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

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).

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).

• 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.

• 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.