A phase I/II study of hepatic artery infusion with wtp53-CMV-Ad in metastatic malignant liver tumours

Colorectal cancer (CRC) is the second commonest cause of cancer death in th e UK, with greater than 40% of these patients destined to die of the diseas e despite current medical management. Death is commonly due to liver metast ases with sequelae including progressive liver dysfunction. Most patients w ith liver metastases present with tumours that are unresectable and incurab le with existing therapies. The median survival for CRC patients after diag nosis with liver metastases is approximately 6 months or less. The human p53 gene is a tumour suppressor gene involved in the control of c ell proliferation. Loss of wild-type p53 function is associated with the un controlled growth of many types of human cancers. The reintroduction and ex pression of wild-type p53 into p53 altered tumour cells has been shown to s uppress tumour growth or induce apoptosis in both in vitro and in vivo mode ls. In our experience greater than 50% of CRC tumours have p53 alterations. This study seeks to evaluate the safety, biological efficacy and the effect iveness of wtp53-CMV-Ad treatment which is a recombinant adenoviral vector containing the wild-type human p53 gene. It will be administered by infusio n via the hepatic artery, for the regional gene therapy of malignant liver tumours. Study patients will have incurable metastatic (CRC) malignant tumo urs of the liver with evidence of p53 alteration in their liver tumours. In vitro studies have demonstrated p53-specific antiproliferative effects of wtp53-CMV-Ad on human liver tumour cells and in vivo studies have demonstra ted p53-specific antiproliferative effects on human liver tumour cells. The vector Ad-p53 is a recombinant, replication-defective adenovirus based on adenovirus serotype 5. It contains a sequence encoding wild-type p53 who se expression is under the control of the human cytomegalovirus immediate e arly promoter-enhancer. This construct will be growth in 293 cells which co ntain the adenoviral E1A and E1B coding sequences which have been removed f rom the vector to render it replication defective. The study design is an open-label, non-randomised, single-dose, dose escala tion Phase I/II clinical trial anticipated to involve a maximum of 19 patie nts, wtp53-CMV-Ad will be administered by infusion in a reservoir connected to the hepatic artery, for regional gene therapy (surgically implanted pum p) in 3 escalating doses to successive cohorts of 3 patients each until the maximum tolerated dose is determined. Subsequently, 10 patients mill be tr eated with this dose. Regional wtp53-CMV-Ad therapy will be administered as a single bolus infusion via hepatic artery catheter. The route of administ ration of wtp53-CMV-Ad via hepatic artery infusion is designed to maximise gene therapy exposure to the malignant tumours while minimising exposure to normal tissues outside the liver. The clinical protocol is designed to mon itor treatment toxicity. Another objective is to evaluate the biological ef ficacy, including efficiency and stability of gene transfer by analysis of tumour tissues following therapy. As an important part of this objective th e pharmacokinetics of wtp53-CMV-Ad will be studied. Clinical evidence of an ti-tumour efficacy will also be collected. In addition, the safety and effi cacy of different doses levels of wtp53-CMV-Ad will be studied.