A phase I trial of GMX1777, an inhibitor of nicotinamide phosphoribosyl transferase (NAMPRT), given as a 24-hour infusion

3581 Background: GMX1777 is a pro-drug which converts to GMX1778, a potent and specific small molecule inhibitor of NAMPRT, the rate-limiting enzyme in NAD+ synthesis. 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 administered by 24-hr infusion with acceptable safety for phase II studies, and to determine the pharmacokinetic (PK) parameters of both GMX1777 and GMX1778. Methods: GMX1777 was administered at ascending doses as a 24 hour IV infusion q21 days to successive cohorts of patients with advanced malignancies. Single patient cohorts were utilized until a toxicity >Grade (Gr) 1 was observed during cycle (C) 1; then a standard 3+3 dose escalation schema was used. PK samples were drawn during C1. Results: 19 patients (11 males; median age 57) received doses of 60, 120, 160, 200 or 140 mg/m 2 over 24 hours. 49 doses were administered. There were no toxicities >Gr 1 during C1 at 60 mg/m 2 ; however Gr 2 toxicities were observed at 120 mg/m 2 and the cohort was expanded to 3 patients. Gr 4 GI hemorrhage and Gr 4 thrombocytopenia occurred at 200 mg/m 2 , leading to expansion of the 160 mg/m 2 cohort. 3/6 patients at 160 mg/m 2 had erythematous symmetrical Gr 3 rash occur during C2–5. Six patients enrolled at 140 mg/m 2 had no Gr 3 rash and 140 mg/m 2 was determined to be the MTD. Preliminary data indicate that the most common (>30%) adverse events of all grades were nausea (89%), diarrhea (79%), fatigue (68%), vomiting (58%), anorexia (42%), pruritis (42%), thrombocytopenia (42%), rash (37%), anemia (32%), constipation (32%), dyspnea (32%), and insomnia (32%). Lab findings include lymphopenia. Two patients had stable disease for > 4 cycles (6 & 4 mos), and 3 additional patients had SD for ≥ 3 mos. Preliminary PK data document rapid conversion of GMX1777 to GMX1778 at all dose levels. Conclusions: The MTD for GMX1777 administered as a 24 hour infusion q21 days is 140 mg/m 2 . Thrombocytopenia, GI hemorrhage, and skin rash (the last occurring after multiple cycles) were encountered at higher doses. Single-agent GMX1777 exhibited moderate clinical activity, suggesting that inhibition of NAMPRT should be explored in other schedules or in combination with other agents. [Table: see text]