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

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ClinicalTrials.gov Identifier: NCT00359606
Recruitment Status : Completed
First Posted : August 2, 2006
Last Update Posted : May 6, 2015
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
City of Hope Medical Center

Tracking Information
First Submitted Date  ICMJE August 1, 2006
First Posted Date  ICMJE August 2, 2006
Last Update Posted Date May 6, 2015
Study Start Date  ICMJE April 1999
Actual Primary Completion Date June 2012   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 5, 2015)
  • 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.
Original Primary Outcome Measures  ICMJE Not Provided
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures
 (submitted: May 5, 2015)
  • 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.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 5-Fluoro-2'-Deoxcyctidine and Tetrahydrouridine to Treat Patients With Advanced Cancer
Official Title  ICMJE Phase I Trial of 5-Fluoro-2'-Deoxycytidine With Tetrahydrouridine
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Neoplasms
Intervention  ICMJE
  • 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
Study Arms  ICMJE 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.
Interventions:
  • Drug: 5-Fluoro-2-Deoxycytidine (FdCyd)
  • Other: Laboratory Biomarker Analysis
  • Other: Pharmacological Study
  • Drug: Tetrahydrouridine (THU)
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 5, 2015)
58
Original Enrollment  ICMJE
 (submitted: August 1, 2006)
80
Actual Study Completion Date  ICMJE June 2012
Actual Primary Completion Date June 2012   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00359606
Other Study ID Numbers  ICMJE 98127
PHI-16 ( Other Identifier: California Cancer Consortium )
UM1CA62505 ( Other Grant/Funding Number: National Cancer Institute )
NCI-2015-00655 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
06-C-0221 ( Other Identifier: National Cancer Institute )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party City of Hope Medical Center
Study Sponsor  ICMJE City of Hope Medical Center
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Robert Morgan, MD City of Hope Medical Center
PRS Account City of Hope Medical Center
Verification Date May 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP