5-Fluoro-2'-Deocyctidine and Tetrahydrouridine to Treat Patients With Advanced Cancer
- 5-Fluoro-2'-Deocyctidine (FdCyd) and 5-Fluorouracil (FUra) both belong to a class of anti-cancer drugs called fluoropyrimidines.
- FUra is the most widely used agent in this class of drugs.
- The properties and activity of FdCyd, used together with the experimental drug tetrahydrouridine (THU), may make it a more effective cancer treatment than FUra alone.
- To determine how much FdCyd can be given safely with a fixed dose of THU.
- To determine the side effects of FdCyd administered together with THU.
- To examine how the body handles FdCyd.
-Patients 18 years of age and older whose cancer either has progressed after receiving standard treatment or for whom no standard treatment is available.
- Patients receive FdCyd and THU infusions in 4-week treatment cycles. The drugs are given together through a vein for 3 hours each day for 5 days, 2 weeks in a row, followed by a 2-week rest. Treatment continues unless: 1) the side effects are unacceptable, 2) the tumor grows, 3) the tumor has not shrunk by one-half its size after two treatment cycles, or 4) there is no longer evidence of cancer after two cycles of treatment.
- To determine the optimum dose of FdCyd, the dose is increased in subsequent small groups of patients entering the study until the highest tolerated dose is found.
- Patients are evaluated periodically with physical examinations, blood and urine tests, X-rays and other imaging studies, electrocardiograms, tumor measurements and tumor biopsies (surgical removal of a small piece of tumor tissue).
- The study will accrue a maximum of 80 patients at all centers (18 at the NCI).
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase I Trial of 5-Fluoro-2'-Deoxycytidine With Tetrahydrouridine in Advanced Malignancies|
- 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. [ Time Frame: Cycle 1 ] [ Designated as safety issue: Yes ]
|Study Start Date:||August 2006|
|Study Completion Date:||December 2011|
|Primary Completion Date:||December 2011 (Final data collection date for primary outcome measure)|
To determine the MTD of FdCyd) administered by IV infusion over three hours with concomitant infusion of 350 mg/m2 of THU
Drug: 5-Fluoro-2-deoxycytidine (FdCyd) + THU
5-Fluoro-2'-deoxyuridine (FdUrd) is a potent inhibitor of the growth of human leukemic cells in culture, however, the ubiquitous presence of thymidine and uridine phosphorylases causes rapid cleavage of FdUrd to FUra. THU is an effective nontoxic inhibitor of Cyd/dCyd deaminase, both in vitro and in vivo. FdCyd with THU was more effective than equitoxic doses of FUra, FdUrd or FdCyd alone.
- 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 combination.
- 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 doses.
- 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).
Please refer to this study by its ClinicalTrials.gov identifier: NCT00359606
|United States, California|
|City of Hope National Medical Center|
|Duarte, California, United States, 91010|
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||James H Doroshow, M.D.||National Cancer Institute (NCI)|