Background: Poly(ADP-ribose) polymerase (PARP) enzymes are involved in DNA repair and activated by DNA strand breaks. DNA damage from carboplatin is associated with activation of PARP. Preclinical data indicate that PARP inhibition and trapping potentiates the anti-tumor effect of platinum chemotherapy. Talazoparib (T) is an oral, selective PARP inhibitor. This phase I study combines T with carboplatin (C) and paclitaxel (P). Methods: Two dosing schedules are being investigated. C is administered on day 1 and P on days 1, 8, and 15 of a 21-day cycle. T (100-1000mcg) is dosed once daily for days 1-7 (schedule A) or days 1-3 (schedule B) starting on day 1. Dose escalation is by 3+3 design. Key eligibility criteria include age 18+ with a solid incurable malignancy. Patients (pts) must have tumor type that is expected to respond to C + P or have BRCA germline or somatic mutation and adequate organ function. After 4-6 cycles of combination therapy, pts may continue the combination, change to C and intermittent T without P or change to T alone with continuous dosing. Each schedule will have a 6 pt dose expansion at the MTD. The starting dose for schedule B is the MTD from schedule A. Results: Schedule A results are reported: 23 pts (median age 55 yrs [range 37-70]) have been enrolled. Primary malignancies include breast (9), ovarian (3), SCC of skin/oropharynx (4), pancreatic (1), and other (5). 10 pts have known gBRCA1/2 mutations. Dose level 3 (T 350mcg with C AUC 6 + P 80mg/m²) exceeded the MTD with 2 of 3 pts experiencing hematologic dose limiting toxicities (DLTs). Expansion of dose level 2 (T 250mcg with C AUC 6 + P 80mg/m²) confirmed this level as the MTD. Most common adverse events included neutropenia (grade 3-4: 73.9%), anemia (grade 3-4: 39.1%), and thrombocytopenia (grade 3-4: 30.4%). Pts were on study a median of 15 weeks (range 1-98+). Of 17 pts with measurable disease, 9 (52.9%) had PR and 5 (29.4%) had SD. 35% of patients changed to T alone after combination chemotherapy. PBMC analysis for RAD51 foci, dH2AX, and PAR levels will be reported. Conclusions: The schedule A MTD and RP2D is T 250 mcg with C AUC 6 and P 80mg/m². This combination was tolerated with prolonged responses seen at lower dose T in combination with C+P. Clinical trial information: NCT02317874