2573 Background: TH-302 is a 2-nitroimidazole prodrug of the DNA alkylator, bromo-isophosphoramide mustard (Br-IPM). TH-302 is essentially inactive under normoxia but in severe hypoxia and in the presence of certain reductases, it is reduced and Br-IPM is released. Methods: Eligible patients (pts) had ECOG ≤1, advanced or metastatic solid tumors, evaluable by RECIST, and acceptable hematologic, liver and renal function. A modified accelerated titration design was used. TH-302 was administered intravenously over 30–60 minutes on Day 1, 8 and 15 of a 28-day cycle. CT scans were obtained after every 2 cycles. Detailed pharmacokinetic sampling was performed on Days 1 and 15. The primary objectives of this study were to determine the dose limiting toxicity (DLT) and the maximum tolerated dose (MTD). Results: Twenty-nine pts enrolled at 3 sites at 9 dose levels from 7.5–670 mg/m2. Median age: 64y. 20 male/9 female. ECOG 0/1: 16/13. Primary tumor: prostate (8), colorectal (8), lung (5) other (8). Two of 5 pts at 670 mg/m2 had DLT: Herpes simplex perianal/rectal ulcers and dehydration due to mucositis. Reversible skin and mucosal adverse events (AE) occurred in 12 of 15 (80%) pts at ≥480 mg/m2 including grade 3 events in 3 pts. The most common TH-302-related AEs were nausea, skin lesions, vomiting and fatigue. Hematologic toxicity was mild and limited: two pts with grade 1 and one pt with grade 2 neutropenia and five pts with grade 1 thrombocytopenia. Five pts had grade 3 and one grade 4 lymphopenia. Four pts have enrolled at an intermediate dose of 575 mg/m2 with no DLT so this is likely the MTD and is well above the predicted biologic effective dose of 100 mg/m2. One pt with SCLC treated at 480 mg/m2 and one with melanoma treated at 670 mg/m2 had unconfirmed partial responses; 12 pts had stable disease (6 continuing after 4 or more cycles), 7 had PD, 4 were unevaluable and 4 are too early to assess. Cmax and AUC for TH-302 and Br-IPM increased linearly with no accumulation at Day 15. Conclusions: Weekly TH-302 has remarkably little hematologic toxicity. Skin and mucosal AEs have developed at the higher dose levels. Skin/mucosa are known to have hypoxic regions. TH-302 is the first HAP to demonstrate tumor responses in Phase I. The MTD is likely 575 mg/m2. Studies in combination with chemotherapy are ongoing. [Table: see text]