Background: WEE1 is DNA damage cell-cycle checkpoint protein that inactivates cyclin-dependent kinase 1 (CDC2) and is overexpressed in a variety of malignancies. Pts with deficient p53 expression rely on the WEE1 kinase to arrest cell-cycle progression at the G2 checkpoint for DNA repair. AZD1775, a highly selective, adenosine-triphosphate (ATP) competitive, small-molecule inhibitor of the WEE1 kinase, is being developed for the treatment of advanced solid tumors with TP53-mutated malignancies. Inhibition of WEE1 allows CDC2 phosphorylation and subsequent cell-cycle progression despite DNA damage. This G2 checkpoint abrogation thus sensitizes cells to cytotoxic agents. Preliminary efficacy data have been promising when AZD1775 is used in combination with chemotherapy. In this randomized, phase II trial in pts with platinum-resistant, TP53-mutated cancers, AZD1775 will be added to a standard chemotherapy regimens (paclitaxel, gemcitabine, or carboplatin), with the goal of improving efficacy when compared to chemotherapy alone. The primary endpoints are response rate (Part 1), and progression-free survival (Part 2). Methods: In Part 1, up to 69 pts will be randomized to receive AZD1775 plus paclitaxel, gemcitabine or carboplatin (Arm A: AZD1775 175 mg PO BID Days 1, 2, 8,9,15, and 16 plus gemcitabine 1000 mg/m² IV Days 1, 8, and 15; Arm B: AZD1775, 5 doses of 225 mg PO BID Days 1-3, 8-10, and 15-17 plus paclitaxel 80 mg/m2 IV Days 1, 8, and 15; Arm C: AZD1775, 5 doses of 225 mg PO BID Days 1-3 plus carboplatin AUC 5 IV Day 1). In Part 2, up to 108 pts will be randomized 1:1 to the most efficacious AZD1775/chemotherapy combination identified in Part 1, or chemotherapy alone. Pts will be restaged every 2 cycles and continue treatment until disease progression or unacceptable toxicity. Key eligibility includes: platinum-resistant TP53-mutated epithelial ovarian, fallopian tube, or primary peritoneal cancer, measurable disease per RECIST v 1.1, ECOG PS 0 or 1, QTc < 470 msec, and no known CNS disease. Tumor samples will be collected for evaluation of specific biomarkers. Clinical trial information: NCT02272790