Abstract 4909: Adaptive oncology phase 1 study of first-in-class inhibitor of ataxia telangiectasia mutated protein kinase (ATM), in combination with olaparib

Abstract

Abstract Background: AZD0156 is a highly selective first oral ATM inhibitor in the clinic. Coordinating DNA single and double strand break repair, AZD0156 enhances the preclinical activity of olaparib, leading to its development as an antitumor agent in combination. We report here results from an ongoing phase 1 adaptive dose escalation study of AZD0156 in combination with olaparib. Methods: This phase I study is to assess the safety, tolerability, pharmacokinetics (PK) and preliminary efficacy of escalating doses of AZD0156 in combination with olaparib in patients with advanced malignancies. AZD0156 is mainly metabolized by CYP3A and FMO, which undergo genetic polymorphism. The flexible language incorporated in the protocol also allow rapid dose escalation beyond subtherapeutic doses. Results: PK data from the first 2 dose cohorts were lower than predicted and the AZD0156 dose was increased 4 X and dosing changed from QD (daily) to BD (twice daily). The mean terminal half-life of AZD0156 was 9-12 hours and PK was dose proportional. No significant drug-drug interactions (DDI) were observed with olaparib. Minor toxicities included nausea, vomiting and anemia in about 40% of patients in all cohorts. Grade 3 and 4 hematologic toxicities were observed in AZD0156 120mg BD with olaparib 200mg BD, and this dose level was considered intolerable. At doses of AZD0156 of 30 and 60mg BD, active target engagement was demonstrated. PK profile was similar across FMO genotype. Conclusion: Hematologic toxicities, consistent with the mode of action, emerged as dose-limiting toxicities of AZD0156 in combination with olaparib. Pharmacologically active doses of AZD0156 with olaparib were achieved more quickly in patients by using real-time PK, real-time genotyping, safety, DDI assessment, and PK/PD modelling. Citation Format: Yingxue Chen, Martin Pass, Nuria Bui Bruna, Christine Stephens, Andrew Pierce, Wouter Hanekom, Hani Gabra, Helen Tomkinson, Nidal Al-Huniti. Adaptive oncology phase 1 study of first-in-class inhibitor of ataxia telangiectasia mutated protein kinase (ATM), in combination with olaparib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4909.