Abstract A094: Phase I modular study of AZD0156, a first-in-class oral selective inhibitor of ataxia telangiectasia mutated protein kinase (ATM), in combination with olaparib (AToM Study, Module 1)

Abstract

Abstract Background: ATM (ataxia telangiectasia mutated protein) is a serine-threonine kinase that is a key mediator of the DNA damage response elicited by double strand breaks. AZD0156 is a potent, selective inhibitor of ATM. Preclinical data suggest a synergistic effect of AZD0156 when combined with DNA damage targeting agents, including olaparib. Materials and Methods: This is an international, modular phase I study to assess the safety, tolerability, pharmacokinetics, and preliminary efficacy of escalating doses of AZD0156 in combination with either cytotoxic chemotherapy or novel anticancer agents in patients with advanced malignancies. Here we report the results of Module 1, an evaluation of AZD0156 with olaparib. Patients with solid tumors and PS 0 or 1 were recruited in cohorts of 3 to 6 evaluable patients. Module 2 will be a combination with irinotecan. Results: 46 patients have been recruited in 8 cohorts combining AZD0156 with olaparib (Table 1). The terminal half-life of AZD0156 was approximately 9-12 hours and dose/exposure proportionality was observed. No significant PK interactions 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 cohort 7 (AZD0156 120mg po bd with olaparib 200mg po bd), and this dose level was considered intolerable. At doses of AZD0156 of 60mg bd, plasma concentrations of AZD0156 were consistent with efficacy in gastric cancer cell cultures. Further dosing schedules are being explored. There have been two confirmed partial responses (RECIST): one in a patient whose tumor harboured germline BRCA2 mutations (Cohort 2), and one in a patient whose tumor had unknown tumor genetics but no significant family history (Cohort 4a). One patient with somatic BRCA2 deletion has had stable disease for 18 months (Cohort 1). Conclusions: Hematologic toxicity, consistent with the mode of action, appears to be the treatment-limiting toxicity for AZD0156 in combination with olaparib. AZD0156 can be given at doses and schedules that achieve exposures consistent with in vitro efficacy. Continued exploration of AZD0156 in combination with olaparib and other agents in solid malignancies is a promising area for further research. Cohort / Evaluable patientsDose/Schedule AZD0156Dose/Schedule olaparibComment1 / 62mg od for 3 days out of 7100mg bd continuouslyWell tolerated2 / 58mg od for 3 days out of 7100mg bd continuouslyWell tolerated3 / 630mg od for 3 days out of 7100mg bd continuouslyWell tolerated4a / 630mg bd for 3 days out of 7100mg bd continuouslyWell tolerated4b / 615mg bd for 3 days out of 7200mg bd continuouslyWell tolerated5 / 430mg bd for 3 days out of 7200mg bd continuouslyWell tolerated6a / 460mg bd for 3 days out of 7200mg bd continuouslyWell tolerated. PK indicated AZD0156 exposures are proportional to doses and reach IC90 defined in gastric ca cell line6b / 430mg bd for 3 days out of 7300mg bd continuously1 patient experienced Grade 2 neutropenia & thrombocytopenia7 / 4120mg bd for 3 days out of 7200mg bd continuously1 patient: Grade 2 neutropenia & thrombocytopenia; 1 patient: Grade 3 anaemia, Grade 2 thrombocytopenia and Grade 4 neutropeniaAE’s occurred during Cycle 1 or 2; were not Dose Limiting Toxicities as defined in the protocol, but considered to be non-tolerated by the Safety Review Committee8 / 260mg bd for 3 days out of 7300mg bd continuouslyPotential candidate for efficacy evaluation Citation Format: Wassim Abida, Yung J. Bang, Louise Carter, Analía Azaro, Matthew Krebs, Seock-Ah Im, Yingxue Chen, Núria Buil-Bruna, Yan Li, David Eaton, Christine Stephens, Graham Ross, Martin Pass, Jordi Rodon, Emma Dean. Phase I modular study of AZD0156, a first-in-class oral selective inhibitor of ataxia telangiectasia mutated protein kinase (ATM), in combination with olaparib (AToM Study, Module 1) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A094.