Background: Niraparib (Np) is an oral, highly potent and selective PARP1/2 inhibitor. The hypothesis for this study is 1) PARP inhibition of DNA repair damage is potentiated with TMZ. 2) PARP inhibition restores sensitivity to TMZ mismatch repair-deficient tumors. Methods: This was a multi-center (3), open-label, non-randomized two-part study in patients with advanced cancers. Patients were treated with Np (once daily continuously) + TMZ (once daily for first five days) in 28-day treatment cycles. In Part A, the objective was to determine the preliminary MTD of the two drugs in combination. Part B was to explore the efficacy and tolerability of this combination in two cohorts (recurrent GBM and melanoma). The study was closed after defining MTD in Part A. Results: There were 19 patients treated in Part A with Np at 3 dose levels 30 mg (6 subjects), 40 mg (10 subjects), and 70 mg (3 subjects) and 150 mg/m2 TMZ once daily. The MTD and RP2D was determined to be 40 mg Np and 150 mg/m2 TMZ. The DLT of Grade 4 Thrombocytopenia occurred in 2/10 patients at the 40 mg dose level for Np. The DLT of Grade 4 neutropenia occurred in 1/3 patients at the 70 mg dose level for Np. At this dose level all 3 patients enrolled experienced Grade 4 thrombocytopenia with only one patient meeting protocol-specified DLT criteria. The most frequently reported AEs were thrombocytopenia (78.9%), anemia (68.4%), and leukopenia (57.9%). The most common ≥ grade 3 AEs were thrombocytopenia (52.6%), neutropenia (31.6%), and neoplasm progression (15.8%). Based on the in vitro metabolism data, the likelihood of a drug interaction between Np and TMZ is highly unlikely. Out of 16 evaluable subjects, 1 subject reported a PR (Glioblastoma), 2 subjects experienced SD (Malignant melonama and Serous ovarian carcinoma) and 13 subjects had PD. Conclusions: Niraparib, dosed at 40 mg continuously in combination with 150mg/m2 TMZ was tolerable and demonstrated antitumor activity. 40 mg Np and150 mg/m2 TMZ was considered an MTD and RP2D. A future study will evaluate full dose, 300 mg daily Np in combination with escalating TMZ dose levels. Clinical trial information: NCT01294735.