Background: MK-1775 is a highly selective, investigational oral tyrosine kinase inhibitor of WEE1, which regulates G2 cell cycle checkpoint. Functional p53 mutation impairs G1 checkpoint; hence, targeting G2 checkpoint with MK-1775 in p53 mutants should induce synthetic lethality. Methods: Pts with platinum-sensitive disease-recurrent OC who had measurable disease (RECIST 1.1) with loss of function (LOF) p53 mutations by Roche AmpliChip were eligible. All pts received MK-1775 225mg twice daily (BID) D1-D3 (5 doses) plus carboplatin AUC5 + paclitaxel 175mg/m² every 21 days (CP) for 6 cycles. The objective for the phase I run-in portion of the study was to determine the recommended phase II dose based on safety data. A Toxicity Probability Interval method [Ji et al, Clin Trials 2010; 7(6):653-63] would determine if additional lower doses should be explored. A randomized phase II portion, assessing the efficacy of the combination vs placebo, would start if ≥5 radiological responses and <5 dose-limiting toxicities (DLTs) were observed among the first 13 pts. Results: Of 76 pts screened (26 wt, 43 mutant [24 nonfunctional], 7 undetermined), 19 women had LOF p53 mutations and were eligible. Fifteen consented and were enrolled in the Phase I: median age was 57 (range 38-77); ECOG 0:1 ratio 9:6 pts. Three DLTs were observed: G3 febrile neutropenia, G4 neutropenia, and G4 thrombocytopenia. Diarrhea (84.6%), nausea (76.9%), and fatigue (76.9%) were the most common adverse events (AEs). Seven of 13 pts completed treatment (2 ongoing). Three pts discontinued due to AEs and 3 patients withdrew consent prior to completing treatment. Of 14 evaluable pts by RECIST 1.1 there were 11 partial responses (PRs; 6 confirmed, 5 unconfirmed) and 3 had stable disease; 7 pts were evaluable by CA125 with 3 complete responses and 4 PRs. MK-1775 PK results were similar to those reported for monotherapy studies. Conclusions: The combination of MK-1775 225mg BID x 5 doses with CP is well tolerated, with a preliminary radiological response rate of 78.6%, and has met the safety and efficacy bar for randomized phase II assessment in part 2 of the study. Clinical trial information: NCT01357161.