title: Phase IB randomized, double-blinded, placebo-controlled, dose escalation study of polyphenon E in women with hormone receptor-negative breast cancer.
abstract: 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.
authors: Herbert Irving Comprehensive Cancer Center, Columbia University, 161 Fort Washington Ave, 10-1072, New York, NY 10032, USA. kd59@columbia.edu
authors: Katherine D
authors: KD
authors: Crew
authors: Powel
authors: P
authors: Brown
authors: Heather
authors: H
authors: Greenlee
authors: Therese B
authors: TB
authors: Bevers
authors: Banu
authors: B
authors: Arun
authors: Clifford
authors: C
authors: Hudis
authors: Heather L
authors: HL
authors: McArthur
authors: Jenny
authors: J
authors: Chang
authors: Mothaffar
authors: M
authors: Rimawi
authors: Lana
authors: L
authors: Vornik
authors: Terri L
authors: TL
authors: Cornelison
authors: Antai
authors: A
authors: Wang
authors: Hanina
authors: H
authors: Hibshoosh
authors: Aqeel
authors: A
authors: Ahmed
authors: Mary Beth
authors: MB
authors: Terry
authors: Regina M
authors: RM
authors: Santella
authors: Scott M
authors: SM
authors: Lippman
authors: Dawn L
authors: DL
authors: Hershman
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology; D002392:Catechin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D011960:Receptors, Estrogen / Q000096:biosynthesis; D011980:Receptors, Progesterone / Q000096:biosynthesis
chemical_list: D000970:Antineoplastic Agents; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D002392:Catechin; C472086:polyphenon E