Microtracer‐Based Assessment of the Mass Balance, Pharmacokinetics, and Excretion of [¹⁴C]Berzosertib, an Intravenous ATR Inhibitor, in Patients With Advanced Solid Tumors: A Phase 1 Study

Berzosertib is a small‐molecule ataxia telangiectasia and Rad3‐related protein inhibitor. To assess the clearance mechanism(s) of berzosertib, a Phase 1, 2‐period, open‐label study was conducted in adults with advanced solid tumors who were treated with a single intravenous dose of 210 mg/m 2 berzosertib containing approximately 3 µCi of [ 14 C]berzosertib (Period 1 Mass Balance), followed by assessment of berzosertib in combination with topotecan (Period 2 [Extension]) (NCT05246111). A total of 6 patients were enrolled in Period 1; 5 of them rolled over to Period 2. By Day 14, the mean total recovery of drug‐related material (total radioactivity) in urine and feces combined was 89.5% (feces: 73.7%; urine: 15.8%). Pharmacokinetic data suggested that a substantial amount of various circulating metabolites of berzosertib were present in plasma (78% of drug‐related material), with a longer terminal elimination half‐life of total radioactivity than unchanged berzosertib. M11, which is pharmacologically inactive, was identified as the major circulating metabolite (28.2% of drug‐related material). The safety profile of berzosertib and topotecan was consistent with prior clinical experience. Overall, the study established the predominant role of metabolic clearance in berzosertib disposition and characterized its metabolites structurally. No new safety concerns were identified with berzosertib as a single agent or in combination with topotecan.