A phase I study of the Wee1 kinase inhibitor adavosertib (AZD1775) in combination with chemoradiation in cervical, upper vaginal, and uterine cancers.

Objective: Wee1 kinase is a crucial regulator of the G2/M checkpoint which prevents entry of damaged DNA into mitosis. Adavosertib (AZD1775), a selective inhibitor of Wee1, induces G2 escape and increases cytotoxicity when combined with DNA damaging agents. We aimed to evaluate the safety and efficacy of adavosertib in combination with definitive pelvic radiotherapy and concurrent cisplatin in patients with gynecological cancers.
Methods: A multi-institutional, open-label phase I trial was designed to assess dose escalation (3+3 design) of adavosertib in combination with standard chemoradiation. Eligible patients with locally advanced cervical, endometrial or vaginal tumors were treated with a 5-week course of pelvic external beam radiation 45-50 Gy in 1.8-2 Gy daily fractions plus concurrent weekly cisplatin 40 mg/m ² and adavosertib 100 mg/m ² on days 1, 3 and 5 of each week during chemoradiation. The primary endpoint was to determine the recommended phase II dose of adavosertib. Secondary endpoints included toxicity profile and preliminary efficacy.
Results: Ten patients were enrolled (nine locally advanced cervical and one endometrial cancer). Two patients experienced a dose-limiting toxicity at dose level 1 (adavosertib 100 mg by mouth daily on days 1, 3 and 5), including one patient with grade 4 thrombocytopenia, and one with treatment hold >1 week due to grade 1 creatinine elevation and grade 1 thrombocytopenia. At dose level -1 (adavosertib 100 mg by mouth daily on days 3 and 5), one out of five patients enrolled had a dose-limiting toxicity in the form of persistent grade 3 diarrhea. The overall response rate at 4 months was 71.4%, including four complete responses. At 2 years follow-up, 86% of patients were alive and progression-free.
Conclusion: The recommended phase II dose could not be determined due to clinical toxicity and early trial closure. Preliminary efficacy appears promising, yet selecting the adequate dose/schedule in combination chemoradiation warrants further investigation to limit overlapping toxicities.
Competing Interests: Competing interests: BRC is on advisory boards for GSK, Merck, Immunogen, Imvax, AstraZeneca and Gilead; research funding from Clovis and Immunogen. JLA reports research support from Pfizer and Amgen. HM has been part of advisory boards for Merck, Essai and GSK. YCL in on an advisory board for GSK. VB has been on advisory boards for GSK and AstraZeneca. AMO is PI and on steering committees with AstraZeneca, GSK and Clovis; advisory boards for AstraZeneca and Morphosys; CEO in Ozmosis Research (uncompensated). SL reports support for grants or contracts to their institution from Merck, AstraZeneca, Regeneron, Roche, Repare, GSK, and Seagen; consulting fees from Novocure, Merck, AstraZeneca, GSK, Eisai, and Shattuck Labs; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, GSK, and Eisai; and participation on a data safety monitoring board or advisory board for AstraZeneca. The rest of the authors declare no potential conflicts of interest.
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