Background: Temozolomide (TMZ) is an alkylating agent that generates DNA adducts that are repaired by direct DNA and base excision repair mechanisms. Methoxyamine (MX, TRC-102) is a small molecule that potentiates TMZ by binding to apurinic and apyrimidinic sites after removal of N3-methyladenine and N7-methylguanine, inhibiting site recognition of apurinic/apyrimidinic (AP) endonuclease. We conducted a phase I trial to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of intravenous MX when given with oral TMZ. Methods: Patients (pts) with advanced solid tumors, progression on standard treatment, and no CNS involvement were enrolled. A standard 3+3 design was used to assess TMZ (150-200 mg/m² orally) and MX (15-150 mg/m² IV). Dose Levels (DL) 1-3: TMZ day 1, MX day 4 in first 14 day cycle (C), TMZ days 1-5, MX day 1 in subsequent 28 day C; DL 4-7: TMZ days 1-5, MX day 1 of 28 day C. DLT period was 42 days for DL 1-3 and 28 days for DL 4-7. Tumor response assessed per RECIST and AEs by CTCv4. Pharmacokinetics (PK) of 1-hour MX infusion and comet assays on peripheral blood mononuclear cells were performed. Results: 38 pts were enrolled: 45% male, 82% white, 16% African American, 2% Asian, median age 59.5 years (38-76), mean number of C 2.9 (1-13). No DLTs were observed. Grade 3 AEs: fatigue (n = 2), lymphopenia (n = 2), anemia (n = 1), INR (n = 1), leukopenia (n = 1), neutropenia (n = 1), allergic reaction (n = 1), constipation (n = 1), psychosis (n = 1) and paranoia (n = 1). Late grade 4 AEs: thrombocytopenia (n = 2) and confusion (n = 1). Partial response was seen in 1 pt with pancreatic adenocarcinoma (PAC) (8 mo); prolonged stable disease in 1 pt with PAC (4 mo), pancreatic neuroendocrine tumor (NET) (9 mo), small bowel NET (5.5 mo), ovarian cancer (12.5 mo) and non-small cell lung cancer (5.5 mo). MX PK was linear with dose and was not affected by concomitant TMZ. Geometric means (SD) were: t½ 45.6 (11.5) h, Cl 31.7 (15.6) L/h/m² (n = 31). Conclusions: TMZ 200 mg/m² may be safely administered with MX 150 mg/m² with minimal toxicity. Evidence of antitumor activity was observed, particularly in pancreatic adenocarcinoma and neuroendocrine tumors. Further studies assessing this drug combination are warranted. Clinical trial information: NCT00892385