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

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).
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.
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.
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.
AuthorsEdward 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
JournalCancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 75 Issue 3 Pg. 537-46 (Mar 2015) ISSN: 1432-0843 [Electronic] Germany
PMID25567350 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural)
Chemical References
  • gamma-Globulins
  • Deoxycytidine
  • Tetrahydrouridine
  • DNA (Cytosine-5-)-Methyltransferase
  • 5-fluoro-2'-deoxycytidine
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects, therapeutic use)
  • Chromatography, Liquid
  • DNA (Cytosine-5-)-Methyltransferase (antagonists & inhibitors)
  • Deoxycytidine (administration & dosage, analogs & derivatives)
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Infusions, Intravenous
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasms (drug therapy, pathology)
  • Tandem Mass Spectrometry
  • Tetrahydrouridine (administration & dosage)
  • Treatment Outcome
  • gamma-Globulins (genetics)

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