Purpose: Based on pre-clinical data, we hypothesized that low doses of chemotherapy (10% of therapeutic doses) with full dose of a PARP inhibitor could have improved efficacy and tolerability. Experimental Design: In this Phase 1 dose escalation study, patients with BRCA-normal advanced malignancies were assigned to either talazoparib (TAL)/temozolomide(TMZ) or TAL/irinotecan(IRI). TAL was dose-escalated from 500 mcg to 1 mg daily before dose-escalation of TMZ/IRI. The starting dose of TMZ was 25mg/m2/day orally on days 1-5 and IRI was 25mg/m2/day intravenously on days 1,15. The primary objectives of this trial were safety and tolerability, dose-limiting toxicities (DLTs), and Maximum Tolerated Dose (MTD). Results: Of 40 patients enrolled, 18 (mean: 7 prior therapies) were enrolled in TAL+TMZ and 22 in TAL + IRI. DLT’s were hematologic in both arms, but all hematologic adverse events resolved with either treatment interruption and/or dose reductions of TAL. The MTDs were TAL 1 mg+TMZ 37.5mg/m2 and TAL 1mg+IRI 37.5mg/m2. There were four partial responses in the TAL+TMZ arm and five in the TAL+IRI arm for a response rate of 23% (9/40). The pharmacokinetic profiles of TAL+TMZ/IRI were similar to that of TAL monotherapy. Responses were seen independent of HR status and HRD score. Conclusions: These results show that TAL with low-dose TMZ or IRI is reasonably well-tolerated and demonstrates clinical activity in a wide range of cancers. Randomized trials of TAL with or without low dose chemotherapy are ongoing in small cell lung cancer (SCLC) and ovarian cancer.