Back to Search
Start Over
A phase I, pharmacokinetic, and pharmacodynamic evaluation of the DNA methyltransferase inhibitor 5-fluoro-2'-deoxycytidine, administered with tetrahydrouridine.
- Source :
-
Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2015 Mar; Vol. 75 (3), pp. 537-46. Date of Electronic Publication: 2015 Jan 08. - Publication Year :
- 2015
-
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).<br />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.<br />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.<br />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.
- Subjects :
- Adult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols administration & dosage
Antineoplastic Combined Chemotherapy Protocols adverse effects
Chromatography, Liquid
Deoxycytidine administration & dosage
Deoxycytidine analogs & derivatives
Dose-Response Relationship, Drug
Female
Humans
Infusions, Intravenous
Male
Maximum Tolerated Dose
Middle Aged
Neoplasms pathology
Tandem Mass Spectrometry
Tetrahydrouridine administration & dosage
Treatment Outcome
Antineoplastic Combined Chemotherapy Protocols therapeutic use
DNA (Cytosine-5-)-Methyltransferases antagonists & inhibitors
Neoplasms drug therapy
gamma-Globulins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1432-0843
- Volume :
- 75
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Cancer chemotherapy and pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 25567350
- Full Text :
- https://doi.org/10.1007/s00280-014-2674-7