A Multi-Histology Phase II Study of 5-Fluoro-2'-Deoxycytidine With Tetrahydrouridine (FdCyd + THU)

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Multi-Histology Phase II Study of 5-Fluoro-2'-Deoxycytidine With Tetrahydrouridine (FdCyd + THU)

Conditions
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Head and Neck Neoplasms, Lung Neoplasms, Urinary Bladder Neoplasms, Breast Neoplasms

Intervention / Treatment
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* Drug: 5-Fluoro-2'-Deoxycytidine (FdCyd) + Tetrahydrouridine (THU)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 5-Fluro-2'-Deoxycytidine (FdCyd) + Tetrahydrouridine (THU)<br>FdCyd (100 mg/m(2)) + THU (350 mg/m(2)) administered 5 days/week for 2 weeks in 28-day cycles | Drug: 5-Fluoro-2'-Deoxycytidine (FdCyd) + Tetrahydrouridine (THU)<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | Progression-free survival (PFS) is defined as the time interval from start of treatment to documented evidence of disease progression. Disease progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) and is at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum of the LD recorded since the treatment started or the appearance of one or more new lesions. | until subject progressed or went off study for other reasons (up to approximately 1 year) | 
| Percentage of Participants With (Complete Response (CR) + Partial Response (PR)) to 5-Fluro-2'-Deoxycytidine (FdCyd) | Response was measured using the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response is disappearance of all target lesions. Partial response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum of the LD. | until subject progressed or went off study for other reasons (up to approximately 1 year) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). | Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. | Date treatment consent signed to date off study, approximately 109 months and 16 days. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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