5-Fluoro-2'-Deocyctidine and Tetrahydrouridine to Treat Patients With Advanced Cancer

This study has been completed.
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
First received: August 1, 2006
Last updated: October 9, 2014
Last verified: July 2014


  • 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).

Condition Intervention Phase
Drug: 5-Fluoro-2-deoxycytidine (FdCyd) + THU
Phase 1

Study Type: Interventional
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

Resource links provided by NLM:

Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • 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 ]

Enrollment: 21
Study Start Date: August 2006
Study Completion Date: December 2011
Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: A
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.

Detailed Description:


  • 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.

Study Design:

  • 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).

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

    1. Advanced, histologically-confirmed neoplastic disease refractory to standard therapy or for which no standard therapy exists
    2. Age greater than or equal to 18 years
    3. Karnofsky performance status (Appendix II) of at least 60% and estimated survival of at least two months
    4. Adequate renal function, as evidenced by serum creatinine less than or equal to 2.0 mg/dl or creatinine clearance greater than or equal 50 ml/min
    5. Adequate bone marrow function, as evidenced by ANC greater than or equal to 1,500/microl and platelets greater than or equal to 125,000/microl.
    6. Adequate liver function, as evidenced by bilirubin less than or equal to 1.5 mg/dl and SGOT and SGPT less than or equal to 3 times the upper limits of normal
    7. Prior antineoplastic therapy must have been completed at least four weeks prior to the patient's entry on this study, or patients must have recovered from any expected side effects of the prior therapy. There is no limit on the number of cycles of prior chemotherapy.
    8. Patients must be ineligible for or have refused participation in higher priority institutional protocols.
    9. Written, voluntary, informed consent of the patient must be obtained in compliance with institutional, state and federal guidelines.
    10. Because FdCyd has been shown to be teratogenic in animals, pregnant patients are INELIGIBLE. All patients of child-bearing potential, both male and female, must be advised to practice adequate contraception. Premenopausal women must have a negative pregnancy test prior to entry on this study.
    11. Patients with any non-malignant intercurrent illness (e.g. cardiovascular, pulmonary, or central nervous system disease) which is either poorly controlled with currently available treatment, or which is of such severity that the investigators deem it inappropriate to treat the patient on this protocol are INELIGIBLE.
    12. Patients currently being treated for a severe infection or who are recovering from major surgery are INELIGIBLE until recovery is deemed complete by the investigators.
    13. The presence of measurable disease is NOT required for this phase I study. If bidimensionally measurable disease is present, baseline measurements of up to 3 indicator lesions should be made no earlier than four weeks prior to the first cycle of chemotherapy. Pleural effusions, ascites and bone metastases are not considered measurable.
    14. CBC, differential count, platelet count, and blood chemistries should be done no earlier than 72 hours prior to each cycle of chemotherapy.
    15. Except as noted in Section 5.13 (4 weeks for tumor measurements) and Section 5.14 (72 hours for specified blood work), pretreatment tests should be done no earlier than two weeks prior to the first cycle of chemotherapy.
    16. Priority for accrual will be given to patients with breast cancer due to the in vitro data suggesting potential activity for this disease.
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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
Sponsors and Collaborators
Principal Investigator: James H Doroshow, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
ClinicalTrials.gov Identifier: NCT00359606     History of Changes
Obsolete Identifiers: NCT00378807
Other Study ID Numbers: 060221, 06-C-0221
Study First Received: August 1, 2006
Last Updated: October 9, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
DNA Methylation
Advanced Cancer
Methyltransferase Inhibitor
Gene Re-Expression

Additional relevant MeSH terms:
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on April 23, 2015