Abstract Background: Base excision repair (BER), one of the pathways of DNA damage repair, has been implicated in chemoresistance. TRC102 acts through a novel mechanism to inhibit BER and cause DNA strand breaks, potentiating the antitumor activity of TMZ in preclinical models. We conducted a phase I trial of TRC102 in combination with TMZ to determine the safety, tolerability, and maximum tolerated dose of the combination; to evaluate the pharmacokinetics (PK) of each agent alone and in combination; and to assess DNA damage response (percent nuclear area of γH2AX foci) in circulating tumor cells (CTCs). Methods: Eligible pts were required to have refractory advanced solid tumors that had progressed following standard therapy; ≥ 18 yrs of age; ECOG PS 0-2; and adequate organ function. TRC102 and TMZ were administered orally once daily, D1-5 of q28d cycles; Starting dose level (DL 1) was TRC102 25 mg and TMZ 125mg/m2. Accrual to DL6 (TRC102 125 mg; TMZ 150 mg/m2) is ongoing. CTCs were obtained during C1 and on C2D1. Blood samples for PK analysis were obtained during C1. Results: Twenty pts have been enrolled to date; median age 59 yrs (range 45-78 yrs); median # of prior therapies: 3.5 (1-9); Dx: GI (6), H&N (4), breast (3), GYN (3), lung (2), soft tissue sarcoma (2). Fourteen pts are evaluable for response; 2 partial responses by RECIST have been observed to date (≥ 6 cycles; NSCLC and granulosa cell tumor of the ovary). Grade 3/4 toxicities (#pts): neutropenia (2), thrombocytopenia (1), lymphopenia (1), anemia (1), leucopenia (1), hypophosphatemia (1). PK in combination was similar to single agent PK reported for both drugs, with no evidence of a PK interaction. TRC102 levels required for preclinical activity (50ng/mL) were achieved at DL1. T1/2 of TRC102 was 26 hr. CTC analysis is ongoing. Conclusions: Combination of TRC102 with TMZ is well tolerated and clinical activity was observed with 2 partial responses to date. MTD has not been reached; accrual is ongoing. Paired tumor biopsies to assess for evidence of DNA damage response and apoptosis are planned at the MTD in the expansion phase. Citation Format: Woondong Jeong, Khanh Do, Alice Chen, Jennifer Zlott, Lamin Juwara, Yvonne Horneffer, Robert Kinders, Lihua Wang, Priya Balasubramanian, Larry Anderson, Elad Sharon, Howard Streicher, Richard Piekarz, Barbara Conley, Jerry Collins, James H. Doroshow, Shivaani Kummar. A phase I trial of oral TRC102 (methoxyamine HCl) in combination with temozolomide (TMZ) in patients with relapsed solid tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT316. doi:10.1158/1538-7445.AM2015-CT316