Background: TRC102 is a novel small molecule that binds to reactive aldehyde created in apurinic/apyrimidinic (AP) sites, inhibiting base excision repair (BER), which is implicated as a pathway of resistance to alkylating agents. In preclinical studies, TRC102 demonstrated synergistic anti-tumor activity when TRC102 was combined with the alkylating agent temozolomide (TMZ) and the phase 1 trial of this combination reported 4 patients with partial response, two of which were of granulosa cell ovarian cancer (GCOC) histology. Here we report the phase 2 results of the combination TRC102 and TMZ in the GCOC cohort (NCT01851369). Methods: We conducted an open-label, single center Simon 2-stage trial including patients (pts) with GCOC who received ≥ one line of therapy in the metastatic setting. TRC102 was dosed at 125 mg (100 mg for BSA < 1.6) and TMZ was dosed at 150 mg/m² orally on day (D) 1-5 in 28-day cycle (C). Restaging CT scans every 2 Cs were evaluated by RECIST v1.1. Mandatory paired biopsies (C1D1 pretreatment and C1D4 3-4 hours after drug administration) and optional blood samples for circulating tumor cells (CTC) were collected at set time points for pharmacodynamic analyses. Results: Nine pts with GCOC (7 adult, 2 juvenile histology) were enrolled as of 12/23/2022. Median age was 53 years (range 21-79) and median prior lines of therapy was 6 (range 3-9). Most common grade (G) 1 and G2 treatment-related adverse events (trAE) were fatigue, myelosuppression, nausea, and vomiting. One pt had G3 trAE of vomiting. No toxicity-related treatment discontinuations and no treatment-related deaths were reported. The median PFS for the 8 evaluable pts was 3.7 months. One pt exited the study after one C per pt’s choice with no restaging available. Four pts had stable disease (SD) as their best response. Of those who had SD, one pt completed 26 Cs prior to progression, one pt completed 11 Cs as of data cut-off but continues on study, two pts completed 6 Cs (one pt went off study for PD and one by pt choice). MGMT analysis was performed for 3 pts, including the pt still on study after 11 Cs with SD. MGMT immunohistochemistry (IHC) of pretreatment biopsies were positive for protein expression, consistent with unmethylated MGMT status. No significant induction in the levels of the DNA damage response markers γH2AX, pNbs1, and RAD51 was detected in 5 evaluable post-treatment biopsy samples as compared to the pre-treatment timepoint. Conclusions: TRC102 combined with TMZ was well-tolerated and demonstrated durable disease control in 4 pts, which is promising in this heavily pretreated GCOC cohort. MGMT analysis suggests that unmethylated MGMT status and protein expression does not preclude response to TRC102/TMZ combination therapy. Analysis of CTCs and biopsy samples are ongoing to further elucidate possible biomarkers of response. Funded by NCI Contract No. HHSN261201500003I. Clinical trial information: NCT01851369.