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

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
City of Hope Medical Center
ClinicalTrials.gov Identifier:
NCT00359606
First received: August 1, 2006
Last updated: May 5, 2015
Last verified: May 2015
  Purpose

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.


Condition Intervention Phase
Neoplasms
Drug: 5-Fluoro-2-Deoxycytidine (FdCyd)
Other: Laboratory Biomarker Analysis
Other: Pharmacological Study
Drug: Tetrahydrouridine (THU)
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Trial of 5-Fluoro-2'-Deoxycytidine With Tetrahydrouridine

Resource links provided by NLM:


Further study details as provided by City of Hope Medical Center:

Primary Outcome Measures:
  • Maximum tolerated dose (MTD) of 5-fluoro-2-deoxycytidine (FdCyd) when given with tetrahydrouridine (THU) determined by dose-limiting toxicities [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    Survival and time to failure will be summarized with Kaplan-Meier plots to describe the outcome of patients treated on this protocol.


Other Outcome Measures:
  • Levels of mRNA's of interest [ Time Frame: Up to 13 years ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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.


Enrollment: 58
Study Start Date: April 1999
Study Completion Date: June 2012
Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Names:
  • 5-FLUORO-2'-DEOXYCYTIDINE
  • 5-fluoro-2-deoxycytidine
  • FdCyd
  • Ro 5-1090
Other: Laboratory Biomarker Analysis
Correlative Studies
Other: Pharmacological Study
Correlative Studies
Drug: Tetrahydrouridine (THU)
Given PO and IV
Other Names:
  • Tetrahydrouridine
  • THU

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00359606

Locations
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
Sponsors and Collaborators
City of Hope Medical Center
Investigators
Principal Investigator: Robert Morgan, MD City of Hope Medical Center
  More Information

Additional Information:
Publications:
Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT00359606     History of Changes
Obsolete Identifiers: NCT00378807
Other Study ID Numbers: 98127, PHI-16, UM1CA62505, NCI-2015-00655, 06-C-0221
Study First Received: August 1, 2006
Last Updated: May 5, 2015
Health Authority: United States: Federal Government
United States: Food and Drug Administration

Keywords provided by City of Hope Medical Center:
DNA Methylation
Advanced Cancer
Methyltransferase Inhibitor
Epigenetics
Gene Re-Expression

Additional relevant MeSH terms:
Tetrahydrouridine
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 05, 2015