MIDDLETON GROUP

EARLY PHASE CLINICAL TRIALS

Our aim is to bring the excellent science in Oxford to cancer patients. Our strategy is to develop new treatments or combinations of treatments through the concepts of ‘synthetic lethality’ and oncogenic vulnerability. To deliver this we have established the infrastructure to perform detailed analyses of tumours before, during and after intervention to select patients; to test our a priori hypotheses; and to better understand the biological effects of treatment.

We look to deliver smaller trials involving subsets of patients. These have the ability to change patient care, by focussing our efforts on tightly defined clinical populations to maximise differences in outcome, moving away from one-size-fits-all phase 3 trials with purely correlative translational studies. Through the Oncology Clinical Trials Office (OCTO; setting up studies to run in centres all around Europe) and the Early Phase Clinical Trials Unit (EPCTU; running trials in the Oxford Cancer and Haematology Centre) we have established one of the largest academic early phase trials portfolios in Europe.

MELANOMA TRIALS

Recently we have seen incredible advances in the treatment of advanced melanoma. The challenges now are to understand why not all patients benefit from the new drugs at our disposal. Genetic characteristics or signatures are being explored to identify patients who are likely to benefit from particular treatments and to make informed treatment decisions on the best combinations of drugs to use in the clinic.

For example, we have defined new combinations of radiotherapy with vandetanib and of paclitaxel with trametinib, and are active in the development of new drugs such as IMCgp100, MLN2480, T-Vec and IMM47. We are looking into biological markers to identify patients most likely to benefit from bevacizumab therapy in the national AVAST-M study, starting with those whose melanoma has a mutation in the BRAF gene.

IMPACT

We work on developing new cancer drugs and many of these are now part of standard care including MEK inhibitors, oncolytic viruses and checkpoint blockers. Another example is Tebentafusp, which we developed with the University spin out Immunocore. We helped the company design the early clinical programme and identified Tebentafusp’s activity in uveal melanoma. This led to definitive trials showing improved survival and to licensing.

We are also interested in understanding why immunotherapies work in some patients and not in others, to inform new treatments that overcome resistance. As part of this effort we collaborate to describe immune responses to treatments in our patients. A secondary objective is to identify tools to help determine how best to treat patients. Currently our focus is on the application of ctDNA technologies to optimise the selection and timing of anti-cancer drug treatments.

GROUP INFORMATION

I run my trials in the EPCTU at the Churchill Hospital, delivering the translational elements through research collaborators both in Oxford and around the world. Academic studies are developed with OCTO, often in partnership with national and international consortia. As a clinical researcher I don’t run a single group and instead lead a series of teams focussed on particular trials or translational research questions.