Protocol Number: 06-C-0221

Title:

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

Number:

06-C-0221

Summary:

Background:

-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.

Objectives:

-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.

Eligibility:

-Patients 18 years of age and older whose cancer either has progressed after receiving standard treatment or for whom no standard treatment is available.

Design:

-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).

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility 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.

Special Instructions:

Currently Not Provided

Keywords:

DNA Methylation

Advanced Cancer

Methyltransferase Inhibitor

Epigenetics

Gene Re-Expression

Recruitment Keyword(s):

Advanced Cancer

Condition(s):

Advanced Malignancies

Investigational Drug(s):

5-Fluoro-2-deoxycytidine (FdCyd)

Investigational Device(s):

None

Intervention(s):

Drug: 5-Fluoro-2-deoxycytidine (FdCyd)

Supporting Site:

National Cancer Institute

Contact(s):

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office
Phone: 1-888-NCI-1937
Fax: Not Listed
Electronic Address: ncicssc@mail.nih.gov

Citation(s):

Carter SK. Editorial: Large-bowel cancer-The current status of treatment. J Natl Cancer Inst. 1976 Jan;56(1):3-10. No abstract available.

Doroshow JH, Multhauf P, Leong L, Margolin K, Litchfield T, Akman S, Carr B, Bertrand M, Goldberg D, Blayney D, et al. Prospective randomized comparison of fluorouracil versus fluorouracil and high-dose continuous infusion leucovorin calcium for the treatment of advanced measurable colorectal cancer in patients previously unexposed to chemotherapy. J Clin Oncol. 1990 Mar;8(3):491-501.

Keyomarsi K, Moran RG. Folinic acid augmentation of the effects of fluoropyrimidines on murine and human leukemic cells. Cancer Res. 1986 Oct;46(10):5229-35.

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