Polyethylene Glycol 3350 in Preventing Cancer in Patients at Risk of 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 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 (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 messenger ribonucleic acid (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 (PO) once daily (QD).

ARM II: Patients receive high-dose polyethylene glycol PO QD.

ARM III: 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.

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 immunohistochemistry (IHC) and for EGFR and E-cadherin expression by Western
blot. Samples are also analyzed for mRNA expression of EGFR and SNAIL by real
time-polymerase chain reaction (RT-PCR). Blood samples are collected periodically for RNA
isolation.

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

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 polyethylene glycol (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 aminotrnasferase (ALT) (serum glutamic 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 antiinflammatory 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, 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