Polyphenon E in Treating Patients With High-Risk of Colorectal Cancer

Study Overview
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Brief Summary
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This phase II trial studies how well Polyphenon E works in treating patients with high-risk of colorectal cancer. Polyphenon E contains ingredients that may prevent or slow colorectal cancer.

Detailed Description
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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.

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

Conditions
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Advanced Colorectal Adenomas, Adenocarcinoma of the Colon, Stage I Colon Cancer, Stage II Colon Cancer, Stage III Colon Cancer

Intervention / Treatment
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* Drug: defined green tea catechin extract
* Other: placebo
* Other: questionnaire administration
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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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 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 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 arrhythmia 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

Ages Eligible for Study
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Minimum Age: 40 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (Green Tea Catechin Extract)<br>Patients receive Polyphenon E PO BID. Courses repeat every 28 days for 6 months in the absence of disease progression or unacceptable toxicity. | Drug: defined green tea catechin extract<br>* Given PO<br>* Other names: Polyphenon E;Other: questionnaire administration<br>* Ancillary studies<br>Other: laboratory biomarker analysis<br>* Correlative studies<br>|
| Placebo Comparator: Arm II (placebo)<br>Patients receive placebo PO BID. Courses repeat every 28 days for 6 months in the absence of disease progression or unacceptable toxicity. | Other: placebo<br>* Given PO<br>* Other names: PLCB;Other: questionnaire administration<br>* Ancillary studies<br>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 |
| --- | --- | --- |
| Percent Change in Rectal ACF, Pre- and Post Intervention at 6 Months | The primary endpoint is based on a modified intent-to-treat procedure which includes all patients with baseline and 6-month ACF data. The percent change in rectal ACF (≤ 15 cm from the anal verge) for each patient is calculated as their 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 times 100. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tolerability as Estimated Using the Percent Dose of Treatment Received at 6 Months | Tolerability as estimated using the percent dose of treatment received for each patient by dividing the total dose received by the targeted (i.e., protocol specified) total dose. | 6 months |