In 2019 the Newcastle ECMC successfully opened the MEDALLION-PILOT study, which is a translational research study run using ECMC resource where we are exploring the potential causes of toxicities seen in patients receiving immunotherapy treatment with the immune checkpoint inhibitors. We plan to recruit up to 80 patients, having either combination or single agent immunotherapy.
The study asks patients to allow us to collect blood, skin swab and stool samples when they come to hospital for their immunotherapy treatment visits, and also if they need steroid treatment for any side effects. The study was designed with input from our Early Phase trials PPI team, who were very supportive and felt that understanding the causes of side effects and hopefully being able to predict who might get them was a very important research question. The toxicities which patients develop on checkpoint inhibitors mimics known auto-immune diseases such as inflammatory bowel disease, and rheumatoid arthritis and the MEDALLION-PILOT study team includesresearchers from these disciplines.
The study supports the research projects of 2 PhD students, one clinical and one scientific fellow, and is also designed to develop the pilot data to support an application for an Experimental Medicine Grant to run a larger multi-centre multi-disciplinary study with Glasgow, Oxford, Birmingham and Kings ECMCs.
The impact of this study is likely to be important in two areas. Firstly, we are trying to understand what factors may predict which patients develop toxicity, whether these are genetic, related to blood T-cell changes or environmental and related to skin or gut microbiome. Understanding toxicity and its causes better will help us advice patients on risks and help us develop treatment strategies. We also know that patients who develop more side effects are more likely to get a good response, so we hope to be able to identify signatures for this. Secondly, as we are collecting sequential samples from patients over a number of months of their treatment we can map the course of any map the course of any temporal changes linked to auto-immune disease and potentially identify key factors that trigger its development.
ECMC resource is critical for this study as it supports sample collection and processing and also project management through our Translational Research Team.
First in human trial of Berzosetib
The Newcastle ECMC led the first-in-human, first-in-class study of Berzosertib, an inhibitor of ATR, a protein involved in the DNA damage response. This was a collaboration initially with Vertex Pharmaceuticals and subsequently Merck KGA. The Newcastle ECMC worked closely with Vertex in developing the protocol and led the study globally. For the first part of the study all the study sites were ECMCs in the UK – Newcastle, Oxford, Glasgow and Manchester, with major US centres such as MD Anderson and Dana Faber joining for the later parts of the trial.
ATR is a protein involved in the repair of damaged DNA and the study’s primary aim was to find the safe dose to give to patients, what any side effects might be, and how Berzosertib might be safely combined with a number of chemotherapy drugs to try and improve their effectiveness. This study completed recruitment in 2019, and established the safe single agent dose of Berzosertib and also safe doses in combination with 3 different chemotherapy regimens. The importance of this research by the ECMC network is that we were recognised to have the skills and expertise to take a first-in-class agent into the clinic across the network sites, and the safety data and dose we found have been used in all subsequent studies of this agent.
The impact of this ECMC trial became clear even whilst the trial was still ongoing as the dosing data was used in a single agent study which showed that ATR inhibitors can have activity in tumours with certain mutations, without the need for chemotherapy. This is a much less toxic way to use this class of drugs and identifies a clinical development strategy for a number of other compounds in this class which are currently being developed. In addition, the safe doses we established with chemotherapy have been taken forward in phase II studies, the results of one of these in ovarian cancer was highlighted at ESMO 2019 (DOI: 10.1016/S1470-2045(20)30180-7).
ECMC resource which supported this study funded research coordinators, research nurses and laboratory technicians who are all key parts of the early phase trials team.