Ovarian cancers have a high rate of mutation in TP53, an alteration that produces a G1/S checkpoint deficiency and increases the level of endogenous DNA damage. This can lead to a dependency on WEE1, a multifunctional protein that can induce the G2/M checkpoint, promoting the repair of DNA damage before proceeding through mitosis and cell division. AZD1775 is a highly selective small-molecule inhibitor of WEE1 that showed promising antitumor activity in TP53m refractory/resistant ovarian cancer (OC) when combined with carboplatin (Leijen et al, JCO 2016). This Phase II study (GYN 49; D6010C00004; NCT02272790) is being conducted to further explore the safety, tolerability, and preliminary efficacy of AZD1775 when combined with 4 different chemotherapy regimens in patients (pts) with platinum resistant OC and fallopian and peritoneal cancers.
This is an open-label four-arm study, with a primary endpoint of objective response rate. Study arms are:Table:
|AZD1775||175mg PO daily Days [D]1-2, 8-9, 15-16||225mg PO BID x 5 doses D1-3, 8-10, 15-17||225mg PO BID x 5 doses D1-3||225mg PO BID x 5 doses D1-3, 8-10 (+ D15-17 if tolerated)||175 or 225mg PO BID x 5 doses D1-3|
|Chemotherapy||gemcitabine 1000mg/m2 IV D1, 8, 15 q28D||paclitaxel 80mg/m2 IV D1, 8, 15 q28D||carboplatin AUC 5 IV D1 q21D||carboplatin AUC 5 IV D1 q21D||pegylated liposomal doxorubicin [PLD] 40mg/m2 IV D1 q28D|
Key eligibility criteria include platinum resistant OC or fallopian tube/primary peritoneal cancer (recurrence
Clinical trial identification
Legal entity responsible for the study
K.N. Moore: Advisory roles with several pharmaceutical companies: Clovis, Amgen, AstraZeneca, Immunogen, Genentech/Roche, Merrimack, VSL. S. Ghamande: National PI for a phase 1 dose escalation trial with a HPV Listeria vaccine for cervix cancer sponsored by Advaxis. P.A. Konstantinopoulos: Advisor for Vertex and Merck. D. Spitz: Own stock in Gilead. D. Uyar: Research project funded by Merck. G. Mugundu: Employed by AstraZeneca; owns stock in AstraZeneca and Pfizer. N. Laing: Employed by AstraZeneca, own stock in AstraZeneca, intellectual property interests in AstraZeneca. All other authors have declared no conflicts of interest.