FdCyd and THU for Advanced Solid Tumors

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT01534598
First received: February 15, 2012
Last updated: September 26, 2014
Last verified: September 2014
  Purpose

Background:

- FdCyd (also called 5-fluoro-2'-deoxycytidine) and THU (also called tetrahydrouridine) are experimental cancer treatment drugs. FdCyd may change how genes work in cancer cells. THU helps keep FdCyd from being broken down by the body. FdCyd and THU have been given to people on other cancer treatment trials, usually by vein. Researchers want to give FdCyd and THU by mouth to see if they work against cancers that have not responded to earlier treatments.

Objectives:

- To test oral FdCyd and THU on advanced solid tumors that have not responded to earlier treatments.

Eligibility:

- Individuals at least 18 years of age who have advanced solid tumors that have not responded to standard treatments.

Design:

  • Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Imaging studies and tumor samples will used to study the cancer before treatment.
  • FdCyd and THU will be given in 21-day cycles. THU should be taken 30 minutes before taking FdCyd.
  • Participants will take FdCyd and THU by mouth, once a day, for 3 days at the beginning of the first and second weeks of each cycle (days 1 3 and 8 10). The drugs will not be taken during the entire third week of each cycle.
  • Treatment will be monitored with frequent blood tests and imaging studies.
  • Treatment will continue as long as the cancer is responding to the drugs and serious side effects do not develop....

Condition Intervention Phase
Neoplasms
Drug: FdCyd + THU
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Trial of Oral 5-Fluoro-2-Deoxycytidine With Oral Tetrahydrouridine in Patients With Advanced Solid Tumors ` +

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Safety and tolerability [ Time Frame: 1 cycle ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Pharmacokinetics [ Time Frame: Cycle 1 Day 3 ] [ Designated as safety issue: No ]

Estimated Enrollment: 68
Study Start Date: January 2012
Estimated Study Completion Date: April 2016
Estimated Primary Completion Date: April 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Single Arm
FdCyd + THU administered on an intermittent schedule in 21-day cycles per dose escalation table. THU will be administered orally at a fixed dose of 3000 mg 30 minutes prior to FdCyd.
Drug: FdCyd + THU
Intravenous FdCyd with THU has been evaluated in a Phase I clinical trial with some preliminary evidence of activity. This trial will investigate oral administration of the drugs, which was shown be feasible in an expansion cohort of the previous trial.

Detailed Description:

Background:

  • 5-Fluoro-2-deoxycytidine (FdCyd), a fluoropyrimidine nucleoside analog, has a short (10-minute) half-life and is rapidly degraded in vivo by cytidine deaminase. However, coadministration with tetrahydrouridine (THU), an inhibitor of cytidine/deoxycytidine deaminase, has been shown to increase the AUC of the parent compound more than 4-fold. Increased FdCyd exposure allows it to be taken up intracellularly and converted to its triphosphate, which is incorporated into DNA and inhibits the action of the enzyme DNA methyltransferase (DNMT). Inhibition of DNMT, and in turn DNA methylation, can result in the re-expression of tumor suppressor genes.
  • Intravenous FdCyd with THU has been evaluated in a Phase I clinical trial with some preliminary evidence of activity. This trial will investigate oral administration of the drugs, which was shown to be feasible in an expansion cohort of the previous trial.

Objectives:

  • Establish the safety and tolerability of oral FdCyd in combination with oral THU administered on an intermittent schedule in 21-day cycles to patients with refractory solid tumors
  • Determine the pharmacokinetics of oral FdCyd and oral THU
  • Document preliminary evidence of activity of oral FdCyd and oral THU
  • Determine effect of study treatment on re-expression of select genes silenced by methylation in circulating tumor cells
  • Determine the clinical benefit rate (CR plus PR plus SD at 4 months) in patients treated with study drug combination at the MTD.

Eligibility:

-Adults with histologically documented solid tumors whose disease has progressed after at least one line of standard therapy.

Design:

Please note: As of 02/13, we have received and reviewed PK data through dose level 4. PK data show that the target Cmax has been achieved; therefore, following enrollment to DL5 (160 mg for 3 days/week for 2 out of 3 weeks) we are increasing the number of days of administration of FdCyd with THU per dose escalation.

  • This is a multicenter trial with NCI as the coordinating center.
  • FdCyd and THU will be administered on an intermittent schedule in 21-day cycles. THU will be administered orally at a fixed dose of 3000 mg 30 minutes prior to FdCyd.
  • The trial will follow a standard Phase I dose escalation design (3-6 patients per cohort).
  • Consideration will be given to increasing the days of administration of FdCyd with THU after a target maximum plasma concentration of FdCyd is reached.
  • Blood and urine for pharmacokinetic studies will be obtained from all patients. Blood for

pharmacodynamic studies will be obtained after we achieve a target Cmax of 1microM.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • Patients must have histologically documented solid tumors whose disease has progressed on standard therapy that is known to be associated with a survival advantage or have disease for which there is no known standard therapy.
  • Patients must have measurable or evaluable disease.
  • Diagnosis of malignancy must be confirmed by the department of pathology at the institution where the patient is being enrolled prior to patient enrollment.
  • Patients must have completed any chemotherapy, radiation therapy, biologic therapy, or major surgery greater than or equal to 4 weeks prior to enrollment (6 weeks for nitrosoureas or mitomycin C). Patients must be greater than or equal to 2 weeks since any prior administration of a study drug in a Phase 0 or equivalent study, at the discretion of the Principal Investigator. Patients must have recovered to eligibility levels from prior toxicity or adverse events. Patients with bone metastases or hypercalcemia on IV bisphosphonate treatment prior to study entry may continue this treatment.
  • Age greater than or equal to18 years. Because no dosing or adverse event data are currently available on the use of FdCyd and THU in patients less than 18 years of age, children are excluded from this study, but may be eligible for future pediatric Phase I combination trials.
  • Karnofsky performance status greater than or equal to 60%.
  • Life expectancy of greater than 3 months.
  • Patients must have normal organ and marrow function as defined below:

    • absolute neutrophil count< TAB> greater than or equal to 1,500/mcL
    • platelets< TAB> < TAB> < TAB> greater than or equal to 100,000/mcL
    • total bilirubin< TAB> < TAB> < TAB> less than or equal to 1.5 X institutional upper limit of normal
    • AST(SGOT)/ALT(SGPT)< TAB> greater than or equal to 3 X institutional upper limit of normal
    • creatinine< TAB> < TAB> < TAB> less than 1.5 X institutional upper limit of normal

OR

--creatinine clearance< TAB> < TAB> greater than or equal to 60 ML/min for patients with creatinine levels

< TAB> < TAB> < TAB> < TAB> Above 1.5 X institutional upper limit of normal

  • Because FdCyd has been shown to be teratogenic in animals, pregnant women are excluded from this trial. Nursing women are also excluded, as there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with FdCyd. Women of childbearing potential must agree to either abstain from sexual intercourse or use two forms of acceptable birth control, including one barrier method, for 4 weeks prior to study entry, for the duration of study participation, and for 3 months after completion of study. Men must use a latex condom every time they have sexual intercourse during therapy and for 3 months after study completion, even if they have had a successful vasectomy. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she or her partner should inform the treating physician immediately.
  • Ability to understand and the willingness to sign a written informed consent document.
  • Patients should not be receiving any other investigational agents.
  • Ability to swallow liquids.
  • Willingness to provide blood and urine samples for research purposes.

EXCLUSION CRITERIA:

  • Patients with clinically significant illnesses which would compromise participation in the study, including, but not limited to active or uncontrolled infection, immune deficiencies, known HIV infection requiring protease inhibitor therapy, Hepatitis B, Hepatitis C, uncontrolled diabetes, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  • Patients with known brain metastases or carcinomatous meningitis are excluded from this clinical trial, with the exception of patients whose brain metastatic disease status has remained stable for greater than or equal to 2 months after treatment of the brain metastases. Patients should be on stable doses of anti-seizure medications. These patients may be enrolled at the discretion of the Principal Investigator.
  • History of allergic reactions attributed to fluoropyrimidines (e.g., capecitabine, fluorouracil, fluorodeoxyuridine) or tetrahydrouridine.
  • Malabsorption syndrome or other conditions that would interfere with intestinal absorption.
  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: NCT01534598

Contacts
Contact: Deborah E Allen, R.N. (301) 402-5640 allendeb@mail.nih.gov
Contact: James H Doroshow, M.D. (301) 496-4291 doroshoj@mail.nih.gov

Locations
United States, California
University of California, Davis Recruiting
Davis, California, United States, 95616
University of Southern California Health Sciences Campus Recruiting
Los Angeles, California, United States, 90033
Contact: James Doroshow, M.D.    301-496-4916    doroshoj@mail.nih.gov   
City of Hope Medical Group Recruiting
South Pasadena, California, United States, 91030
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    (888) NCI-1937      
United States, Pennsylvania
Penn State Hershey Cancer Institute Recruiting
Hershey, Pennsylvania, United States
Sponsors and Collaborators
Investigators
Principal Investigator: James H Doroshow, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT01534598     History of Changes
Other Study ID Numbers: 120066, 12-C-0066
Study First Received: February 15, 2012
Last Updated: September 26, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
DNA Methylation
Advanced Cancer
Methyltransferase Inhibitor
Epigenetics
Gene Re-Expression
Cancer
Solid Tumor

ClinicalTrials.gov processed this record on October 30, 2014