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Randomized Phase II Trial of Polyphenon E vs.Placebo in Patients at High Risk of Recurrent Colonic Neoplasia

Phase 2
40 Years
Not Enrolling
Advanced Colorectal Adenomas, Adenocarcinoma of the Colon, Stage I Colon Cancer, Stage II Colon Cancer, Stage III Colon Cancer

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Trial Information

Randomized Phase II Trial of Polyphenon E vs.Placebo in Patients at High Risk of Recurrent Colonic Neoplasia

PRIMARY OBJECTIVES: I. To determine whether POLYE (Polyphenon E) 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., number of
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. Residual tissue will be
stored for further analysis. VI. To study the association of clinical (toxicity and/or ACF
response or activity) with the pharmacokinetic parameters, and/or biologic (pharmacodynamic)
results. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients
receive Polyphenon E orally (PO) twice daily (BID). ARM II: Patients receive placebo PO
BID. Courses in both arms repeat every 28 days for 6 months in the absence of disease
progression or unacceptable toxicity. After completion of study treatment, patients are
followed up for 5 years.

Inclusion Criteria:

- Current or prior advanced adenomas. Participants with advanced adenomas are defined
as participants who have polyps >= 1 cm, who have tubulovillous adenomas (25-75
percent villous features), who have villous adenomas (>75 percent villous), or who
have severe dysplasia

- Prior curatively resected Tumor, Node, Metastasis (TNM) stage II and III colon cancer
>= 3 years out from treatment by surgery with/without adjuvant chemotherapy; NOTE:
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

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

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

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

- Willingness to provide mandatory tissue and blood for protocol specified research;
residual tissue and/or blood may be used for future research Negative pregnancy
test =< 7 days prior to registration/randomization

- Hemoglobin (Hgb) >= 12.0 g/dL (women), >= 13.5 g/dL (men) at Mayo Clinic or within
normal limits at an outside laboratory

- Platelet count >= 100,000/ul

- White blood cells (WBC) >= 3,000/ul

- Alanine aminotransferase (ALT) within institutional limits of normal

- Alkaline phosphatase within institutional upper limit of normal (ULN)

- Aspartate aminotransferase (AST) within institutional limits of normal

- Total bilirubin within institutional limits of normal

- Serum calcium =< institutional ULN

- Serum creatinine =< 1.5 x institutional ULN

- >= 5 rectal ACF detected by chromoendoscopy =< 45 days prior to

- 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 visualized; this may be done at the same time as the chromoendoscopy

Exclusion Criteria:

- Any history of rectal cancer; Exception: transanal excision without radiation

- Known diagnosis of colon heritable cancer syndrome (Familial adenomatous polyposis
[FAP], hereditary nonpolyposis colorectal cancer [HNPCC]) or inflammatory bowel
disease (Crohn's disease, ulcerative colitis)

- Inability to swallow capsules

- Bleeding diathesis

- Any 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

- History of gastroduodenal ulcers documented =< 1 year

- Known inability to participate in the scheduled follow-up tests

- Significant medical or psychiatric problems which would make the participant a poor
protocol candidate, in the opinion of the treating physician

- Total colectomy

- Colostomy

- History of pelvic or rectal radiation therapy

- History of liver disease

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac

- Concomitant corticosteroids or anticoagulants needed on a regular or predictable
intermittent basis

- Use of non-study investigational agent(s) =< 3 months prior to preregistration

- Chemotherapy =< 6 months prior to pre-registration; Note: Topical chemotherapy will
be assessed on a case-by-case basis

- Any of the following: * Pregnant women * Nursing women * Men or women of childbearing
potential who are unwilling to employ adequate contraception Note: This study
involves an investigational agent whose genotoxic, mutagenic, and teratogenic effects
on the developing fetus and newborn are unknown

- Over-the-counter green tea or green tea extract use =< 6 weeks prior to
pre-registration; consumption of over the counter green tea extracts or drinking of
green tea is not permitted during the treatment portion of this trial

- 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

- Use of non-study investigational agents while on study

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Outcomes Assessor), Primary Purpose: Treatment

Outcome Measure:

Percent change in rectal ACF, pre- and post intervention at 6 months

Outcome Description:

Calculated as patients pre-registration number of rectal ACF minus the number of rectal ACF present at the 6-month post-intervention exam, divided by the number of rectal ACF present at pre-registration.

Outcome Time Frame:

6 months

Safety Issue:


Principal Investigator

Frank Sinicrope

Investigator Role:

Principal Investigator

Investigator Affiliation:

Mayo Clinic


United States: Food and Drug Administration

Study ID:




Start Date:

June 2012

Completion Date:

Related Keywords:

  • Advanced Colorectal Adenomas
  • Adenocarcinoma of the Colon
  • Stage I Colon Cancer
  • Stage II Colon Cancer
  • Stage III Colon Cancer
  • Adenocarcinoma
  • Adenocarcinoma, Mucinous
  • Adenoma
  • Colonic Neoplasms



Mayo ClinicRochester, Minnesota  55905
University of IllinoisChicago, Illinois  60612