Background: RX-3117 is an oral small-molecule antimetabolite, cyclopentyl pyrimidyl nucleoside that is activated by uridine cytidine kinase 2. RX-3117’s efficacy in xenograft models (Colo-205, H460, H69 and CaSki), which are moderately sensitive or resistant to gemcitabine, indicates that RX-3117 may have the potential to treat tumors that do not respond to gemcitabine or have become gemcitabine resistant. Methods: This phase I, open-label, multicenter study evaluates the efficacy and safety of RX-3117 in subjects with solid tumors). RX-3117 is administered 3 times a week for 3 weeks with 1 week off during each 4 week cycle. Dose escalation starts with an accelerated design treating 1 subject per dose followed by a standard 3 + 3 design using a modified Fibonacci sequence after the occurrence of a single related Grade 2 or greater adverse event. The primary endpoint is the overall safety profile characterized by the type, frequency, severity, timing of onset, duration and relationship to study therapy of any adverse events, or abnormalities of laboratory tests or electrocardiograms, any dose limiting toxicities that occur during Cycle 1, serious adverse events, or adverse events leading to study treatment discontinuation. Secondary endpoints include pharmacokinetic parameters (e.g., time to maximum observed concentration [T_max], maximum observed plasma concentration [C_max], trough concentration [C_trough], area under the concentration-time curve [AUC]) and Indices of anti-tumor activity (e.g., overall response rate , time to response, duration of response, and progression-free survival). Exploratory endpoints are baseline biomarker expression/concentration, including (but not limited to) concentrative nucleoside transporter 2; equilibrative nucleoside transporter 1; uridine-cytidine kinase 1 and 2; DNA methyltransferase 1, 3a and 3b; and ribonucleotide reductases 1 and 2. Target recruitment is approximately 30 subjects. Eligible subjects must have confirmed histologic or cytologic evidence of metastatic or locally advanced solid neoplasm that has failed to respond to standard therapy, progressed despite standard therapy or for which standard therapy does not exist. Clinical trial information: NCT02030067