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A Phase I Trial of 5-Fluoro-2'-Deoxycytidine With Tetrahydrouridine in Advanced Malignancies


Phase 1
18 Years
N/A
Not Enrolling
Both
Advanced Malignancies

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Trial Information

A Phase I Trial of 5-Fluoro-2'-Deoxycytidine With Tetrahydrouridine in Advanced Malignancies


Background:

- 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.

Objectives:

- 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.

Eligibility:

- 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).

Inclusion Criteria


- PATIENT ELIGIBILITY CRITERIA:

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.

Type of Study:

Interventional

Study Design:

Primary Purpose: Treatment

Outcome Measure:

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.

Principal Investigator

James H Doroshow, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)

Authority:

United States: Federal Government

Study ID:

060221

NCT ID:

NCT00359606

Start Date:

August 2006

Completion Date:

December 2011

Related Keywords:

  • Advanced Malignancies
  • DNA Methylation
  • Advanced Cancer
  • Methyltransferase Inhibitor
  • Epigenetics
  • Gene Re-Expression
  • Neoplasms

Name

Location

National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland  20892
City of Hope National Medical Center Los Angeles, California  91010