Phase I clinical trial of temozolomide and methoxyamine (TRC-102) in patients with advanced solid tumors.

2558 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 REC...