Abstract CT248: AZD7648: A Phase I/IIa first-in-human trial of a novel, potent and selective DNA-PK inhibitor in patients with advanced malignancies

Background: DNA-dependent protein kinase (DNA-PK) is a critical sensor of DNA double-strand breaks (DSBs) and orchestrates their repair through non-homologous end joining (NHEJ). AZD7648 is a novel, potent and highly selective inhibitor of DNA-PK being evaluated as monotherapy or in combination with doxorubicin or olaparib in a Phase I/II first-in-human study. The objectives of this trial are to assess safety and tolerability, establish a Recommended Phase 2 Dose (RP2D) and evaluate early clinical activity. Pre-clinically, AZD7648 monotherapy leads to tumour growth inhibition in ATM deficient models in vivo, demonstrating potential to enhance the effects of endogenous tumour damage clinically. AZD7648 is also an efficient sensitizer of doxorubicin-induced DNA damage and demonstrates enhanced efficacy in combination with olaparib. Both combinations induce sustained regressions in vivo across a range of tumour xenografts with differing genetic alterations, accompanied by robust pharmacodynamic biomarker modulation. These data provide the rationale to explore AZD7648 as monotherapy and in combination with either doxorubicin or olaparib. Methods: This is a Phase I/IIa study comprising 3 modules: Core Module (AZD7648 monotherapy - dose escalation), combination module 1 (AZD7648 + pegylated liposomal doxorubicin [PLD]), and combination module 2 (AZD7648 + olaparib). Each combination evaluates AZD7648 in a Phase I escalation (Part A) and a Phase IIa expansion (Part B). Patients are assigned to a single study Part, but intra-patient dose escalation is permitted in Part A. The study incorporates a Bayesian adaptive dose escalation trial design which combines prior expectations about the dose toxicity relationship and applies the data at the end of each cohort to recommend a dose for the next cohort. The study will investigate pharmacodynamic (PD) and exploratory biomarker (DNA, RNA, proteins or metabolites) profiles in exclusive cohorts, and study their relationship to drug effect. Eligible patients are aged ≥18 years with advanced solid tumours, who have failed standard therapies. In Part A, patients are assessed for dose-limiting toxicities during the evaluable period. Blood samples are collected for pharmacokinetic (PK) analysis following a single dose of AZD7648 and at steady state. Single patient cohorts may occur for the first four cohorts (or until drug-related ≥ Grade 2 toxicity). From cohort 5 onwards, a minimum of 3 patients will be enrolled into each dose cohort until the Maximum Tolerated Dose, Maximum Feasible Dose or RP2D is identified. Enrolment into the study commenced in Oct 2019 and is currently enrolling cohort 3 in the monotherapy dose escalation. To date, no DLTs have been reported in prior cohorts. [clinicaltrials.gov identifier: NCT03907969] Citation Format: Timothy A. Yap, Yingxue Chen, Lisa H. Butler, Si-houy Lao-Sirieix, Elaine Cadogan, Lenka Oplustil O9Connor, Karthick Vishwanathan, Younghwa Kim, Donal Landers, Emma Dean. AZD7648: A Phase I/IIa first-in-human trial of a novel, potent and selective DNA-PK inhibitor in patients with advanced malignancies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT248.