Phase IB Randomized, Double-Blinded, Placebo-Controlled, Dose Escalation Study of Polyphenon E in Women with Hormone Receptor-Negative Breast Cancer
Mené sur 40 patientes atteintes d'un cancer du sein HR- de stade I à III, cet essai randomisé de phase Ib évalue, sur une période de 6 mois de traitement, la dose maximale tolérable d'épigallocatéchine-3-gallate, un polyphénol du thé vert, dans la chimioprévention de la maladie
Epidemiologic data support an inverse association between green tea intake and breast cancer risk and numerous experimental studies have demonstrated the anti-tumor effects of its main component, epigallocatechin gallate (EGCG). We conducted a phase IB dose escalation trial in women with a history of stage I-III hormone receptor-negative breast cancer of an oral green tea extract, Polyphenon E (Poly E) 400mg, 600mg, 800mg bid 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≥2). 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 400mg, 11 at 600mg, 3 at 800mg). There was 1 DLT at 400mg (grade 3 rectal bleeding), 3 DLTs at 600mg (grade 2 weight gain, grade 3 indigestion and insomnia), and 1 DLT at 800mg (grade 3 liver function abnormality). The DLT rate at 600mg was 27% (3/11). 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 600mg bid. This study highlights the importance of assessing toxicity for any chemopreventive agent being developed for chronic use in healthy individuals.