Abstract CT214: ATRiUM: A first-in-human dose escalation phase I trial of ceralasertib (AZD6738) and gemcitabine as combination therapy
Authors: de Paula Bruno Henrique , Basu Bristi , Mander Adrian , Khan Josephine , Bundi Purity , Goodwin Richard , Thaventhiran James , Alberto Gonzalez-Lopes , Edmund Godfrey , Islam Sabita , Anand Subha , Evans Jeff , Graziano Vincenzo , Serrao Eva , Pawula Maria , Hernandez Tatiana , Dean Emma , Smith Simon , Jodrell Duncan 
Published: July 2021

Abstract
Background:ATRiUM is a phase 1 trial to assess the safety, tolerability, pharmacokinetics and preliminary antitumour activity of ascending doses of combined therapy with the ATR inhibitor ceralasertib AZD6738 and gemcitabine, Using a Model based design NCT03669601. The combination was shown to act synergistically in laboratory models of pancreatic cancer. Based on these data, ATRiUM is now open to recruitment in Cambridge and Glasgow, UK. Methods:ATRiUM utilises a novel Bayesian model-based design for dual-agent dose escalation, that handles three levels of toxicity the highest of which is a dose limiting toxicity and two dosing schedules. The model assumes that the toxicity levels come from a multinomial distribution and toxicity increases monotonically as doses increase. Different schedules and doses 40-120 mg of ceralasertib; intermittent days 1-4, 8-11, 15-18 and continuous days 1-21 with gemcitabine 625-1000 mg/m2 administered on days 3, 10 and 17 of a 28-day cycle, will be assessed using the Bayesian framework. The aim is to recruit up to 55 patients, including up to 40 in the dose escalation phase across 3 gemcitabine doses and 6 ceralasertib dose/schedules. An expansion cohort (10-15 patients) is planned in patients with pancreatic cancer, based on our pre-clinical findings. Tumour monitoring will be undertaken by CT imaging RECIST 1.1, liquid biopsies circulating free DNA and advanced imaging radiomics. Baseline tissue biopsies will be analysed to identify potential predictive biomarkers e.g. ATM loss, as described pre-clinically. Imaging MSI will be used to characterise the intra-tumoural distribution of gemcitabine, its metabolites and ceralasertib and compared to plasma PK. Detailed studies of sequential tumour biopsies will include immunohistochemistry, RNAseq and Imaging Mass Cytometry IMC and be used to evaluate early pharmacodynamic responses to the combination. To investigate whether the combination increases tumour immunogenicity, the immune effects of the combination will be evaluated in both tumour by IMC and RNAseq and peripherally, by the serial collection and analysis of PBMCs and plasma for cytokine analysis. Adults with solid tumours are eligible for the dose escalation, if fulfilling standard Phase I eligibility criteria with measurable tumour lesions amenable to biopsy. Two out of six planned cohorts have been completed with no DLTs identified and cohort 3 will open in January 2021. ATRiUM is supported by the Integrative Cancer Medicine theme of the CRUK Cambridge Centre, the NIHR Cambridge Biomedical Centre, the Cambridge ECMC and a grant from AstraZeneca.
Citation Format: Bruno Henrique de Paula, Bristi Basu, Adrian Mander, Josephine Khan, Purity Bundi, Richard Goodwin, James Thaventhiran, Gonzalez-Lopes Alberto, Godfrey Edmund, Sabita Islam, Subha Anand, Jeff Evans, Vincenzo Graziano, Eva Serrao, Maria Pawula, Tatiana Hernandez, Emma Dean, Simon Smith, Duncan Jodrell. ATRiUM: A first-in-human dose escalation phase I trial of ceralasertib (AZD6738) and gemcitabine as combination therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT214.