LAUSR

Upregulation of DNA-dependent protein kinase (DNA-PK) is associated with poor prognosis and decreased response to DNA-damaging agents across cancer types. A Phase I/IIa study (NCT03907969) investigated the highly potent, selective DNA-PK inhibitor AZD7648 as monotherapy or combined with pegylated liposomal doxorubicin (PLD) in patients with advanced cancer. Thirty patients received escalating doses of AZD7648 as monotherapy (n = 14), starting at 5 mg QD, or with PLD 40 mg/m2 (n = 16). The primary objective was safety and tolerability. AZD7648 monotherapy was administered at 5–160 mg BID. The most frequent class of adverse events was gastrointestinal disorders (9/14 patients, 64.3%); one patient (160 mg BID) experienced dose-limiting toxicities (DLTs). No responses to AZD7648 monotherapy were observed. The maximum dose of combination therapy was AZD7648 40 mg QD days 1–7 + PLD every 28 days. 13/16 patients (81.3%) experienced gastrointestinal disorders and 11/16 (68.8%) patients had anaemia. Three patients experienced DLTs (two at AZD7648 20 mg QD 7 days + PLD; one at AZD7648 30 mg QD 7 days + PLD). Limited efficacy was observed, with one RECIST partial response. Toxicity of AZD7648 + PLD was greater than expected and antitumour activity was limited, leading to early study termination.