Background: TRC102 inhibits BER by binding to abasic sites and acting as a topo II poison to cause DNA strand breaks; it potentiates the activity of alkylating agents including TMZ in murine models. In xenograft studies, TRC102 efficiently enhanced the antitumor effect of TMZ regardless of cell line genetic characteristics, e.g., O⁶-methylguanine DNA-methyltransferase, mismatch repair (MMR), or p53 status. This is the first report for the expansion phase (the escalation phase was reported previously (ASCO2016)). Methods: We conducted a phase 1 trial of TRC102with TMZ in patients (pts) with refractory solid tumors. Eligibility criteria included adults that had progressed on standard therapy, ECOG PS of 0-2, and adequate organ function. TRC102 and TMZ were given orally days 1-5, in 28-day cycles. The pharmacokinetic and pharmacodynamic profile of TRC102 with TMZ was evaluated. Antitumor responses were determined using RECIST 1.1 criteria. The DNA damage response (DDR) markers γH2Ax, pNbs1, and Rad51 were evaluated in the expansion cohort at DL6, tested by previously described methods on paired tumor biopsies prior to and after the first course of therapy. Results: After the recommended Phase 2 Dose was defined as DL6 (TRC102 125mg, TMZ 150mg/m² D1-5), 15 pts were accrued to the expansion cohort between 9/2015 to 11/2016. A total of 52 pts were enrolled (37 escalation, 15 expansion). Grade 3/4 adverse events included neutropenia (13%), anemia (the DLT;10%), thrombocytopenia (7%), hemolysis (5%) or hypophosphatemia (3%). 4 pts had a partial response (PR) (NSCLC, ovarian (2), and colon); 13 pts had stable disease (SD), 29 progressive disease (PD), and 6 were not evaluable; three pts remain on study. 11/14 paired biopsies were suitable for analysis. Rad51 signal was induced in 6/11pts. One patient showed γH2Ax and 2 showed pNbs1 induction. 4/5 colon cancer specimens had evidence of DDR marker induction. Conclusions: The combination of TRC 102/TMZ is active with 4 PRs and 13 SDs, and the side effect profile is manageable. DDR markers were induced in 4 of 5 paired colon biopsies indicating DNA damage following treatment. A phase 2 trial of patients with colon cancer, NSCLC, and granulosa cell ovarian cancer is accruing. Clinical trial information: NCT01851369