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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


Phase 1
21 Years
65 Years
Open (Enrolling)
Female
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

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Trial Information

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


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.

Inclusion Criteria


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

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

MTD defined as the dose that causes 25% DLT assessed using NCI CTCAE version 3.0

Outcome Time Frame:

6 months

Safety Issue:

Yes

Principal Investigator

Dawn Hershman

Investigator Role:

Principal Investigator

Investigator Affiliation:

M.D. Anderson Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2009-00858

NCT ID:

NCT00516243

Start Date:

July 2007

Completion Date:

Related Keywords:

  • 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
  • Breast Neoplasms

Name

Location

M D Anderson Cancer CenterHouston, Texas  77030