Background: The PARPi O has single-agent activity against BRCA1/2 mutation carriers (Br/Ov mut+) Br/OvCa. We hypothesized addition of C to O to stress the DNA repair machinery would further improve this clinical benefit. Methods: A 3x3 dose escalation (NCT00647062) incorporated daily oral O at 100 or 200 mg q12h (dose level [DL] 1/2) with IV C AUC3 on day 8 then every 21d; DL6-9 gave O d1-7 at 200 then 400mg q12h, with C AUC 3 on d2 then escalation to AUC5 (no DL3-5). No more than 8 O/C cycles were given, then O was taken daily until progression. Safety was assessed every cycle and response assessed every other cycle. PBMCs were collected preC1, d3 or d7, and prior to C2 for PARP activity measured by a PAR incorporation ELISA. Results: 30 women (26 serous Ov/4 Br) were treated on 6 DLs. All OvCa pts were previously exposed to platinum (from last platinum 6-55mos, median=14). DLT was thrombocytopenia and delayed neutropenic recovery (DL2: O 200 mg q12h/C AUC3 [2/5 pts]). MTD was not reached. RP2D is DL9, O 400mg q12h d1-7 with C AUC5 [1/6 DLT, delayed marrow recovery]. Gr 3/4 AEs included anemia (10%), thrombocytopenia (20%), neutropenia (17%), fatigue (3%) and C hypersensitivity (13%). 6 pts prematurely discontinued C due to either allergic reaction (4) or myelosuppression (2). 3 pts with C AUC5 required PEG-filgrastim on at least 1 cycle. Of 27 evaluable pts, PR was seen in 8/23 OvCa pts (4-24 cycles) and 3/4 BrCa pts (2 TNBC; 1 ER/PR+; 6-8 cycles); stabilization occurred in 11/23 OvCa pts (4-24 cycles) and 1 BrCa pt (10 cycles): clinical benefit 83% OvCa, 4/4 BrCa. PBMC PAR concentrations were markedly reduced with O at all DL. A subset of women had rebound of PAR incorporation prior to cycle 2 (p=0.0027). This did not correlate with frequency or duration of response. Conclusions: O 400 mg bid d1-7 with C AUC4/5 q21d is active and tolerable in Br/OvCa mut+ pts. Interactive marrow suppression was observed. An expansion cohort in Br/Ov mut+ pts nears accrual completion; paired tumor biopsies and PBMCs will be used to measure DNA damage endpoints and biomarkers. Patient cohorts with low probability of BRCA mutation TNBC and high-grade serous OvCa continue dose escalation.