Purpose: This study reports the safety, tolerability, maximum tolerated dose (MTD), recommended Phase II dose (RP2D), pharmacokinetic/pharmacodynamic profile and preliminary antitumor activity of ceralasertib combined with carboplatin in patients with advanced solid tumors. It also examined exploratory predictive and pharmacodynamic biomarkers.Patients and methods: Eligible patients (n=36) received a fixed dose of carboplatin (AUC5) with escalating doses of ceralasertib (20 mg BID to 60 mg QD) in 21-day cycles.Sequential and concurrent combination dosing schedules were assessed.Results: Two ceralasertib MTD dose schedules, 20 mg BID on days 4-13 and 40 mg BID on days 1-2, were tolerated with carboplatin AUC5; the latter was declared the RP2D. The most common treatment-emergent adverse events (CTCAE grade ≥3) were anemia (39%), thrombocytopenia (36%), and neutropenia (25%). Dose-limiting toxicities of grade 4 thrombocytopenia (n=2; including one grade 4 platelet count decreased) and a combination of grade 4 thrombocytopenia and grade 3 neutropenia occurred in three patients. Ceralasertib was quickly absorbed (t max ~1 hour), with a terminal plasma halflife of 8-11 hours. Upregulation of pRAD50, indicative of ATM activation, was observed in tumor biopsies during ceralasertib treatment. Two patients with absent or low ATM or SLFN11 protein expression achieved confirmed RECIST v1.1 partial responses.Eighteen of 34 (53%) response-evaluable patients had RECIST v1.1 stable disease. Conclusions:The RP2D for ceralasertib plus carboplatin was established as ceralasertib 40 mg QD on days 1-2 administered with carboplatin AUC5 every 3 weeks, Research.

MotivationThe literature on complex diseases is abundant but not always quantitative. This is particularly so for Inflammatory Bowel Disease (IBD), where many molecular pathways are qualitatively well described but this information cannot be used in traditional quantitative mathematical models employed in drug development. We propose the elaboration and validation of a logic network for IBD able to capture the information available in the literature that will facilitate the identification/validation of therapeutic targets.ResultsIn this article, we propose a logic model for Inflammatory Bowel Disease (IBD) which consists of 43 nodes and 298 qualitative interactions. The model presented is able to describe the pathogenic mechanisms of the disorder and qualitatively describes the characteristic chronic inflammation. A perturbation analysis performed on the IBD network indicates that the model is robust. Also, as described in clinical trials, a simulation of anti-TNFα, anti-IL2 and Granulocyte and Monocyte Apheresis showed a decrease in the Metalloproteinases node (MMPs), which means a decrease in tissue damage. In contrast, as clinical trials have demonstrated, a simulation of anti-IL17 and anti-IFNγ or IL10 overexpression therapy did not show any major change in MMPs expression, as corresponds to a failed therapy. The model proved to be a promising in silico tool for the evaluation of potential therapeutic targets, the identification of new IBD biomarkers, the integration of IBD polymorphisms to anticipate responders and non-responders and can be reduced and transformed in quantitative model/s.

are former employees of AstraZeneca JL has served a consultant/advisory role for Mirati and Oncologie.All remaining authors have no conflicts of interest to declare. Grant SupportThis investigator-initiated trial was funded by a study-drug donation and partial funding from AstraZeneca.

Supplementary data are available at Bioinformatics online.