Introduction
cancer, death
CANCER, DNA DAMAGE, SOLID TUMORS
Adavosertib (AZD1775) is a first-in-class selective small-molecule inhibitor of the tyrosine kinase Wee1, a regulator of the intra-S and G2/M cell-cycle checkpoints. Wee1 regulates mitosis and DNA replication via phosphorylation and inhibition of cyclin-dependent kinases (CDK) 1 and 2 [In preclinical studies, Wee1 inhibition caused dysregulation of CDK1 and CDK2, stimulating replication stress and DNA damage, which led to replication catastrophe, DNA damage, and ultimately cell death in various cancer cell lines [Adavosertib may also enhance the cytotoxic effect of chemotherapeutic agents by suppressing the DNA damage response, causing DNA damage to accumulate [A previous Phase I adavosertib monotherapy study reported an acceptable and manageable safety and tolerability profile in 80 patients with advanced solid tumors [This study investigated the safety and efficacy of additional treatment schedules to identify the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of adavosertib monotherapy in patients with locally advanced or metastatic solid tumors. The effect of a high-fat meal on adavosertib pharmacokinetics was also investigated.