The DNA-PK inhibitor AZD7648 alone or combined with pegylated liposomal doxorubicin in patients with advanced cancer: results of a first-in-human Phase I/IIa study
Timothy A. Yap, Patricia LoRusso, Rowan Miller, Rebecca Kristeleit, Amanda G. Paulovich, Stephen McMorn, Lenka Oplustil O’Connor, Benedetta Lombardi, Paola Marco‐Casanova, Eric T. Gangl, Bharat Patel, Mark J. O’Connor, Emma Dean, Roman Zviezdin, Ruth Plummer
Abstract
BACKGROUND: 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. METHODS: (n = 16). The primary objective was safety and tolerability. RESULTS: 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. DISCUSSION: Toxicity of AZD7648 + PLD was greater than expected and antitumour activity was limited, leading to early study termination.