A Multi-Histology Phase II Study of 5-Fluoro-2'-Deoxycytidine With Tetrahydrouridine (FdCyd + THU)
Condition: Head and Neck Neoplasms; Lung Neoplasms; Urinary Bladder Neoplasms; Breast Neoplasms
MeSH terms: Neoplasms; Breast Neoplasms; Lung Neoplasms; Head and Neck Neoplasms; Urinary Bladder Neoplasms
Study type: Interventional
Phase: Phase 2

Summary: 
      Background:

        -  Two experimental drugs, FdCyd (also called 5-fluoro-2'-deoxcytidine), and THU (also
           called tetrahydrouridine), are undergoing trials to test their effectiveness in treating
           cancer that has not responded to standard therapies. FdCyd is thought to work by
           changing how genes work in cancer cells. THU does not have any anticancer effects on its
           own, but it helps keep the other drug, FdCyd, from being broken down by the body.

        -  These drugs are being tested in several separate clinical trials.

      Objectives:

        -  To determine if FdCyd and THU can work together to control tumor growth.

        -  To evaluate the safety and tolerability of FdCyd and THU when given together.

      Eligibility:

      - Individuals 18 years of age and older who have advanced non-small cell lung cancer, breast
      cancer, bladder cancer, or head and neck cancer that has progressed after receiving standard
      treatment or for which no effective therapy exists.

      Design:

        -  The drugs are given over 28-day periods called cycles. FdCyd and THU are given through a
           vein for about 3 hours each day on days 1, 5 and 8, 12 of each cycle.

        -  Clinical Center visits: FdCyd and THU will be given through a vein on days 1, 5 and 8,
           12 of each cycle. During the Clinical Center visits, researchers will perform study
           tests and procedures to see how the study drugs are affecting the body.

        -  Patients will undergo a number of tests and procedures during the treatment cycle,
           including physical examinations, blood and urine samples for standard tests, imaging
           studies (ultrasound, magnetic resonance imaging (MRI) or computed tomography (CT) scans)
           to evaluate tumor growth, and blood and urine samples to evaluate the amount of FdCyd
           and THU in the body and the body's response to the drugs.

        -  Patients may continue to receive FdCyd and THU if their cancer does not grow, if they do
           not have too many side effects, and if they are willing to do so.
    

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 area under the curve (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 deoxyribonucleic acid (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.

      Primary objective:

      -Determine progression-free survival (PFS) and/or the response rate (Complete Response (CR) +
      Partial Response (PR)) of FdCyd administered 5 days per week for 2 weeks, in 28-day cycles,
      by intravenous infusion over 3 hours along with THU in patients with breast cancer, head and
      neck cancer, non-small cell lung cancer (NSCLC), and urothelial transitional cell carcinoma.

      Exploratory objectives:

        -  Evaluate whether treatment with FdCyd and THU alters DNA methylation patterns in tumor
           biopsy samples before and during treatment by long interspersed nuclear element-1
           (LINE-1) analysis.

        -  Evaluate the safety and tolerability of FdCyd (100 mg/m(2)) + THU (350 mg/m(2))
           administered 5 days per week for 2 weeks, in 28-day cycles, by intravenous infusion over
           3 hours.

        -  Measure changes in the number of circulating tumor cells (CTCs) following treatment with
           FdCyd plus THU.

      Eligibility:

      -Patients with histologically documented non-small cell lung cancer, head and neck cancer,
      urothelial transitional cell carcinoma, and breast carcinoma.

      Design:

        -  This is a multicenter trial with National Cancer Institute (NCI) as the coordinating
           center and the California Cancer Consortium and University of Pittsburgh Medical Center
           (UPMC) as participating sites.

        -  FdCyd will be administered as an intravenous (IV) infusion over 3 hours with 20% of the
           daily dose of THU administered as an IV push and the remaining 80% co-administered with
           FdCyd by 3-hour infusion daily for 5 consecutive days of treatment per week for 2
           consecutive weeks, followed by 2 weeks of no treatment, in a 28-day cycle.

        -  Blood and optional tumor biopsies for pharmacodynamic and pharmacokinetic studies will
           be obtained.

        -  The study will accrue a maximum of 165 patients including all centers.
    

Intervention name(s): 5-Fluoro-2'-Deoxycytidine (FdCyd) + Tetrahydrouridine (THU)
Intervention type(s): Drug
Intervention description(s): FdCyd, a fluoropyrimidine nucleoside analog, has a short (10-minute) half-life and is rapidly degraded in vivo by cytidine deaminase. However, co-administration with THU, an inhibitor of cytidine/deoxycytidine deaminase, has been shown to increase the area under the curve (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 deoxyribonucleic acid (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.
Intervention MeSH terms: Tetrahydrouridine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: DNA Methylation; Advanced Cancer; Methyltransferase Inhibitor; Epigenetics; Gene Re-Expression; Breast Cancer; Head and Neck Cancer; Lung Cancer; Non-Small Cell Lung Cancer; Bladder Cancer