aberrant crypt foci (ACF) number and to compare the reduction in ACF number between the low dose (8 g PEG 3350/day) and higher dose (17 g PEG 3350/day) groups. II. To determine the effect of PEG 3350 on mucosal epithelial proliferation (marker of proliferation Ki-67 [Ki-67]). III. To determine the effect of PEG 3350 on mucosal apoptosis (cleaved caspase-3). IV. To determine the effect of PEG 3350 on snail family zinc finger 1 (SNAIL) protein expression. V. To determine the effect of PEG 3350 on messenger ribonucleic acid (mRNA) expression of SNAIL and EGFR. OUTLINE: Patients are randomized to 1 of 3 treatment arms. ARM A: Patients receive high-dose macrogol 3350-based oral osmotic laxative orally (PO) once daily (QD). ARM B: Patients receive low-dose macrogol 3350-based oral osmotic laxative PO QD. ARM C: Patients receive placebo (i.e., maltodextrose powder) PO QD. In all arms, treatment begins within 6-10 days after colonoscopy and continues for up to 6 months in the absence of unacceptable toxicity. After completion of study treatment, patients are followed at 30 days.

Official Title
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Polyethylene Glycol for ACF Reduction and Biomarker Modulation in Individuals With CRC Risk

Conditions
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Adenomatous Polyp, Colorectal Carcinoma

Intervention / Treatment
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* Drug: macrogol 3350-based oral osmotic laxative
* Other: Placebo
* Other: Laboratory Biomarker Analysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: History of any size adenoma, known adenoma on present exam, or colon cancer within the last 6 years Scheduled for colonoscopy Ability to understand and the willingness to sign a written informed consent document Willingness to forego PEG laxative during the study period; if the patient has been on a consistent dose of non-PEG laxative for 90 days prior to study entry, the participant may continue those laxatives; participants must agree to restrict additional laxative use to the rescue medication (bisacodyl) provided Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (equivalent to Karnofsky >= 70%) Leukocytes >= 3,000/uL Absolute neutrophil count >= 1,500/uL Platelets >= 100,000/uL International normalized ratio (INR) =< 1.5 Total bilirubin =< 1.5 X institutional upper limit of normal (ULN) Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 1.5 X institutional ULN Estimated glomerular filtration rate (eGFR) > 45 Blood urea nitrogen (BUN) < 40 Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; restricting intercourse to a surgically sterilized partner; abstinence) for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately If patients are on a dose of cardioprotective aspirin, they must have been on a stable dose for three months prior to colonoscopy and agree to remain at that dose for the six months duration of the study; in addition, patients must agree to limit therapeutic nonsteroidal anti-inflammatory drug (NSAID) use (e.g. pain relief) to no more than 30 cumulative days during the six month duration of the trial Exclusion Criteria: Average of > 2 bowel movements per day for the 90 days preceding study entry as assessed by self-report at baseline Average consistency of stools described as watery or loose for the 90 days preceding study entry as assessed by self-report at baseline Systemic chemotherapy for any cancer within 18 months prior to enrollment or evidence of active malignant disease Radiation to the rectum within 24 months prior to enrollment Polyethylene glycol use within 3 months of enrollment (except as part of colonoscopy preparation) Systemic corticosteroid use Anticoagulant therapy Inflammatory bowel disease Removal of the rectum Evidence of proctitis (radiation, inflammatory bowel disease [IBD], infectious, etc.) by history or endoscopy Other investigational agent use within 30 days prior to enrollment History of adverse reactions attributed to compounds of similar chemical or biologic composition to polyethylene glycol, bisacodyl or methylene blue Uncontrolled intercurrent 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 Pregnancy Patient must not have used suppository medication or enemas for the three months prior to the trial or for the duration of the trial except as directed for colonoscopy or flexible sigmoidoscopy procedure bowel preparation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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 (high-dose PEG 3350)<br>Patients receive high-dose macrogol 3350-based oral osmotic laxative PO QD. Treatment continues for up to 6 months in the absence of unacceptable toxicity. | Drug: macrogol 3350-based oral osmotic laxative<br>* Given PO<br>* Other names: Colonlytely;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|
| Experimental: Arm B (low-dose polyethylene glycol)<br>Patients receive low-dose macrogol 3350-based oral osmotic laxative PO QD. Treatment continues for up to 6 months in the absence of unacceptable toxicity. | Drug: macrogol 3350-based oral osmotic laxative<br>* Given PO<br>* Other names: Colonlytely;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|
| Placebo Comparator: Arm C (placebo)<br>Patients receive placebo PO QD. Treatment continues for up to 6 months in the absence of unacceptable toxicity. | Other: Placebo<br>* Given PO<br>* Other names: PLCB;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference (After Treatment Minus Before Treatment) of EGFR Expression | Evaluate the effect of polyethylene glycol (PEG) 3350 (administered at 8g or 17g/day for six months) versus placebo on EGFR expression. | 6 months - baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in ACF Count as Measured in Endoscopically Normal (Non-ACF) Mucosal Biopsies | To determine the effect of PEG 3350 on aberrant crypt foci (ACF) number and to compare the reduction in ACF number between the low dose (8g PEG 3350 / day) and higher dose (17g PEG 3350 / day) groups | 6 months - baseline | 
| Change in Ki-67 (Proliferation) Expression as Measured in Endoscopically Normal (Non-ACF) Mucosal Biopsies | To determine the effect of PEG 3350 on mucosal epithelial proliferation (Ki-67) | 6 months - baseline | 
| Change in Mucosal Apoptosis (Cleaved Caspase-3) as Measured in Endoscopically Normal (Non-ACF) Mucosal Biopsies | Change in activated caspase-3 (apoptosis) expression as measured in endoscopically normal (non-ACF) mucosal biopsies | 6 months - baseline | 
| Change in SNAIL Expression as Measured in Endoscopically Normal (Non-ACF) Mucosal Biopsies |  | 6 months - baseline | 
| Change in E-cadherin Expression as Measured in Endoscopically Normal (Non-ACF) Mucosal Biopsies |  | 6 months - baseline |