Green Tea Catechin Extract in Preventing Polyps in Patients at High-Risk for Recurrent Colon Polyps

PRIMARY OBJECTIVES:

I. To determine whether green tea catechin extract (POLYE) treatment is associated with a
significant percent decrease in the number of rectal aberrant crypt foci (ACF) (% change in
ACF) identified during the pre-intervention and post-intervention chromoendoscopy exams.

SECONDARY OBJECTIVES:

I. To determine the relative tolerability and safety of treatment with 2 capsules of POLYE
taken twice a day by mouth (Note: each capsule of polyphenon E contains approximately 200 mg
of epigallocatechin gallate [EGCG]) versus placebo administered for 6 months.

TERTIARY OBJECTIVES:

I. To determine the effect of the study drug vs placebo on EGCG levels in plasma and to
correlate EGCG levels with drug compliance and toxicity.

II. To characterize ACF based on four criteria and correlate such characterizations with the
intervention (vs placebo), as well as exploring the natural history of ACF over 6 months in
persons at high risk for colorectal cancer randomized to placebo.

III. To correlate the 6-month measurements of ACF size (e.g., #crypts/ACF), number,
morphology, and histopathology with the adenoma recurrence data at the next surveillance
endoscopy.

IV. To assess caffeine and black tea consumption via a Beverage Consumption Questionnaire
and correlate with study endpoints.

V. To assess the effects of POLYE versus placebo on a focused panel of tissue biomarkers
using re- and post-intervention biopsy samples obtained from ACF and normal-appearing rectal
mucosa.

VI. To study the association of clinical (toxicity and/or ACF response or activity) with the
pharmacokinetic parameters, and/or biologic (pharmacodynamic) results.

OUTLINE: This is a multicenter study. Participants are stratified according to disease
history (advanced adenomas vs prior colon cancer), institution (Mayo Clinic in Rochester, MN
vs University of Illinois at Chicago Medical Center), and chronic use of low-dose aspirin
(81 mg) taken prior to study entry (yes vs no). Participants are randomized to 1 of 2
treatment arms.

ARM I: Participants receive green tea catechin extract orally (PO) twice daily (BID) on days
1-28. Treatment repeats every 28 days for 6 months in the absence of disease progression or
unacceptable toxicity.

ARM II: Participants receive placebo PO BID on days 1-28. Treatment repeats every 28 days
for 6 months in the absence of disease progression or unacceptable toxicity.

Participants undergo blood and tumor tissue sample collection at baseline and periodically
during treatment for cell proliferation (Ki-67 labeling index and distribution), apoptosis
(caspase-3 expression assay), drug effect markers (COX-1,-2, polyamines, PGE2), and
apoptotic regulatory proteins and EGFR from aberrant crypt foci (ACF) and normal-appearing
mucosa (and adenomas, if present) analysis by immunohistochemistry, microarray, and real
time-polymerase chain reaction (PCR). Participants complete the Beverage Consumption
Questionnaire that includes black tea and caffeine intake at baseline.

After completion of study treatment, participants are followed up for 5 years.

Inclusion Criteria:

- One of the following:

- Current or prior advanced adenomas; participants with advanced adenomas are
defined as participants who have polyps ≥ 1 cm, who have tubulovillous adenomas
(25-75% villous features), who have villous adenomas (> 75% villous), or who
have severe dysplasia

- Prior curatively resected TNM stage II and III colon cancer ≥ 3 years out from
treatment by surgery with/without adjuvant chemotherapy

- Patients with stage I (T1-2, N0) colon cancer treated by endoscopic or
surgical therapy are eligible at anytime after such therapy

- Patients with prior stage IV disease must be ≥ 5 years status post surgical
resection of all metastatic disease

- ≥ 5 rectal ACF detected by chromoendoscopy ≤ 45 days prior to
registration/randomization

- Endoscopy ≤ 45 days prior to registration/randomization; Note: all adenomas or polyps
will be removed according to institutional standards of care, and the cecum must be
visualized; this may be done at the same time as the chromoendoscopy

- Willingness to provide mandatory tissue and blood for protocol-specified research;
residual tissue and/or blood may be used for future research

- No history of rectal cancer (exception: transanal excision without radiation)

- Eastern Cooperative Group (ECOG) performance status (PS) 0 or 1

- Ability to understand and the willingness to sign a written informed consent document

- Negative pregnancy test ≤ 7 days prior to registration/randomization

- Hemoglobin (Hgb) ≥ 12.0 g/dL (women), ≥ 13.5 g/dL (men)

- Platelet count ≥ 100,000/µl

- White blood cell (WBC) ≥ 3,000/µl

- Alanine aminotransferase (ALT) within institutional limits of normal (ULN)

- Alkaline phosphatase within institutional ULN

- Aspartate aminotransferase (AST) within ULN

- Total bilirubin within institutional ULN

- Serum calcium ≤ institutional ULN

- Serum creatinine ≤ 1.5 times institutional ULN

- No known diagnosis of inherited colon cancer syndrome (familial adenomatous polyposis
[FAP], hereditary non-polyposis colorectal cancer syndrome [HNPCC]) or inflammatory
bowel disease (Crohn disease, ulcerative colitis)

- No inability to swallow capsules

- No bleeding diathesis

- No invasive malignancy ≤ 5 years prior to pre-registration; exceptions: patients with
nonmelanoma skin cancers that were treated with simple excisional biopsy or stage I
(T1-2, N0) colon cancer treated by endoscopic therapy or surgery are eligible

- No history of gastroduodenal ulcers documented ≤ 1 year

- No known inability to participate in the scheduled follow-up tests

- No significant medical or psychiatric problems that would make the participant a poor
protocol candidate, in the opinion of the treating physician

- No history of liver disease

- No uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac
arrhythmia

- None of the following:

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate
contraception

- See Disease Characteristics

- Willingness to discontinue regular usage of calcium supplements (exception:
multi-vitamin); regular use defined as a frequency of 7consecutive days for > 3 weeks

- No total colectomy

- No colostomy

- No history of pelvic or rectal radiation therapy

- No concomitant corticosteroids or anticoagulants needed on a regular or predictable
intermittent basis

- No use of non-study investigational agent(s) ≤ 3 months prior to pre-registration

- No chemotherapy ≤ 6 months prior to pre-registration; Note: topical chemotherapy will
be assessed on a case-by-case basis

- No over-the-counter (OTC) green tea or green tea extract use ≤ 6 weeks prior to
pre-registration; consumption of OTC green tea extracts or drinking of green tea is
not permitted during the treatment portion of this trial

- No regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) ≤ 6 weeks prior to
pre-registration; regular use of NSAIDs is defined as a frequency of 7 consecutive
days (1 week) for> 3 weeks; participant must abstain from regular use of NSAIDs for
the duration of the study (exception: low-dose aspirin [81 mg] for those participants
who are chronic users of aspirin prior to the beginning of the study)

- No use of non-study investigational agents while on study