Skip to content

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

Phase I Trial of 5-Fluoro-2'-Deoxycytidine With Tetrahydrouridine

Status
Completed
Phases
Phase 1
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT00359606
Enrollment
58
Registered
2006-08-02
Start date
1999-04-30
Completion date
2012-06-30
Last updated
2015-05-06

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Neoplasms

Keywords

DNA Methylation, Advanced Cancer, Methyltransferase Inhibitor, Epigenetics, Gene Re-Expression

Brief summary

This phase I trial studies the side effects and best dose of 5-fluoro-2-deoxycytidine when given together with tetrahydrouridine in treating patients with solid tumors that have spread to other places in the body and usually cannot be cured or controlled with treatment (advanced). Drugs used in chemotherapy, such as 5-fluoro-2-deoxycytidine and tetrahydrouridine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Detailed description

PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of 5-fluoro-2'-deoxycytidine (5-fluoro-2-deoxycytidine) (FdCyd) administered by intravenous (IV) infusion over three hours with concomitant infusion of 350 mg/m2 of tetrahydrouridine (THU). II. To describe the toxicities of FdCyd co-infused with THU. III. To obtain preliminary evidence of anti-tumor activity in patients treated with this combination. IV. To evaluate the pharmacokinetics of FdCyd and THU when co-infused. V. To evaluate the oral bioavailability of FdCyd when co-administered with THU. VI. When feasible, to measure the relative levels of the messenger ribonucleic acid (mRNA)'s for thymidylate synthase, deoxycytidine kinase, deoxycytidylate (dCMP) deaminase and other relevant enzymes; and the methylation status of p16 and other genes relevant to neoplasia. OUTLINE: This is a dose-escalation study of 5-fluoro-2-deoxycytidine. Patients receive tetrahydrouridine orally (PO) on day 1; 5-fluoro-2-deoxycytidine PO on days 1 and 8; tetrahydrouridine IV over 3 hours on days 2-5, 8, and 9-12; and 5-fluoro-2-deoxycytidine IV over 3 hours on days 2-5 and 9-12 of course 1. For all subsequent courses, patients receive tetrahydrouridine IV over 3 hours and 5-fluoro-2-deoxycytidine IV over 3 hours on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically.

Interventions

DRUG5-Fluoro-2-Deoxycytidine (FdCyd)

Given PO and IV

OTHERLaboratory Biomarker Analysis

Correlative Studies

OTHERPharmacological Study

Correlative Studies

Given PO and IV

Sponsors

National Cancer Institute (NCI)
CollaboratorNIH
City of Hope Medical Center
Lead SponsorOTHER

Study design

Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE

Eligibility

Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No

Inclusion criteria

* Advanced, histologically-confirmed neoplastic disease refractory to standard therapy or for which no standard therapy exists * Karnofsky performance status of at least 60% and estimated survival of at least two months * Serum creatinine =\< 2.0 mg/dl or creatinine clearance \>= 50 ml/min * Absolute neutrophil count (ANC) \>= 1,500/ul * Platelets \>= 125,000/ul * Bilirubin =\< 1.5 mg/dl * Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) =\< 3 times the upper limits of normal * 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 * Patients must be ineligible for or have refused participation in higher priority institutional protocols * Written, voluntary, informed consent of the patient must be obtained in compliance with institutional, state and federal guidelines * 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 * 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 * 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 * 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 * Complete blood count (CBC), differential count, platelet count, and blood chemistries should be done no earlier than 72 hours prior to each cycle of chemotherapy * Pretreatment tests should be done no earlier than two weeks prior to the first cycle of chemotherapy * Priority for accrual will be given to patients with breast cancer due to the in vitro data suggesting potential activity for this disease

Design outcomes

Primary

MeasureTime frameDescription
Maximum tolerated dose (MTD) of 5-fluoro-2-deoxycytidine (FdCyd) when given with tetrahydrouridine (THU) determined by dose-limiting toxicities28 daysMTD is defined as the highest dose tested in which \< 33% of patients experienced dose limiting toxicity. The toxicities observed at each dose level will be summarized in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity (by National Cancer Institute Common Toxicity Criteria version 2.0 and nadir or maximum values for the laboratory measures), time of onset (i.e., cycle number), duration, and reversibility or outcome. Tables will be created to summarize these toxicities and side effects by dose and by cycle.
SurvivalTime from registration to time of death due to any cause, assessed up to 13 yearsSurvival and time to failure will be summarized with Kaplan-Meier plots to describe the outcome of patients treated on this protocol.
Time to treatment failureTime from registration to the first observation of disease progression, death due to any cause, or early discontinuation of treatment, assessed up to 13 yearsSurvival and time to failure will be summarized with Kaplan-Meier plots to describe the outcome of patients treated on this protocol.

Other

MeasureTime frameDescription
Levels of mRNA's of interestUp to 13 yearsThe relative levels of mRNA's of interest and other biochemical assessments will be tabulated and described. These levels will be compared with clinical response in an exploratory manner. However, the heterogeneity of the patient population and the small number of patients treated at each dose make formal statistical analysis of the molecular studies unlikely.
Pharmacokinetic parameters of 5-fluoro-2-deoxycytidine in combination with tetrahydrouridineBaseline, 15 & 30 minutes, 1, 2, 4, 6, 9 hours on days 1 & 8; baseline, 15 & 30 minutes, 1, 2, 2.5 hours after infusion start & 15 & 30 minutes, 1, 2, 4, 6 hours after infusion end on day 2; baseline on days 3, 9, & 15; 2.5 hours after infusion on day 12The pharmacokinetic data will be analyzed using compartmental and non-compartmental models for each patient. The estimated parameters will be tabulated by dose level with summary statistics (means and standard deviations, or medians and ranges). If appropriate, summary statistics will also be provided for the entire group of patients.

Countries

United States

Outcome results

None listed

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026