A phase I, pharmacokinetic, and pharmacodynamic evaluation of the DNA methyltransferase inhibitor 5-fluoro-2′-deoxycytidine, administered with tetrahydrouridine

Edward M. Newman, Robert J. Morgan, Shivaani Kummar, Jan H. Beumer, M. Suzette Blanchard, Christopher Ruel, Anthony B. El-Khoueiry, Mary I. Carroll, Jessie M. Hou, Chun Li, Heinz J. Lenz, Julie L. Eiseman, James H. Doroshow

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

Purpose: 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/m2/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/m2/day without dose-limiting toxicity (DLT) prior to transitioning to the 4-week schedule, which resulted in an MTD of 134 mg/m2/day; one of six patients had a first-cycle DLT (grade 3 colitis). FdCyd ≥40 mg/m2/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/m2 FdCyd + 350 mg/m2 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/m2/day, the phase II dose for our ongoing multi-histology trial is 100 mg/m2/day FdCyd with 350 mg/m2/day THU.

Original languageEnglish (US)
Pages (from-to)537-546
Number of pages10
JournalCancer Chemotherapy and Pharmacology
Volume75
Issue number3
DOIs
StatePublished - Mar 2015
Externally publishedYes

Keywords

  • DNA methylation
  • First-in-human
  • Fluorodeoxycytidine
  • Pharmacodynamics
  • Pharmacokinetics
  • Phase I clinical trial

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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