5-Fluoro-2'-Deoxcyctidine and Tetrahydrouridine to Treat Patients With Advanced Cancer
|ClinicalTrials.gov Identifier: NCT00359606|
Recruitment Status : Completed
First Posted : August 2, 2006
Last Update Posted : May 6, 2015
|Condition or disease||Intervention/treatment||Phase|
|Neoplasms||Drug: 5-Fluoro-2-Deoxycytidine (FdCyd) Other: Laboratory Biomarker Analysis Other: Pharmacological Study Drug: Tetrahydrouridine (THU)||Phase 1|
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||58 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase I Trial of 5-Fluoro-2'-Deoxycytidine With Tetrahydrouridine|
|Study Start Date :||April 1999|
|Actual Primary Completion Date :||June 2012|
|Actual Study Completion Date :||June 2012|
Experimental: Treatment (5-fluoro-2-deoxycytidine, tetrahydrouridine)
Patients receive tetrahydrouridine 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.
Drug: 5-Fluoro-2-Deoxycytidine (FdCyd)
Given PO and IV
Other: Laboratory Biomarker Analysis
Other: Pharmacological Study
Drug: Tetrahydrouridine (THU)
Given PO and IV
- Maximum tolerated dose (MTD) of 5-fluoro-2-deoxycytidine (FdCyd) when given with tetrahydrouridine (THU) determined by dose-limiting toxicities [ Time Frame: 28 days ]MTD 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.
- Survival [ Time Frame: Time from registration to time of death due to any cause, assessed up to 13 years ]Survival and time to failure will be summarized with Kaplan-Meier plots to describe the outcome of patients treated on this protocol.
- Time to treatment failure [ Time Frame: Time from registration to the first observation of disease progression, death due to any cause, or early discontinuation of treatment, assessed up to 13 years ]Survival and time to failure will be summarized with Kaplan-Meier plots to describe the outcome of patients treated on this protocol.
- Levels of mRNA's of interest [ Time Frame: Up to 13 years ]The 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 tetrahydrouridine [ Time Frame: Baseline, 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 12 ]The 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.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00359606
|United States, California|
|City of Hope National Medical Center|
|Duarte, California, United States, 91010|
|USC/Norris Comprehensive Cancer Center|
|Los Angeles, California, United States, 90089|
|University of California, Davis Cancer Center|
|Sacramento, California, United States, 95817|
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike|
|Bethesda, Maryland, United States, 20892|
|Principal Investigator:||Robert Morgan, MD||City of Hope Medical Center|