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
Intervention: 5-Fluoro-2'-Deoxycytidine (FdCyd) + Tetrahydrouridine (THU)
Intervention description: 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
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 95.0
Sex: All
Minimum age: 18 Years
Maximum age: 120 Years
Healthy volunteers: No
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

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.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Patients must have histologically documented metastatic or unresectable non-small cell
             lung cancer, head and neck cancer, urothelial transitional cell carcinoma, or breast
             cancer whose disease has progressed after at least one line of standard therapy.

          -  Patients with solid tumors (non-small cell lung cancer, head and neck cancer,
             urothelial transitional cell carcinoma, and breast cancer) must have measurable
             disease, defined as at least one lesion that can be accurately measured in at least
             one dimension (longest diameter to be recorded) as greater than or equal to 20 mm with
             conventional techniques or as greater than or equal 10 mm with spiral computed
             tomography (CT) scan. Patients with the above tumor types whose disease is limited to
             the skin are eligible at the discretion of the principal investigator (PI) and must
             have a physical exam with documentation of skin lesion(s) by color photography,
             including a ruler to estimate the size of the lesion(s).

          -  Diagnosis of malignancy must be confirmed by the department of pathology at the
             institution where the patient is enrolled prior to patient enrollment.

          -  Any prior therapy must have been completed greater than or equal to 4 weeks prior to
             enrollment on protocol and the participant must have recovered to eligibility levels
             from prior toxicity. Patients should be at least six weeks out from nitrosoureas and
             mitomycin C. Prior radiation should have been completed greater than or equal to 4
             weeks prior to study enrollment and all associated toxicities resolved to eligibility
             levels. Patients must be greater than or equal to 2 weeks since any investigational
             agent administered as part of a Phase 0 study (also referred to as an "early Phase I
             study" or "pre-Phase I study" where a sub-therapeutic dose of drug is administered) at
             the PI's discretion, and should have recovered to eligibility levels from any
             toxicities.

          -  Age greater than or equal to 18 years. Because no dosing or adverse event data are
             currently available on the use of 5-Fluoro-2'-Deoxycytidine (FdCyd) and
             Tetrahydrouridine (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 greater than or equal to 1,500/mcL

               -  platelets greater than or equal to 100,000/mcL

               -  total bilirubin less than 1.5 times institutional upper limit of normal

               -  Aspartate transaminase (AST)(Serum glutamic-oxaloacetic transaminase
                  (SGOT))/Alanine transaminase (ALT)(Serum glutamic pyruvic transaminase (SGPT))
                  less than or equal to 3 times institutional upper limit of normal; less than or
                  equal to 5 times upper limit of normal (ULN) for patients with liver metastases

        creatinine less than 1.5 times institutional upper limit of normal

        OR

        creatinine clearance greater than or equal to 60 mL/min for patients with creatinine levels
        above 1.5 times institutional upper limit of normal.

          -  Because FdCyd has been shown to be teratogenic in animals, pregnant women will be
             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 child-bearing potential and men must agree to use adequate
             contraception (hormonal or barrier method of birth control; abstinence) for the
             duration of study participation, and for 3 months after completion of study. 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.

        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 or confirmed diagnosis of human immunodeficiency virus (HIV) infection,
             active infection with Hepatitis B or 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.

          -  History of allergic reactions attributed to fluoropyrimidines (e.g., capecitabine,
             fluorouracil, fluorodeoxyuridine) or tetrahydrouridine.