ADAGIO: A phase IIb, open-label, single-arm, multicenter study assessing the efficacy and safety of adavosertib (AZD1775) as treatment for recurrent or persistent uterine serous carcinoma

TPS5612 Background: There is a high unmet medical need for therapies treating uterine serous carcinoma (USC), an aggressive type of endometrial carcinoma with an increased likelihood of recurrence and limited therapeutic options. 5-year overall survival (OS) for USC is estimated to be 35–50% for women with stage I–II disease and 0–15% for women with stage III–IV disease (Acharya et al. Lancet Oncol 2005). USC exhibits high rates of mutation in TP53 ( > 90% of cases), as well as mutations or amplifications in other cell-cycle regulators or oncogenes, including CCNE1, FBXW7, MYC, RB1, and KRAS/ NRAS (Zhao et al. PNAS 2013; Levine DA et al. Nature 2013), which may contribute to increased replication stress and susceptibility to inhibition of the tyrosine kinase WEE1. WEE1 inhibition is expected to release a tumor cell from DNA-damage-induced arrest at the G2/M boundary, so that unrepaired DNA damage may be taken into mitosis, leading to cell death. A Phase II study of the WEE1 inhibitor adavosertib in 34 women with recurrent or persistent USC reported an objective response rate (ORR) of 29.4% and a median duration of response (DoR) of 9.0 months; further correlative analysis and a translational biopsy cohort are planned (Liu et al. J Clin Oncol 2020). This Phase IIb study, ADAGIO, a single-arm, multicenter, global study (NCT04590248), aims to expand on these findings and will evaluate the efficacy and safety of adavosertib in women with recurrent or persistent USC who have previously received platinum-based chemotherapy. Methods: Women aged ≥18 years with histologically confirmed recurrent or persistent USC who have previously received at least one platinum-based chemotherapy regimen for the management of USC and have evidence of measurable disease according to RECIST v1.1 are eligible for this study. Participants with carcinosarcomas are not eligible. Prior receipt of immune checkpoint inhibitors, vascular endothelial growth factor inhibitors and human epidermal growth factor receptor 2 targeted therapy is permitted, with no restriction on the number of prior lines of systemic therapy a participant may have previously received. Approximately 120 eligible participants will receive oral adavosertib 300 mg qd on days 1–5 and 8–12 of a 21-day treatment cycle until disease progression, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met. The primary outcome measure is ORR, defined as the percentage of patients with measurable disease at baseline who have a confirmed complete or partial response, as determined by blinded independent central review (RECIST v1.1 assessment every 6 weeks for the first 48 weeks, then every 9 weeks). Secondary outcome measures include DoR, depth of response, progression-free survival, OS, disease control rate, biomarkers, safety, tolerability, and pharmacokinetics. Clinical trial information: NCT04590248.