A phase I, pharmacokinetic, and pharmacodynamic evaluation of the DNA methyltransferase inhibitor 5-fluoro-2'-deoxycytidine, administered with tetrahydrouridine - PubMed (original) (raw)

Clinical Trial

doi: 10.1007/s00280-014-2674-7. Epub 2015 Jan 8.

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

Affiliations

Clinical Trial

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

Edward M Newman et al. Cancer Chemother Pharmacol. 2015 Mar.

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/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.

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Conflict of interest statement

Conflict of interest None.

Figures

Fig. 1

Fig. 1

Partial response in a heavily pre-treated patient pre- and post-treatment CT scans of a 61-year-old female with metastatic breast cancer who had received multiple chemotherapy and hormonal regimens including high-dose chemotherapy and autologous stem cell transplant prior to enrolling on the phase I trial of FdCyd + THU

Fig. 2

Fig. 2

Pharmacokinetics of FdCyd and its two major metabolites, FdUrd and FU a The maximum plasma concentrations of FdCyd, FdUrd, and FU are plotted as a function of the dose of FdCyd. Note the difference in scale between FdCyd (0–8000 ng/mL) and the metabolites (0–60 ng/mL). b Average FdCyd plasma concentration versus time profiles in patients after administration of 67 mg/m2 FdCyd (triangle N = 7), 100 mg/m2 FdCyd (square N = 16), and 133 mg/m2 FdCyd (circle N = 6). Samples with concentrations below LLQ were given a value of 0 for the purpose of this graph

Fig. 3

Fig. 3

Relative fetal hemoglobin expression for the purpose of illustration, the data are normalized to each patient’s cycle 1 pre-treatment sample and presented as the mean of the normalized data for each dose level

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