Abstract CT084: A Phase I dose-escalation study of ATR inhibitor monotherapy with AZD6738 in advanced solid tumors (PATRIOT Part A)

Many cancers have high levels of replication stress and a poorly functional G1/S DNA damage checkpoint. This may render them more susceptible than normal tissues to inhibition of ATR, an apical kinase in the DNA damage response and critical part of the response to DNA replication stress. We report the early results of the monotherapy dose-escalation phase of the PATRIOT study of AZD6738, an orally active ATR inhibitor in patients (pts) with advanced solid tumors (NCT02223923), whose endpoints were MTD, safety, tolerability, pharmacokinetics (PK) and preliminary efficacy. 26 pts were enrolled between July 2014 and July 2016 in a 3+3 design. Pts received continuous BD dosing. PK analyses were performed. Dose limiting toxicities (table 1) were thrombocytopenia (G3 with epistaxis, 1 participant; G4, 2 participants), pancytopenia (G4, 1 participant), increased amylase (G3, 1 participant). Other treatment-related AEs (probably or definitely caused by AZD6738) affecting ≥2 participants were fatigue (9; 35% G1-4, 0% G3-4), anemia (7; 23% G1-4, 12% G3-4), nausea (4; 15% G1-4, 0% G3-4), thrombocytopenia (5; 19% G1-4, 15% G3-4), anorexia (3; 12% G1-4, 0% G3-4), dysgeusia (3; 12% G1-4, 0% G3-4), vomiting (2; 8% G1-4, 0% G3-4). The MTD was 160 mg BD, given continuously. Two RECIST partial responses were observed in pts with SCCHN and nasopharyngeal carcinoma, one confirmed. Median duration taking AZD6738 was 97 days, range 30-279 days (evaluable patients only). Two pts remain on treatment, three pts discontinued due to treatment-related toxicity. Expansion cohorts have been initiated at 160mg BD, exploring a number of alternative treatment schedules designed to offset cumulative toxicity and test efficacy of AZD6738 monotherapy and the presence of high replication stress, DNA damage response deficiencies or ATM loss. Schedules include: AZD6738 given at 160mg BD for 21 of a 28 day cycle and 5 days on, 2 days off. A parallel study is investigating AZD6738 in combination with palliative radiotherapy.[Funded by CRUK CRUKD/14/007] Dose Level (mg)Evaluable (total treated)Number DLTsG3-4 AEs203 (3)0elevation GGT (1, G3)403 (3)0nil806 (7)1Thrombocytopenia with epistaxis (1, G3)1606 (6)0Anaemia (1, G3)2406 (7)4Thrombocytopenia (2, G4), pancytopenia (1, G4), elevated amylase (1, G3), photosensitivity (1, G3), mucositis (1, G3), anemia (1, G3)Baseline DemographicsTumor TypesMedian (range) age59 (40-79)SCCHN6 (23%)Median (range) prior systemic therapy2 (1-4)Colorectal6 (23%)% Female31Nasopharyngeal2 (8%)Other12 (46%) Citation Format: Magnus T. Dillon, Aude Espinasse, Sally Ellis, Kabir Mohammed, Lorna G. Grove, Lyndall McLellan, Simon A. Smith, Graham Ross, Sola Adeleke, Kin Woo, Eleni Josephides, James F. Spicer, Martin D. Forster, Kevin J. Harrington. A Phase I dose-escalation study of ATR inhibitor monotherapy with AZD6738 in advanced solid tumors (PATRIOT Part A) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT084. doi:10.1158/1538-7445.AM2017-CT084