Polyethylene Glycol 3350 in Preventing Cancer in Patients at Risk of Colorectal Cancer

• Changes in Ki-67 (proliferation), activated caspase-3 (apoptosis), EGFR, SNAIL and E-cadherin expression as measured in endoscopically normal (non-ACF) mucosal biopsies by IHC or Western blot [ Designated as safety issue: No ]
• mRNA expression of EGFR and SNAIL as measured by RT-PCR [ Designated as safety issue: No ]

This randomized phase II trial is studying how well 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 polyethylene glycol 3350 may stop cancer from growing in patients who are at risk of colorectal cancer. It is not yet known which treatment regimen is more effective in preventing colorectal cancer.

PRIMARY OBJECTIVE:

I. To evaluate the effect of polyethylene glycol (PEG) 3350 (administered at 8g or 17g/day for six months) versus placebo on EGFR expression.

SECONDARY OBJECTIVES:

I. To determine the effect of PEG 3350 on aberrant crypt foci (ACF) number. An exploratory comparison between the reduction in ACF number between the low dose (8g PEG 3350 / day) and higher dose (17g PEG 3350 / day) groups.

II. To determine the effect of PEG 3350 on mucosal epithelial proliferation (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 protein expression. V. To determine the effect of PEG 3350 on mRNA expression of SNAIL and EGFR.

OUTLINE: is a multicenter study. Patients are stratified according to recruitment site and number of aberrant crypt foci (ACF) (> 20 vs 11-20 vs 5-10). Patients are randomized to one of three treatment arms.

ARM I: Patients receive low-dose polyethylene glycol orally once daily.

ARM II: Patients receive high-dose polyethylene glycol orally once daily.

ARM III: Patients receive placebo (i.e., maltodextrose powder) orally once daily.

In all arms, treatment begins within 6-10 days after colonoscopy and continues for up to 6 months in the absence of unacceptable toxicity.

Patients undergo flexible sigmoidoscopy at baseline (during prestudy colonoscopy) and at completion of study treatment. Patients undergo biopsies of normal mucosa (i.e., at least 1 cm from an ACF) and ACF sites (if present) to obtain tissue for evaluation of treatment response and tissue biomarkers. Tissue samples are assessed for cleaved caspase-3, Ki-67, and SNAIL by IHC and for EGFR and E-cadherin expression by Western blot. Samples are also analyzed for mRNA expression of EGFR and SNAIL by RT-PCR. Blood samples are collected periodically for RNA isolation.

After completion of study treatment, patients are followed at 30 days.

• Adenomatous Polyp
• Colorectal Cancer
• Precancerous Condition

• Drug: polyethylene glycol
  Given orally
  Other Names:

  • PEG
  • Poly(oxyethylene)
  • Polyethylene Glycol 400
  • Polyethylene Glycol 8000
  • Polyethylene Oxide
• Other: placebo
  Given orally
  Other Name: PLCB
• Procedure: colonoscopy
  Patients undergo diagnostic procedure
  Other Name: colonoscopic studies
• Procedure: sigmoidoscopy
  Patients undergo diagnostic procedure
  Other Name: Proctosigmoidoscopy
• Other: laboratory biomarker analysis
  correlative study

• Experimental: Arm I (low-dose polyethylene glycol)
  Patients receive low-dose polyethylene glycol orally once daily. Treatment continues for up to 6 months in the absence of unacceptable toxicity.
  Interventions:

  • Drug: polyethylene glycol
  • Procedure: colonoscopy
  • Procedure: sigmoidoscopy
  • Other: laboratory biomarker analysis
• Experimental: Arm II (high-dose polyethylene glycol)
  Patients receive high-dose polyethylene glycol orally once daily. Treatment continues for up to 6 months in the absence of unacceptable toxicity.
  Interventions:

  • Drug: polyethylene glycol
  • Procedure: colonoscopy
  • Procedure: sigmoidoscopy
  • Other: laboratory biomarker analysis
• Placebo Comparator: Arm III (placebo)
  Patients receive placebo orally once daily. Treatment continues for up to 6 months in the absence of unacceptable toxicity.
  Interventions:

  • Other: placebo
  • Procedure: colonoscopy
  • Procedure: sigmoidoscopy
  • Other: laboratory biomarker analysis

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
• ECOG performance status 0-1 (equivalent to Karnofsky >= 70%)
• Leukocytes >= 3,000/uL
• Absolute neutrophil count >= 1,500/uL
• Platelets >= 100,000/uL
• INR =< 1.5
• Total bilirubin =< 1.5 X institutional ULN
• AST (SGOT)/ALT (SGPT) =< 1.5 X institutional ULN
• eGFR > 45
• 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 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, 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