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Background <p>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.</p> Methods <p>Thirty patients received escalating doses of AZD7648 as monotherapy (<i>n</i> = 14), starting at 5 mg QD, or with PLD 40 mg/m<sup>2</sup> (<i>n</i> = 16). The primary objective was safety and tolerability.</p> Results <p>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.</p> Discussion <p>Toxicity of AZD7648 + PLD was greater than expected and antitumour activity was limited, leading to early study termination.</p>

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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

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  • 发表日期：

    2025年5月17日

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  • Timothy A. Yap,
  • Patricia LoRusso,
  • Rowan E. 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

摘要

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

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.

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.