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

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.