Plenary Speaker

Innovations in Cancer Drug Development
David J Kerr

 
Increasingly, Clinical Trials of novel anti-cancer agents combine clinical observation with pharmacokinetic (PK) and pharmacodynamic endpoints (PD) in an attempt to provide proof of mechanism. This should allow refinement of drug development pathways, with the potential to explore success or failure in a rational way, and thus improve the efficiency of drug development.

The oxido reductase NQO2 converts CB1954, in the presence of the co-factor EP0152R, to a cytotoxic bifunctional alkylating agent. NQO2 activity in hepatocellular tumour tissue is 6-fold higher than other cancer types and 20-fold higher than bone marrow. The x-ray crystal structural binding model of CB1954 and EP0152R to NQO2 suggested the optimal infusional schedule for a phase I trial combining the two agents. Thirty-two patients were treated and diarrhoea and transaminitis defined the clinically tolerated dose of the combination. There was remarkable pharmacokinetic interaction, with EP0152R inducing a 1000 fold increase in clearance of CB1954, in keeping with model predictions. The comet assay detected DNA interstrand crosslinks caused by nitroreduced CB1954 in tumour biopsies taken from treated patients, demonstrating proof of mechanism. This trial, therefore gives an example of how the drug development pathway can be mechanistically tested in the clinic.