title: A phase I, pharmacokinetic, and pharmacodynamic evaluation of the DNA methyltransferase inhibitor 5-fluoro-2'-deoxycytidine, administered with tetrahydrouridine.
abstract: OBJECTIVE
  Inhibitors of DNA (cytosine-5)-methyltransferases (DNMT) are active antineoplastic agents. We conducted the first-in-human phase I trial of 5-fluoro-2'-deoxycytidine (FdCyd), a DNMT inhibitor stable in aqueous solution, in patients with advanced solid tumors. Objectives were to establish the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of FdCyd + tetrahydrouridine (THU).
  
  
  METHODS
  FdCyd + THU were administered by 3 h IV infusion on days 1-5 every 3 weeks, or days 1-5 and 8-12 every 4 weeks. FdCyd was administered IV with a fixed 350 mg/m(2)/day dose of THU to inhibit deamination of FdCyd. Pharmacokinetics of FdCyd, downstream metabolites and THU were assessed by LC-MS/MS. RBC γ-globin expression was evaluated as a pharmacodynamics biomarker.
  
  
  RESULTS
  Patients were enrolled on the 3-week schedule at doses up to 80 mg/m(2)/day without dose-limiting toxicity (DLT) prior to transitioning to the 4-week schedule, which resulted in an MTD of 134 mg/m(2)/day; one of six patients had a first-cycle DLT (grade 3 colitis). FdCyd ≥40 mg/m(2)/day produced peak plasma concentrations >1 µM. Although there was inter-patient variability, γ-globin mRNA increased during the first two treatment cycles. One refractory breast cancer patient experienced a partial response (PR) of >90 % decrease in tumor size, lasting over a year.
  
  
  CONCLUSIONS
  The MTD was established at 134 mg/m(2) FdCyd + 350 mg/m(2) THU days 1-5 and 8-12 every 4 weeks. Based on toxicities observed over multiple cycles, good plasma exposures, and the sustained PR observed at 67 mg/m(2)/day, the phase II dose for our ongoing multi-histology trial is 100 mg/m(2)/day FdCyd with 350 mg/m(2)/day THU.
authors.affiliation: Department of Molecular Pharmacology, City of Hope Beckman Research Institute, 1500 East Duarte Road, Duarte, CA, 91010-3000, USA, enewman@coh.org.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Newman
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Morgan
authors.forename: Shivaani
authors.initials: S
authors.lastname: Kummar
authors.forename: Jan H
authors.initials: JH
authors.lastname: Beumer
authors.forename: M Suzette
authors.initials: MS
authors.lastname: Blanchard
authors.forename: Christopher
authors.initials: C
authors.lastname: Ruel
authors.forename: Anthony B
authors.initials: AB
authors.lastname: El-Khoueiry
authors.forename: Mary I
authors.initials: MI
authors.lastname: Carroll
authors.forename: Jessie M
authors.initials: JM
authors.lastname: Hou
authors.forename: Chun
authors.initials: C
authors.lastname: Li
authors.forename: Heinz J
authors.initials: HJ
authors.lastname: Lenz
authors.forename: Julie L
authors.initials: JL
authors.lastname: Eiseman
authors.forename: James H
authors.initials: JH
authors.lastname: Doroshow
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002853:Chromatography, Liquid; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D053719:Tandem Mass Spectrometry; D013767:Tetrahydrouridine / Q000008:administration & dosage; D016896:Treatment Outcome; D005719:gamma-Globulins / Q000235:genetics*
chemical_list: D005719:gamma-Globulins; D003841:Deoxycytidine; D013767:Tetrahydrouridine; D004248:DNA (Cytosine-5-)-Methyltransferases; C007746:5-fluoro-2'-deoxycytidine