Meeting Proceedings of the “Phase I: Where Science Becomes Medicine” Conference, Manchester, UK

Donna M. Graham1,2,3, Louise Carter1,2,3, Matthew G. Krebs1,2,3, Duncan Jodrell4, Anne Armstrong2,3, Elaine Kilgour1,2,5, Tim Illidge1,2,3, Joseph Clarke,2 Rachel Chown2, Kaye Williams1,2, Caroline Dive1,2,5, Janelle Yorke1,2, Clare Dickinson2,3, Andrew Hughes1,2,5, Fiona Thistlethwaite1,2,3, Rob Bristow,1,2,3 Natalie Cook1,2,31Division of Cancer Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK, 2Manchester Cancer Research Centre, Manchester, UK, 3The Christie NHS Foundation Trust, Manchester, UK, 4Cancer Research UK Cambridge Institute (CRUK), University of Cambridge, Cambridge, UK, 5CRUK Manchester Institute, Manchester, UKPhase I clinical trials are the gateway to establishing new treatments for cancer patients by translating preclinical scientific advances to the clinic. The traditional Phase I design has involved small groups of patients, investigating toxicity and patient safety, and the pharmacodynamic and pharmacokinetic activities of novel treatments. Recent years have seen a rapid evolution in the scope and conduct of Phase I trials.The “Phase I: Where Science Becomes Medicine” conference, was held between the 14th and 16th of July 2019 in Manchester, UK with a dedicated focus on Phase I cancer trials and an overview of the dynamic landscape of the field. Global experts presented and discussed the key issues facing Phase I clinical triallists in a city with a long history of drug development and translational cancer research.Discussions were held across 10 sessions on a range of interlinked topics related to Phase I clinical trials. These included: novel drug targets and their impact on trial design, biomarkers and precision medicine, immunooncology, radiotherapy combinations, advanced therapies and trial methodology. The conference involved a mixture of plenary lectures, keynote speaker sessions, debates, poster presentations, a parallel nursing workshop, and exhibitions from various organizations.Over 220 delegates attended the conference with global representation. Delegates had diverse backgrounds spanning academia, industry and International professional healthcare bodies. Each session of the conference commenced with a video featuring patients’ and caregivers’ voices. These detailed first-hand accounts of how cancer and clinical trials affect participating patients and their families and provided a reminder of the importance of these trials and a focus for each session. In addition, 31 abstracts were accepted to be presented as posters and are included in the conference proceedings. Prizes were awarded to the top five posters (abstract numbers 7, 8, 18, 20 and 26).The meeting was opened by Professor Robert Bristow and Dr Natalie Cook who described the vision for the Phase I program in Manchester and the changes in cancer treatments over recent years. This included the increasing use of personalised therapies and genomic profiling, incorporation of novel combination therapies and the use of radiotherapy within a real-world evidence clinical database.Professor Lillian Siu, Chair of the Drug Development Program at Princess Margaret Cancer Centre in Toronto, delivered the first keynote of the conference, presenting “Phase I: Past and present”. She gave a fascinating overview of the evolution of Phase I clinical trials with novel designs, increasing patient numbers, incorporation of biomarkers and the emergence of immunotherapy as areas of change over recent years. Alongside these changes, Phase I trialists are also carrying the responsibilities of Phase II and III triallists due to the evolution of trial design. Despite this, the critical endpoints of safety and establishing recommended Phase II dose remain. Professor Siu highlighted a shift in trial design, where patients play an increasingly important role in both the development of and participation in Phase I trials.Dr Howard (Skip) Burris, Chief Medical Officer and Head of the Drug Development Programme of the Sarah Cannon Research Institute and 2019 President of the American Society of Clinical Oncology (ASCO) detailed the “Next steps for Phase I”. He highlighted the prominence of Phase I trials at the recent ASCO annual meeting and reiterated critical themes of biomarkers for drug selection and expansion of patient numbers. He also emphasized the role of real-world data for potential patient benefit and issued the challenge to the Phase I community to consider how eligibility criteria for trials can be broadened to allow access for a greater proportion of the patient population to provide greater possibility of benefit and to expedite the drug approval process.Genomics and biomarkers were the focus of the debate session, where the question: “Every cancer patient should have comprehensive genomic profiling prior to each experimental therapy” was debated by Dr Timothy Yap who argued for, and Professor Jeff Evans who argued against the motion. Rebuttals were delivered from Dr Donna Graham and Dr Matthew Krebs. Debate around this question centered around health economics and equity of access, lack of available drug targets, the emergence of circulating tumor DNA (ctDNA) as a potentially more cost effective, quicker and for some patients, a more feasible alternative to tumor profiling, matching rates to targeted therapy clinical trials, and associated response rates. The house voted in favor of comprehensive genomic profiling prior to each experimental therapy.The panel session on novel targets and the impact on trial designs offered insightful commentary on the future of Phase I trials. Professor Ruth Plummer started the discussion with an evaluation of how low prevalence targets have affected the goal and conduct of clinical trials. Professor Sarah Blagden then focused on some of the challenges and opportunities we currently face in the UK around complex trial designs. Dr Alan Jordan concluded the session by talking about the drug development pipeline. He stressed the vital approach of coordination and collaboration between research clinicians, chemists developing new drugs and scientists to design better drugs which meet the criteria patients consider important for quality of life. The three speakers concluded that collaboration and patient insight is needed throughout the drug development and discovery processes, and stressed the importance of pharmacodynamics and predictive biomarkers in designing appropriate clinical trials.A recurrent focus of the conference was the role of biomarkers for precision medicine. Professor Caroline Dive discussed the Tumour chARacterisation to Guide Experimental Targeted therapy (TARGET) trial[1] which includes a ctDNA profile and the development of the digital platform eTARGET. This is used to capture genomic data and personalize trial selection to the genomic sequence of the patient’s tumor. Professor Gary Middleton highlighted practical considerations in developing studies to match patients to trials citing the MATRIX trial for lung cancer patients.[2] Following this, Professor Steven Jones detailed the potentially transformative role of transcriptomics in providing effective individualized treatment options for patients. A key message of this session was the need for well-validated and clinic ready biomarkers to drive development of new precision medicine strategies.The final session of day two focused on immuno-oncology. Dr Charles Ferté from AstraZeneca provided an overview of the current immunotherapy research and the potential benefits offered by combination approaches. The topic of immunotherapy combinations was further developed by Dr Stefan who highlighted the of clinical trials currently and the scientific that should development of Dr the session by and as potential treatment targets for novel This session the challenge to for combinations and the role predictive biomarkers play in combination final day of the conference started with a discussion around the challenges and opportunities of developing radiotherapy drug combinations in Phase I trials. 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