A Phase I Trial of 5-Fluoro-2'-Deoxycytidine With Tetrahydrouridine in Advanced Malignancies
- In pre-clinical models, 5-fluoro-2'-deoxycytidine (FdCyd), administered along with
tetrahydrouridine (THU; an inhibitor of cytidine/deoxycytidine deaminase), has shown
superior anti-tumor activity as compared with 5-fluorouracil.
- FdCyd can be phosphorylated to 5-fluoro-2'-deoxycytidylate (FdCMP) by deoxycytidine
kinase and the nucleotide deaminated to FdUMP by deoxycytidylate (dCMP) deaminase. The
activity of dCMP deaminase is reported to be higher in human malignancies than in
normal tissues, which may result in selective cytotoxicity.
- FdCyd is an inhibitor of DNA methyltransferase and DNA methylation, resulting in
re-expression of genes silenced by DNA hypermethylation.
- To determine the maximum tolerated dose (MTD) of FdCyd administered by intravenous
infusion over 3 hours with concomitant infusion of 350 mg/m2 of THU.
- To describe the toxicities of FdCyd co-infused with THU.
- To obtain preliminary evidence of anti-tumor activity in patients treated with this
- To evaluate the pharmacokinetics of FdCyd and THU when co-infused.
- To evaluate the oral bioavailability of FdCyd when co-administered with THU.
- When feasible, to measure the relative levels of the mRNAs for thymidylate synthase,
deoxycytidine kinase, dCMP deaminase and other relevant enzymes; and the methylation
status of p16 and other genes relevant to neoplasia.
- Patients with advanced, histologically-confirmed malignancies refractory to standard
therapy or for which no standard therapy exists.
- Patients should have adequate liver, renal and bone marrow function.
- Except for one cycle in which FdCyd and THU will be administered orally on the first
day (cycle 2 or a subsequent cycle), FdCyd will be administered as an IV infusion over
3 hours along with the infusion of THU daily for 5 consecutive days of treatment per
week for 2 consecutive weeks, followed by 2 weeks of no treatment, for 28-day cycles.
On the first day of the cycle in which pharmacokinetic samples are obtained (cycle 2 or
a subsequent cycle), a single oral dose of THU followed immediately by a single oral
dose of FdCyd will be administered to determine the oral bioavailability of FdCyd when
administered with THU.
- The intravenous dose of THU is fixed at 350 mg/m2/day; the single oral dose of THU will
be 1750 mg/m2. The dose of FdCyd will be escalated based on tolerability of lower
- Three to six patients will be enrolled at each dose level.
- Plasma and urine for PKs will be obtained during the first, second, and third day of
the second cycle (or subsequent cycle, but not the first cycle).
- Blood for pharmacodynamic studies will be obtained before treatment and with the first
interim weekly labs of each cycle. Tumor biopsies will be collected from patients
before treatment and during the second week of cycle 2 only.
- The study will accrue a maximum of 80 patients at all centers (28 at the NCI).
Primary Purpose: Treatment
To determine the maximum tolerated dose (MTD) if FdCyd administered by intravenous infusion over 3 hours with concomitant infusion of 350 mg/m2 of THU.
James H Doroshow, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|
|City of Hope National Medical Center||Los Angeles, California 91010|