Phase IB randomized, double-blinded, placebo-controlled, dose escalation study of polyphenon E in women with hormone receptor-negative breast cancer.

Epidemiologic data support an inverse association between green tea intake and breast cancer risk, and numerous experimental studies have shown the antitumor effects of its main component, epigallocatechin gallate (EGCG). We conducted a phase IB dose escalation trial in women with a history of stage I to III hormone receptor-negative breast cancer of an oral green tea extract, polyphenon E (Poly E) 400, 600, 800 twice daily or matching placebo for 6 months. The primary endpoint was to determine the maximum tolerated dose (MTD), defined as the dose that causes 25% dose-limiting toxicity (DLT, grade ≥II). Assignment to dose level was based upon an adaptive design, the continual reassessment method. A mammogram and random core biopsy of the contralateral breast were obtained at baseline and 6 months and serial blood/urine collections every 2 months for biomarker analyses. Forty women were randomized: 10 to placebo, 30 to Poly E (16 at 400 mg, 11 at 600 mg, 3 at 800 mg). There was one DLT at 400 mg (grade III rectal bleeding), three DLTs at 600 mg (grade II weight gain, grade III indigestion and insomnia), and one DLT at 800 mg (grade III liver function abnormality). The DLT rate at 600 mg was 27% (3 of 11). Pharmacologic levels of total urinary tea polyphenols were achieved with all three dose levels of Poly E. Using a novel phase I trial design, we determined the MTD for Poly E to be 600 mg twice daily. This study highlights the importance of assessing toxicity for any chemopreventive agent being developed for chronic use in healthy individuals.