FdCyd and THU for Advanced Solid Tumors

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, co-administration 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. Primary 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 Exploratory objectives: * Determine the pharmacokinetics of oral FdCyd and oral THU * Document preliminary evidence of activity of oral FdCyd and oral THU * Determine the clinical benefit rate (CR+PR+SD at 4 months) in patients treated with study drug combination at the MTD * Determine effect of study treatment on re-expression of p16 and other select genes silenced by methylation in circulating tumor cells and tumor biopsies * Evaluate the effect of study treatment on DNA (cytosine-5)-methyltransferase 1 and 3 (DNMT1 and DNMT3) expression in tumor biopsies Eligibility: -Adults with histologically documented solid tumors whose disease has progressed after at least one line of standard therapy. Design: * 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 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. * Up to 25 patients will be enrolled in the expansion cohort, from which mandatory pre- and post-dose tumor biopsies will be collected for the assessment of pharmacodynamic endpoints, at dose level 8 (160 mg FdCyd + 3000 mg THU 1x daily days 1-6 week 1, days 8-13 week 2, in 21-day cycles).