Abstract CN06-02: Phase IB randomized, double-blinded, placebo-controlled, dose escalation study of Polyphenon E in women with a history of hormone receptor-negative breast cancer

Background : Priorities in breast cancer chemoprevention include developing safe and tolerable agents for potential chronic use that are effective against hormone receptor (HR)-negative breast cancer and validating intermediate biomarkers which correlate with breast cancer risk. Various epidemiologic studies have demonstrated an inverse association between green tea consumption and breast cancer risk. The primary polyphenol of green tea, epigallocatechin gallate (EGCG), is a potent antioxidant that acts on multiple stages of carcinogenesis. The primary objective of this phase IB trial was to demonstrate the safety of using an oral green tea extract, Polyphenon E (Poly E), over a 6-month period in patients with a history of HR-negative breast cancer. Secondary exploratory objectives were to investigate the dose-related biologic effects of Poly E on breast tissue, radiographic, serum and urine-based biomarkers. Methods : Forty women with stage I-III HR-negative breast cancer who completed adjuvant treatment were randomized to oral Poly E: (1) 400mg, (2) 600mg, or (3) 800mg (2–4 capsules) bid or matching placebo for 6 months. The primary endpoint of this dose escalation study was to determine the maximum tolerated dose (MTD) of Poly E in this patient population, defined as the dose that causes 25% dose limiting toxicity (DLT, grade 2 or higher). Assignment to dose level was based upon an adaptive clinical trial design called the time-to-event continual reassessment method, such that more participants were assigned to the MTD. Safety was assessed by monitoring clinical and laboratory parameters during monthly visits. At baseline and 6 months, a mammogram and random core biopsy of the contralateral breast and serial blood and urine collections were obtained for biomarker analyses. Secondary exploratory endpoints included breast tissue-based biomarkers (Ki-67, ER), mammographic density, serum hormone metabolites (estradiol, testosterone, IGF-I, IGFBP-3, SHBG), inflammatory and oxidative stress biomarkers (serum CRP, urine PGE-M, 8-OHdG, isoprostane). Results : From July 2007 to Sept 2009, 40 women were enrolled from 4 sites. Baseline characteristics included median age: 55 (39–65); pre/postmenopausal: 10/30; White/Hispanic/Black/Asian: 23/9/7/1; stage I/II/III: 16/15/9; median time since diagnosis: 33 months (10–170). Eighteen participants were each assigned to dose levels 1 and 2, four participants to dose level 3. There was 1 DLT at dose level 1 (grade 3 rectal bleeding), 3 DLTs at dose level 2 (grade 2 weight gain and indigestion, grade 3 insomnia), and 1 DLT at dose level 3 (grade 3 liver function abnormality). As a result, 600mg bid was found to be the MTD for Poly E. Biomarker analyses are currently ongoing. Conclusions : Using a novel clinical trial design for phase I testing which evaluates long-term toxicity, we determined the MTD for Poly E that will serve as the upper safety limit in future breast cancer chemoprevention trials. We also obtained preliminary data on the biological effects of Poly E on biomarkers of breast cancer risk, which can elucidate potential mechanisms of action and possibly serve as surrogate endpoints in future clinical efficacy trials. Citation Information: Cancer Prev Res 2011;4(10 Suppl):CN06-02.