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

• Sponsor: Mayo Clinic (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01606124
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 39
• Locations: 3
• Arms: 2
• Duration (Months): 35.6
• Patients Per Site: 13
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Advanced Colorectal Adenomas; Adenocarcinoma of the Colon; Stage I Colon Cancer; Stage II Colon Cancer; Stage III Colon Cancer	Drug: defined green tea catechin extract; Other: placebo; Other: questionnaire administration; Other: laboratory biomarker analysis	Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 39 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Randomized Phase II Trial of Polyphenon E vs.Placebo in Patients at High Risk of Recurrent Colonic Neoplasia
• Study Start Date: Jun 1, 2012
• Actual Primary Completion Date: May 21, 2015
• Actual Study Completion Date: May 21, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I (Green Tea Catechin Extract) 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; Given PO; Other Names: Polyphenon E ; Other: questionnaire administration; Ancillary studies; Other: laboratory biomarker analysis; Correlative studies
Placebo Comparator: Arm II (placebo) Patients receive placebo PO BID. Courses repeat every 28 days for 6 months in the absence of disease progression or unacceptable toxicity.	Other: placebo; Given PO; Other Names: PLCB ; Other: questionnaire administration; Ancillary studies; Other: laboratory biomarker analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Percent Change in Rectal ACF, Pre- and Post Intervention at 6 Months [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.

Secondary Outcome Measures

1. Tolerability as Estimated Using the Percent Dose of Treatment Received at 6 Months [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Illinois	Chicago	Illinois	United States	60612
2	Hines Veteran's Administration Hospital	Hines	Illinois	United States	60612
3	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Frank Sinicrope, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT01606124
• Other Study ID Numbers: MC084C; NCI-2012-00058; NCT01974960
• First Posted: May 25, 2012
• Last Update Posted: Oct 27, 2017
• Last Verified: May 1, 2017

• Additional relevant MeSH terms: Colonic Neoplasms; Adenoma; Epigallocatechin gallate

Study Results

Participant Flow

Recruitment Details	The study was closed to accrual early due to a pending expiration of the supply of study agent.

Arm/Group Title	Arm I (Polyphenon E)	Arm II (Placebo)
Arm/Group Description	Patients receive two capsules Polyphenon E (each capsule of Polyphenon E contains approximately 200 mg epigallocatechin gallate (EGCG)) PO BID. Courses repeat every 28 days for 6 months in the absence of disease progression or unacceptable toxicity.	Patients receive two capsules placebo PO BID. Courses repeat every 28 days for 6 months in the absence of disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	19	20
COMPLETED	19	20
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Arm I (Polyphenon E)	Arm II (Placebo)	Total
Arm/Group Description	Patients receive two capsules Polyphenon E (each capsule of Polyphenon E contains approximately 200 mg epigallocatechin gallate (EGCG)) PO BID. Courses repeat every 28 days for 6 months in the absence of disease progression or unacceptable toxicity.	Patients receive two capsules placebo PO BID. Courses repeat every 28 days for 6 months in the absence of disease progression or unacceptable toxicity.	Total of all reporting groups
Overall Participants	19	20	39
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.5 (17.0)	61.4 (7.9)	59.9 (13.0)
Sex: Female, Male (Count of Participants)
Female	6 31.6%	8 40%	14 35.9%
Male	13 68.4%	12 60%	25 64.1%
Region of Enrollment (Count of Participants)
United States	19 100%	20 100%	39 100%

Outcome Measures

1. Primary Outcome

Title	Percent Change in Rectal ACF, Pre- and Post Intervention at 6 Months
Description	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.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

Patients with baseline and 6-month ACF data were included in this analysis.

Arm/Group Title	Arm I (Polyphenon E)	Arm II (Placebo)
Arm/Group Description	Patients receive two capsules Polyphenon E (each capsule of Polyphenon E contains approximately 200 mg epigallocatechin gallate (EGCG)) PO BID. Courses repeat every 28 days for 6 months in the absence of disease progression or unacceptable toxicity.	Patients receive two capsules placebo PO BID. Courses repeat every 28 days for 6 months in the absence of disease progression or unacceptable toxicity.
Measure Participants	15	17
Mean (Standard Deviation) [percentage change]	3.7 (49.1)	0.0 (62.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Polyphenon E), Arm II (Placebo)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5631
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Secondary Outcome

Title	Tolerability as Estimated Using the Percent Dose of Treatment Received at 6 Months
Description	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.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm I (Polyphenon E)	Arm II (Placebo)
Arm/Group Description	Patients receive two capsules Polyphenon E (each capsule of Polyphenon E contains approximately 200 mg epigallocatechin gallate (EGCG)) PO BID. Courses repeat every 28 days for 6 months in the absence of disease progression or unacceptable toxicity.	Patients receive two capsules placebo PO BID. Courses repeat every 28 days for 6 months in the absence of disease progression or unacceptable toxicity.
Measure Participants	19	20
Mean (Standard Deviation) [percentage of targeted dose]	83.2 (29.3)	91.7 (24.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I (Polyphenon E), Arm II (Placebo)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1439
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	6 months
Adverse Event Reporting Description	CTCAE term (AE description) and grade: The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. Each CTCAE term in the current version is a unique representation of a specific event used for medical documentation and scientific analysis and is a single MedDRA Lowest Level Term (LLT).
Arm/Group Title	Arm I (Polyphenon E)		Arm II (Placebo)
Arm/Group Description	Patients receive two capsules Polyphenon E (each capsule of Polyphenon E contains approximately 200 mg epigallocatechin gallate (EGCG)) PO BID. Courses repeat every 28 days for 6 months in the absence of disease progression or unacceptable toxicity.		Patients receive two capsules placebo PO BID. Courses repeat every 28 days for 6 months in the absence of disease progression or unacceptable toxicity.
All Cause Mortality
	Arm I (Polyphenon E)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/20 (0%)
Serious Adverse Events
	Arm I (Polyphenon E)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Arm I (Polyphenon E)		Arm II (Placebo)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/19 (21.1%)		1/20 (5%)
Gastrointestinal disorders
Abdominal pain	0/19 (0%)	0	1/20 (5%)	6
Diarrhea	1/19 (5.3%)	1	0/20 (0%)	0
Dyspepsia	0/19 (0%)	0	1/20 (5%)	6
Nausea	2/19 (10.5%)	2	1/20 (5%)	6
General disorders
Fatigue	0/19 (0%)	0	1/20 (5%)	6
Flu like symptoms	0/19 (0%)	0	1/20 (5%)	6
Investigations
Alanine aminotransferase increased	1/19 (5.3%)	1	0/20 (0%)	0
Aspartate aminotransferase increased	1/19 (5.3%)	1	0/20 (0%)	0
Musculoskeletal and connective tissue disorders
Myalgia	0/19 (0%)	0	1/20 (5%)	6
Nervous system disorders
Dizziness	0/19 (0%)	0	1/20 (5%)	6
Headache	0/19 (0%)	0	1/20 (5%)	6

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.