Outcomes
toxicities
ADVERSE EVENT, DNA DAMAGE, DISEASE, CONGESTIVE CARDIAC FAILURE
Dose-limited toxicities including cardiovascular (prolongation of QT interval, congestive cardiac failure or reduction in LVEF) were evaluated from the start of cycle 1 to the end of cycle 2. Disease status was assessed by CT scan and evaluated using RECIST v1.1 at baseline, week 12 and every 12 weeks during treatment. Progression-free survival (PFS) and OS were measured. Adverse events were assessed according to CTCAE v4.03 until 30 days post last trial treatment administration.Pharmacokinetic and pharmacodynamic studies were carried out as per protocol. Exploratory biological endpoints included analysis of DNA damage and repair by the single-cell gel electrophoresis (Comet) assay in peripheral blood mononuclear cells (PBMCs), profiling of patient serum for ligands including amphiregulin (AR), epidermal growth factor (EGF), heparin-binding EGF (HBEGF) and transforming growth factor alpha (TGF-α) and analysis of circulating exosomes. ERBB dimerisation status was assessed in circulating exosomes.PBMCs were isolated from patients in Phase I and analysed for the effect of AZD8931 on DNA damage and repair using single-cell gel electrophoresis (Comet) assay [Exosomes from plasma of 13 patients in the Phase I trial, before and after their first dose of AZD8931 were extracted using an in-house optimised ultracentrifugation protocol (