Phase II study with Wee1 inhibitor AZD1775 plus carboplatin in patients with p53 mutated ovarian cancer refractory or resistant (<3 months) to standard first line therapy.

2507 Background: AZD1775 (formerly MK-1775) is a potent and selective inhibitor of Wee1, a kinase that phosphorylates CDC2. Phosphorylation of CDC2 inactivates the CDC2/cyclin B complex and is therefore essential for normal G2 checkpoint function. As most p53-deficient tumors lack a functional G1 checkpoint, they rely on the G2 checkpoint for cell cycle arrest in response to DNA damage. G2 checkpoint abrogation, using a Wee1 inhibitor may therefore sensitize p53 deficient tumor cells to DNA-damaging anti-cancer agents. In a phase I study the maximum tolerated dose (MTD) of AZD1775 in combination with carboplatin demonstrated target engagement (NCT00648648). Methods: Patients (pts) with p53 mutated ovarian cancer refractory or resistant ( < 3 months) to standard first line therapy (carboplatin plus paclitaxel) were re-exposed to carboplatin (AUC 5), plus 5 bi-daily doses of 225 mg AZD1775 in a 21 day cycle (MTD) (NCT01164995). p53 mutation status was analyzed by both sequencing analysis (TP53 exons 2-10) a...