Early Clinical Trials
Over the last 3 years we have established a core team and designated clinic for early clinical trials of novel anti-cancer therapies.
Our key translational collaboration is with the Clinical Trials Pharmacology Laboratory working to Good Clinical Laboratory Practice standards (headed by Dr P. Loadman) at the Institute for Cancer Therapeutics in Bradford (Director, Prof. L. Patterson).
We want to perform hypothesis-driven studies, prioritising therapeutics developed locally or through the Cancer Research UK New Agents Committee. We are identifying co-investigators within the tumour-specific teams so we can conduct studies of targeted agents. We also have strong links to the Biotherapies Group in Leeds.
We were the co-ordinating and translational centre for a “proof-of-principle” clinical study of AQ4N, an inactive pro-drug designed to be selectively activated to the cytotoxic AQ4 in hypoxic areas of tumours. After treatment with AQ4N, parent drug and active metabolite were quantified and hypoxia identified in tumour/normal tissues obtained at surgery (Figure 1). Levels of AQ4 correlated with hypoxia (Figure 2).
We have treated over 100 patients on more than 10 early Trials, and Leeds has been recognised as a Cancer Research UK Centre for early clinical trials. These activities will increase following our successful Experimental Cancer Medicine Centre bid and the enhanced facilities within the New Oncology Wing.
Figure1 A Q4N and AQ4 identified in tumour (left); hypoxic areas of tumour stained for Glut 1 (Dr R Phillips, right).
Figure 2 Correlation between extent of hypoxia and amount of active AQ4 (Low vs high P=0.0007).
Poole C.; Earl H.M.; Hiller, L.; Dunn J.; Bathers, S.; Grieve R.; Spooner D.A.; Agarwal, R.J.; Fernado, I.N.; Brunt, A.M.; O’Reilly, S.M.; Crawford S.M.; Rea, D.W.; Simmonds, P.; Mansi, J.M.; Stanley, A.; Harvey, P.; McAdam K.; Foster L.; Leonard, R.L.; Twelves, C.J. (2006) Epirubicin and Cyclophosphamide, Methotrexate, and Fluorouracil as Adjuvant Therapy for Early Breast Cancer. The New England Journal of Medicine, 355(18), pp.1851-1862.
Twelves, C.J.; Wong A.; Nowacki, M.P.; Abt, M.; Burris H.A.; Carrato, A.; Cassidy J.; Cervantes, A.; Fagerberg, J.; Georgoulias, V.; Husseini, F.; Jodrell D.; Koralewski P.; Kroning, H.; Maroun J.; Marschner N.; McKendrick J.; Pawlicki, M.; Rosso R.; Schuller, J.; Seitz J.F.; Stabuc, B.; Tujakowski J.; van Hazel G.; Zaluski J.; Scheithauer W. (2005) Capecitabine as adjuvant treatment for stage III colon cancer. The New England Journal of Medicine, 352(26), pp.2696-2704.
Harris, P. A., C. R. Dunk, M. R. Albertella, P. M. Loadman, R.M.Phillips, P. Jones and C. Twelves “Tumor-specific activation of the hypoxic cell cytotoxin AQ4N: a phase I clinical study in solid tumors.” AACR Annual Meeting, Washington. (2006).