Defined Green Tea Catechin Extract in Treating Women With Hormone Receptor Negative Stage I-III Breast Cancer

Study Overview
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Brief Summary
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This randomized phase I trial studies the side effects and best dose of defined green tea catechin extract in treating women with hormone receptor-negative stage I-III breast cancer. Green tea extract contains ingredients that may prevent or slow the growth of breast cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. Demonstrate the safety of green tea catechin extract (Polyphenon E) in women with a history of hormone receptor-negative breast cancer. II. Determine the maximum tolerated dose of Polyphenon E in women with a history of hormone receptor-negative breast cancer. SECONDARY OBJECTIVES: I. Determine the efficacy of Polyphenon E in modulating histologic changes (nonproliferative, proliferative without atypia, atypical hyperplasia) on core biopsy of the contralateral breast. II. Determine the efficacy of Polyphenon E in modulating immunohistochemical expression of Ki-67 (proliferation index), p53, EGFR, HER2/neu, cleaved caspase-3 (apoptosis marker), and estrogen receptor on core biopsy tissue of the contralateral breast. III. Determine the efficacy of Polyphenon E in modulating mammographic breast density of the contralateral breast. IV. Determine the efficacy of Polyphenon E in modulating hormone metabolites (serum estradiol, testosterone, IGF-1, IGFBP-3, SHBG). V. Determine the efficacy of Polyphenon E in modulating eicosanoid levels (urine PGE-M). VI. Determine the efficacy of Polyphenon E in modulating biomarkers of oxidative damage (urine 8-OHdG, isoprostane). VII. Determine the efficacy of Polyphenon E in modulating serum C-reactive protein. VIII. Determine the activity of Polyphenon E in relation to COMT genotype. IX. Assess quality of life and attitudes toward complementary and alternative medicine in women with a history of breast cancer. OUTLINE: This is a dose-escalation study. Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive defined green tea catechin extract orally (PO) twice daily (BID) for 6 months in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive placebo PO BID for 6 months in the absence of disease progression or unacceptable toxicity. Patients undergo a core biopsy and mammogram of the contralateral breast at baseline and after 6 months for histological evaluation, IHC analysis, and mammographic density reading. Core biopsy tissue is assessed for proliferative changes and presence of atypia using standardized histological criteria. Core biopsy tissue is also analyzed by IHC for the following proteins: Ki-67 (proliferation index), p53, EGFR, HER2/neu, cleaved caspase-3 (apoptosis marker), and estrogen receptor (ER). Blood and urine samples are collected at baseline and every 2 months during treatment to measure drug effect biomarkers: serum estradiol, testosterone, insulin-like growth factor-1 (IGF-1), IGF binding protein-3 (IGFBP-3), and sex hormone-binding globulin (SHBG) by immunological laboratory methods; urine prostaglandin levels (PGE-M) by tandem mass spectrometry; urine oxidative damage markers (8-OHdG, isoprostane) and serum C-reactive protein (CRP) by ELISA; and catechol-O-methyltransferase (COMT) genotype (at baseline only). Patients complete a questionnaire assessing quality of life (SF-36) and attitudes toward complementary and alternative medicine at baseline and at 6 months. After completion of study treatment, patients are followed for 1 month.

Official Title
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Phase IB Randomized, Double-Blinded, Placebo-Controlled, Dose Escalation Study of Polyphenon E in Women With a History of Hormone Receptor-Negative Breast Cancer

Conditions
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Estrogen Receptor-negative Breast Cancer, Progesterone Receptor-negative Breast Cancer, Stage I Breast Cancer, Stage II Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer

Intervention / Treatment
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* Other: placebo
* Other: quality-of-life assessment
* Procedure: questionnaire administration
* Procedure: laboratory biomarker analysis
* Drug: defined green tea catechin extract


Participation Criteria
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Eligibility Criteria
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Criteria: History of histologically confirmed stage I, II, or III breast carcinoma without evidence of disease at study entry No evidence of recurrent disease (patients with resected local recurrence are eligible) Normal mammogram of the contralateral breast within the past 12 months, defined as no new suspicious calcifications or other abnormal findings warranting a breast biopsy No history of histologically confirmed bilateral breast cancer No evidence of metastatic breast cancer Registered in the outpatient medical oncology clinic at Columbia University Medical Center (CUMC), MD Anderson Cancer Center (MDACC), Memorial Sloan Kettering Cancer Center (MSKCC), or the Weill-Cornell campus of New York Presbyterian Hospital (NYP-WC) Hormone receptor status: Estrogen- and progesterone-receptor negative Menopausal status: Pre- or postmenopausal ECOG performance status < 2 (Karnofsky > 60%) Leukocytes >= 3,000/uL Absolute neutrophil count >= 1,500/uL Platelets >= 100,000/uL Total bilirubin within normal institutional limits AST/ALT =< 2.5 times institutional upper limit of normal Serum creatinine within normal institutional limits Not pregnant or nursing Negative pregnancy test Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation No history of allergic reactions attributed to compounds of similar chemical or biologic composition to green tea extract (Polyphenon E), such as green tea food products or supplements containing EGCG No history of gastrointestinal bleeding including, but not limited to, any of the following: Diverticulosis; Peptic ulcer disease; Erosive gastritis; Varices No uncontrolled or significant co-morbid illness including, but not limited to, any of the following: active or serious infection requiring intravenous antibiotics; symptomatic congestive heart failure; unstable angina pectoris; cardiac arrhythmia; active gastrointestinal bleeding; active liver disease; psychiatric illness/social situations that would limit compliance with study requirements No active malignancy, except for squamous cell carcinoma of the skin; basal cell carcinoma of the skin; carcinoma in situ; stage IA or IB invasive squamous cell carcinoma of the cervix treated by surgery and/or radiation therapy; or stage IA grade 1 adenocarcinoma of the endometrium treated by surgery At least 6 months since prior chemotherapy, radiation therapy, and/or breast surgery No prior radiation therapy or implant in the contralateral breast More than 30 days since prior and no concurrent medications, herbs, or vitamin and mineral supplements that contain tea compounds or caffeine At least 30 days since prior and no other concurrent investigational agents At least 30 days since prior and no concurrent tea consumption Willing to limit regular coffee consumption to =< three 8-ounce cups per day for 30 days prior to baseline evaluation and during the study intervention Total daily caffeine consumption should not exceed 375 mg/day No concurrent hormone replacement therapy, tamoxifen, or raloxifene Concurrent oral contraceptives allowed provided the dose has not been changed for at least 6 months prior to study entry No concurrent chemotherapy or radiation therapy

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Female

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 (defined green tea catechin extract)<br>Patients receive defined green tea catechin extract PO BID for 6 months in the absence of disease progression or unacceptable toxicity. | Other: quality-of-life assessment<br>* Ancillary studies<br>* Other names: quality of life assessment;Procedure: questionnaire administration<br>* Ancillary studies<br>Procedure: laboratory biomarker analysis<br>* Correlative studies<br>Drug: defined green tea catechin extract<br>* Given PO<br>* Other names: Polyphenon E;|
| Placebo Comparator: Arm II (placebo)<br>Patients receive placebo PO BID for 6 months in the absence of disease progression or unacceptable toxicity. | Other: placebo<br>* Given PO<br>* Other names: PLCB;Other: quality-of-life assessment<br>* Ancillary studies<br>* Other names: quality of life assessment;Procedure: questionnaire administration<br>* Ancillary studies<br>Procedure: 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 |
| --- | --- | --- |
| MTD defined as the dose that causes 25% DLT assessed using NCI CTCAE version 3.0 |  | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Breast tissue histology (nonproliferative, proliferative without atypia, atypical hyperplasia) | Generalized linear models will be used. | Up to 6 months | 
| COMT genotype | Generalized linear models will be used. | Up to 6 months | 
| Quality-of-life measures assessed using SF-36 | Generalized linear models will be used. | Up to 6 months | 
| Protein expression levels in benign breast tissue (Ki-67, p53, EGFR, HER2/neu, cleaved caspase-3, and ER) | Generalized linear models will be used. | Up to 6 months | 
| Quantitative mammographic breast density | Generalized linear models will be used. | Up to 6 months | 
| Hormone metabolite levels (estradiol, testosterone, IGF-1, IGFBP-3, SHBG) | Generalized linear models will be used. | Up to 6 months | 
| Eicosanoid levels (urine PGE-M) | Generalized linear models will be used. | Up to 6 months | 
| Levels of oxidative damage biomarkers (urine 8-OHdG, isoprostane) | Generalized linear models will be used. | Up to 6 months | 
| Serum CRP levels | Generalized linear models will be used. | Up to 6 months |