title: A phase I study of the chinese herbal medicine PHY906 as a modulator of irinotecan-based chemotherapy in patients with advanced colorectal cancer.
abstract: PHY906 is a novel Chinese herbal preparation that has been used in the Orient for over 1800 years to treat a wide range of gastrointestinal side effects including diarrhea, abdominal cramps, vomiting, fever, and headache. Preclinical and clinical studies were conducted to further investigate the biologic and clinical activities of this herbal medicine. To ensure standardization and maintain interbatch reliability of PHY906, high performance liquid chromatography (HPLC) was used to establish a "chemical fingerprint" of PHY906. In vivo preclinical studies using the murine Colon 39 tumor model showed that PHY906 protected against the weight loss associated with irinotecan treatment. In the presence of PHY906, mice were able to tolerate otherwise lethal doses of irinotecan. Significantly improved antitumor activity and overall survival were observed in animals treated with the combination of irinotecan and PHY906 versus irinotecan alone. The combination of PHY906 with irinotecan, 5-fluorouracil (5-FU), and leucovorin (LV) also resulted in at least additive antitumor activity with no increased host toxicity. Based on these in vivo studies, a phase I multicenter, double-blind, randomized, placebo-controlled, dose escalation, cross-over study of PHY906 as a modulator of the weekly, bolus regimen of irinotecan, 5-FU, and LV (IFL) in the first-line treatment of patients with advanced colorectal cancer (CRC) was conducted. The specific objectives of this clinical trial were to determine the safety and tolerability of PHY906 when administered concomitantly with the bolus, weekly IFL regimen. Treatment with PHY906 did not alter the pharmacokinetics of 5-FU, irinotecan, or the irinotecan metabolite SN-38.
authors.affiliation: Department of Medicine and Pharmacology, Developmental Therapeutics Program, Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Shivaani
authors.initials: S
authors.lastname: Kummar
authors.forename: M Sitki
authors.initials: MS
authors.lastname: Copur
authors.forename: Michal
authors.initials: M
authors.lastname: Rose
authors.forename: Scott
authors.initials: S
authors.lastname: Wadler
authors.forename: Joe
authors.initials: J
authors.lastname: Stephenson
authors.forename: Mark
authors.initials: M
authors.lastname: O'Rourke
authors.forename: Wayne
authors.initials: W
authors.lastname: Brenckman
authors.forename: Robert
authors.initials: R
authors.lastname: Tilton
authors.forename: Shwu-Huey
authors.initials: SH
authors.lastname: Liu
authors.forename: Zaoli
authors.initials: Z
authors.lastname: Jiang
authors.forename: Tahmun
authors.initials: T
authors.lastname: Su
authors.forename: Yung-Chi
authors.initials: YC
authors.lastname: Cheng
authors.forename: Edward
authors.initials: E
authors.lastname: Chu
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004365:Drugs, Chinese Herbal / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006207:Half-Life; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008875:Middle Aged; D008517:Phytotherapy / Q000379:methods*
chemical_list: D004365:Drugs, Chinese Herbal; C476037:PHY 906; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin