title: Phase I pharmacodynamic study of time and sequence dependency of hydroxyurea in combination with gemcitabine: a California Cancer Consortium Trial.
abstract: Preclinical studies in our laboratory have demonstrated that prior exposure to hydroxyurea increases the percentage of cells in S phase, enhancing the cytotoxicity of subsequent gemcitabine treatment in human oropharyngeal KB cells. To evaluate the clinical implications of this time- and sequence-dependent potentiation, we performed a phase I trial of hydroxyurea given over 24 h followed by a 30-min infusion of gemcitabine in weeks 1 and 2 of a 3-week cycle. The dose of hydroxyurea was fixed at 500 mg orally every 6 h for four doses starting 24 h before each dose of gemcitabine. The initial dose level of gemcitabine was 250 mg/m(2) on days 2 and 9, and this was escalated stepwise to 1000 mg/m(2) on days 2 and 9. Gemcitabine pharmacokinetics were determined on days 2 and 9 of the first cycle. Of 27 patients enrolled (12 female, 15 male), 24 were evaluable for response and 23 were evaluable for toxicity. Their median age was 56 years (range 27-76 years). Tumor types included lung, head and neck, pancreas, breast, colon, prostate, stomach, ovary, esophagus, germ cell, thyroid, gallbladder, and unknown primary. A total of 80 cycles of treatment were completed. One patient (unknown primary) had an objective partial response lasting 21 months, and 12 patients had stable disease. All observed dose-limiting toxicities were related to myelosuppression. The gemcitabine maximum tolerated dose was established at 750 mg/m(2) on days 2 and 9. Hydroxyurea had no effect on the plasma pharmacokinetics of gemcitabine. These results suggest that hydroxyurea followed by gemcitabine can be safely administered and has activity on this schedule. We are presently developing a phase II trial of this regimen for patients with platinum-resistant head and neck cancer.
authors.affiliation: Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA 91010-3000, USA. yyen@coh.org
authors.forename: Yun
authors.initials: Y
authors.lastname: Yen
authors.forename: Warren
authors.initials: W
authors.lastname: Chow
authors.forename: Lucille
authors.initials: L
authors.lastname: Leong
authors.forename: Kim
authors.initials: K
authors.lastname: Margolin
authors.forename: Robert
authors.initials: R
authors.lastname: Morgan
authors.forename: James
authors.initials: J
authors.lastname: Raschko
authors.forename: Stephen
authors.initials: S
authors.lastname: Shibata
authors.forename: George
authors.initials: G
authors.lastname: Somlo
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Twardowski
authors.forename: Paul
authors.initials: P
authors.lastname: Frankel
authors.forename: Jeff
authors.initials: J
authors.lastname: Longmate
authors.forename: Timothy
authors.initials: T
authors.lastname: Synold
authors.forename: Edward M
authors.initials: EM
authors.lastname: Newman
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
authors.forename: David
authors.initials: D
authors.lastname: Gandara
authors.forename: James H
authors.initials: JH
authors.lastname: Doroshow
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001855:Bone Marrow Diseases / Q000139:chemically induced; D002140:California; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004334:Drug Administration Schedule; D004357:Drug Synergism; D005260:Female; D006801:Humans; D006918:Hydroxyurea / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D006918:Hydroxyurea; D000093542:Gemcitabine