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 the UK, with greater than 40% of these patients destined to die of the disease despite current medical management. Death is commonly due to liver metastases with sequelae including progressive liver dysfunction. Most patients with liver metastases present with tumours that are unresectable and incurable with existing therapies. The median survival for CRC patients after diagnosis with liver metastases is approximately 6 months or less. The human p53 gene is a tumour suppressor gene involved in the control of cell proliferation. Loss of wild-type p53 function is associated with the uncontrolled growth of many types of human cancers. The reintroduction and expression of wild-type p53 into p53 altered tumour cells has been shown to suppress tumour growth or induce apoptosis in both in vitro and in vivo models. In our experience greater than 50% of CRC tumours have p53 alterations. This study seeks to evaluate the safety, biological efficacy and the effectiveness of wtp53-CMV-Ad treatment which is a recombinant adenoviral vector containing the wild-type human p53 gene. It will be administered by infusion via the hepatic artery, for the regional gene therapy of malignant liver tumours. Study patients will have incurable metastatic (CRC) malignant tumours 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 demonstrated 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 whose expression is under the control of the human cytomegalovirus immediate early promoter-enhancer. This construct will be growth in 293 cells which contain the adenoviral E1A and E1B coding sequences which have been removed from the vector to render it replication defective. The study design is an open-label, non-randomised, single-dose, dose escalation Phase I/II clinical trial anticipated to involve a maximum of 19 patients. wtp53-CMV-Ad will be administered by infusion in a reservoir connected to the hepatic artery, for regional gene therapy (surgically implanted pump) in 3 escalating doses to successive cohorts of 3 patients each until the maximum tolerated dose is determined. Subsequently, 10 patients will be treated with this dose. Regional wtp53-CMV-Ad therapy will be administered as a single bolus infusion via hepatic artery catheter. The route of administration 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 monitor treatment toxicity. Another objective is to evaluate the biological efficacy, including efficiency and stability of gene transfer by analysis of tumour tissues following therapy. As an important part of this objective the pharmacokinetics of wtp53-CMV-Ad will be studied. Clinical evidence of anti-tumour efficacy will also be collected. In addition, the safety and efficacy of different doses levels of wtp53-CMV-Ad will be studied.