Early Phase Clinical Trials & Melanoma Therapy
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.
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.
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.
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.
- Immune checkpoint blockade sensitivity and progression-free survival associates with baseline CD8+ T cell clone size and cytotoxicity (2021). Watson RA, Tong O, Cooper R, Taylor CA, Sharma PK, de Los Aires AV, Mahé EA, Ruffieux H, Nassiri I, Middleton MR, Fairfax BP. Sci Immunol. 6(64):eabj8825.
- Phase 1 study of the ATR inhibitor berzosertib (formerly M6620, VX-970) combined with gemcitabine ± cisplatin in patients with advanced solid tumours (2021). Middleton MR, Dean E, Evans TRJ, et al. Br J Cancer. 125(4):510-519.
- Activated Regulatory T-Cells, Dysfunctional and Senescent T-Cells Hinder the Immunity in Pancreatic Cancer (2021). Sivakumar S, Abu-Shah E, Ahern DJ, Arbe-Barnes EH, Jainarayanan AK, Mangal N, Reddy S, Rendek A, Easton A, Kurz E, Silva M, Soonawalla Z, Heij LR, Bashford-Rogers R, Middleton MR, Dustin ML. Cancers 13(8):1776.
- Tebentafusp, A TCR/Anti-CD3 Bispecific Fusion Protein Targeting gp100, Potently Activated Antitumor Immune Responses in Patients with Metastatic Melanoma (2020). Middleton MR, McAlpine C, Woodcock VK, et al. Clin Cancer Res. 26(22):5869-5878.
- Peripheral CD8+ T cell characteristics associated with durable responses to immune checkpoint blockade in patients with metastatic melanoma. (2020). Fairfax BP, Taylor CA, Watson RA, Nassiri I, Danielli S, Fang H, Mahé EA, Cooper R, Woodcock V, Traill Z, Al-Mossawi MH, Knight JC, Klenerman P, Payne M, Middleton MR. Nat Med. 26(2):193-199.
- Safety and feasibility of ultrasound-triggered targeted drug delivery of doxorubicin from thermosensitive liposomes in liver tumours (TARDOX): a single-centre, open-label, phase 1 trial (2018). Lyon PC, Gray MD, Mannaris C, Folkes LK, Stratford M, Campo L, Chung DYF, Scott S, Anderson M, Goldin R, Carlisle R, Wu F, Middleton MR, Gleeson FV, Coussios CC. Lancet Oncol. 19(8):1027-1039.
- Adjuvant bevacizumab for melanoma patients at high risk of recurrence: survival analysis of the AVAST-M Trial (2018). Corrie PG, Marshall A, Nathan PD, Lorigan P, Gore M, Tahir S, Faust G, Kelly CG, Marples M, Danson SJ, Marshall E, Houston SJ, Board RE, Waterston AM, Nobes JP, Harries M, Kumar S, Goodman A, Dalgleish A, Martin-Clavijo A, Westwell S, Casasola R, Chao D, Maraveyas A, Patel PM, Ottensmeier CH, Farrugia D, Humphreys A, Eccles B, Young G, Barker EO, Harman C, Weiss M, Myers KA, Chhabra A, Rodwell SH, Dunn JA, Middleton MR; AVAST-M Investigators. Ann Oncol. 29(8):1843-1852.
- Circulating tumor DNA predicts survival in patients with resected high-risk stage II/III melanoma (2018). Lee RJ, Gremel G, Marshall A, Myers KA, Fisher N, Dunn JA, Dhomen N, Corrie PG, Middleton MR, Lorigan P, Marais R. Ann Oncol. 29(2):490-496.
- Predicting Pathologic Response of Esophageal Cancer to Neoadjuvant Chemotherapy: The Implications of Metabolic Nodal Response for Personalized Therapy (2017). Findlay JM, Bradley KM, Wang LM, Franklin JM, Teoh EJ, Gleeson FV, Maynard ND, Gillies RS, Middleton MR. J Nucl Med. 58(2):266-275. doi: 10.2967/jnumed.116.176313. Erratum in: J Nucl Med. 58(5):852.
- PACMEL: a phase 1 dose escalation trial of trametinib (GSK1120212) in combination with paclitaxel (2015). Coupe N, Corrie P, Hategan M, Larkin J, Gore M, Gupta A, Wise A, Suter S, Ciria C, Love S, Collins L, Middleton MR. Eur J Cancer. 51(3):359-66.