14568 Background: GMX1777 is a soluble pro-drug which rapidly converts in serum to GMX1778, recently established to be a small molecule inhibitor of NAMPRT, the rate-limiting enzyme in the NAD+ salvage pathway. NAMPRT activity is increased in tumor cells dependent on the glycolytic pathway. The aims of this first-in-man study were to define a dose of GMX1777 for Phase II studies, characterize the safety of 24-hour infusions of GMX1777, and to determine the pharmacokinetic (PK) parameters of both GMX1777 and GMX1778. Methods: GMX1777 was administered at ascending doses as a 24 hour infusion every 21 days to successive cohorts of patients with advanced malignancies with no additional standard therapy options. Single patient cohorts were utilized until a toxicity >Grade (Gr) 1 was observed during cycle 1; then a standard 3+3 dose escalation schema was utilized to enroll patients in subsequent cohorts. During Cycle 1, PK samples were drawn at regular intervals before, during and after the 24 hour infusion. Results: Nine patients received doses of 60, 120, 160 or 200 mg/m2 over 24 hours. Twenty-seven doses have been administered. There were no toxicities >Gr 1 in the single patient enrolled at 60 mg/m2 during cycle 1; however Gr 2 toxicities were observed at 120 mg/m2 and the cohort was expanded to 3. Preliminary data indicate that adverse events of all grades with > 25% incidence overall were diarrhea (89%), nausea (67%), vomiting (66%), fatigue (56%) anemia (44%), insomnia (44%), pruritis (44%), rash (44%), thrombocytopenia (33%), myalgia (33%), and neuropathy (33%). Gr 3 and 4 events were single events of Gr 3 diarrhea at 60 mg/m2; Gr 3 infusion site infection and dehydration at 120 mg/m2; Gr 3 pruritis and purpura at 160 mg/m2; Gr 4 GI hemorrhage and Gr 4 thrombocytopenia at 200 mg/m2. The Gr 4 thrombocytopenia was a DLT. Three patients have had stable disease for > 3 months. Preliminary PK data document rapid conversion of GMX1777 to GMX1778 at all dose levels tested to date, and that exposure increases in a more than dose- proportional manner. Conclusions: GMX1777 can be administered as a 24 hour infusion with a tolerable safety profile. Identification of the mechanism of action of GMX1777 and its principal target organs for toxicity will allow more efficient optimization of its schedule of administration.