Day 1: 13 April 2005

Present: Professor Norman Nevin (Chair), Professor Terry Hamblin, Professor Jim Neil, Dr Adrian Lepper, Mrs Debbie Beirne, Professor Nick Lemoine, Dr Caroline Benjamin, Dr Peter Harris, Dr Michael Waterhouse, Dr Richard Ashcroft, Professor Andrew Lever, Professor Alex Markham

Secretariat: Dr Monika Preuss, Dr Jayne Spink, Mr Daniel Gooch

Observers: Dr Liz Pollitt and Dr Paul Raptopoulos (MHRA), Dr Matthew Penrose (HSE).

Item 1: Welcome

The Chair welcomed the Committee to its 53rd meeting, the second 2 day meeting in less than 6 months. The Chair also welcomed back Dr Jayne Spink and recorded the Committee's thanks to Dr Cathleen Schulte who had now left the Secretariat.

The Eleventh Annual Report was published on 3 April 2005 and the Secretariat distributed the report both at the public meeting and the BSGT conference in Manchester. There was positive feedback from researchers who were particularity pleased with the summaries of the closed studies.

There was a short summary of the successful Manchester public meeting.

Item 2: Minutes of the 52nd meeting of GTAC

The minutes were agreed as an accurate and true record of the 52nd meeting.

Item 3: Matters Arising

A number of letters were sent out, and received, concerning correspondence arising from the last meeting, none of which gave rise to significant discussion or any actions.

Item 4: A phase I study of adoptive transfer of autologous tumour antigen-specific T cells with pre-conditioning chemo-therapy and intravenous IL-2 in patients with CD19 positive malignancy

This study is similar to a study approved by GTAC in 2004. It describes a complex scheme of gene therapy and chemotherapy for patients with CD19 positive cancers. CD19 is found in the majority of B cell derived malignancies as well as in Non-Hodgkin's lymphoma. Patients eligible for this trial must have confirmed CD19 positive cancers with evidence of persistent or progressive disease. The study product is a retroviral vector. The study involves the harvest of T cells from patients with CD19 positive cancers, exposure of these T cells to the study vector, followed by the expansion of modified T cells in the laboratory, and, finally, the re-infusion of the modified T cells back to the patient. After some discussion the Committee decided to decline the application while asking the proposers to address a number of points.

GTAC 104: Safety, immunology and efficacy evaluation of Trovax in patients with stage IV clear cell renal carcinoma

TroVax has been used in a number of GTAC approved clinical trials. It has recently been reformulated which required a bridging study to compare the characteristics of the original and new formulations. TroVax is based on modified Vaccinia Ankara Virus (MVA) which carries the gene for "oncofoetal antigen" or "5T4" which is found on the surface of many cancer cells. The strategy is to immunise patients against 5T4 in an attempt to alert the immune system to the presence of the cancer cells. After some discussion the Committee decided to award conditional approval, subject to the outcome of the bridging study.

Item 5: Update of GTAC/CSM working party meeting

The GTAC/CSM meeting on retroviruses took place on 14 March and there was a brief summary of the meeting.

Item 6: Query regarding the issue of compassionate use, and import, of gene therapy agents in the UK

GTAC discussed briefly a number of issues in relation to the off-protocol use of gene therapy products (named patient exemptions) and procedures around the import of such materials.

Item 7: Amendment to GTAC's reporting requirements

At the last GTAC meeting, there was some discussion of reporting to GTAC of SAEs and SUSARs. A representative of MHRA's clinical trials unit gave a brief presentation for information to the committee.

Item 8: SAE Update

The Secretariat had compiled a list of the new SAEs received since the last meeting, none of which gave rise to any significant discussion.

Item 9: An ascending dose trial of the safety, tolerability and biological effect of intra-arterial injection of the selectively replication-competent herpes simplex virus HSV1716 in patients with unresectable hepatocellular carcinoma

HSV1716 is a modified HSV virus which cannot infect cells that are not themselves rapidly dividing. Tumour cells are rapidly dividing and HSV1716 should be able to selectively infect these cells and hopefully kill them. The same vector has been used in a number of GTAC approved studies. Patients eligible for this new trial have unresectable hepatocellular carcinoma (HCC) that is unsuitable for liver resection or liver transplantation. The primary objective of the trial is to determine whether HSV1716 given by direct intra-arterial injection in patients with HCC is safe and well tolerated. After some discussion the Committee decided to decline the application while asking the proposers to address a number of points.

Day 2: 14 April 2005

Present: Professor Norman Nevin (Chair), Professor Terry Hamblin, Professor Jim Neil, Dr Adrian Lepper, Mrs Debbie Beirne, Rev Dr Lee Rayfield, Professor Nick Lemoine, & Mrs Fiona Sandford

Secretariat: Dr Monika Preuss, Dr Jayne Spink, Mr Daniel Gooch

Observers: Dr Liz Pollitt and Dr Paul Raptopoulos (MHRA), Dr Matthew Penrose (HSE).

The Chairman briefly welcomed members to the second day of the GTAC meeting.

Item 1: A phase I study of intra-peritoneal Ad-hTR-NTR and CB1954, an adenovirus-delivered telomerase-directed enzyme-prodrug therapy, in patients with advanced intra-abdominal cancer

A central cause for the immortality of cancer cells is known to be associated with high levels of activity of a cellular enzyme called "telomerase". This phenomenon can be exploited as a method to target a gene therapy agent to cancer cells with high telomerase activity. The study product is an adenoviral vector. It is replication defective and contains as the therapeutic gene the sequence of the bacterial nitroreductase (NTR) enzyme. The production of NTR is driven by the telomerase promoter which restricts the production of NTR to cancer cells with high telomerase activity. NTR converts the relatively harmless prodrug CB1954 into its active, toxic, form which is hoped will kill the cancer cell (gene directed enzyme prodrug therapy). This strategy will be used in patients with advanced, inoperable, intra-abdominal carcinoma with ascites. After discussion GTAC decided to award the study conditional approval, subject to a number of minor amendments.

Item: A phase II exploratory study of the safety and biological activity of OncoVEX^GM-CSF in combination with radiotherapy and cisplatin in the treatment of locally advanced epithelial cancer of the head and neck

OncoVEX is a Herpes Simplex Virus (HSV) vector used as a potential treatment of solid tumours. The product has already been approved for a clinical trial in the UK. The new study focuses on head and neck cancer. OncoVEX results in death of infected cells, which causes the release of antigens from these cells. The antigens can then be recognised by the immune system. Once stimulated in this way, it is hoped that the immune system can mount an attack on the tumour tissue. The OncoVex construct combines oncolytic tumour therapy, which will destroy the tumour with the action of an immune-stimulatory molecule (GM-CSF). The primary objective is to assess the safety of OncoVEX combined with chemo-radiotherapy in patients with locally advanced cancer of the head and neck prior to radical neck dissection. After discussion GTAC decided to award conditional approval to the protocol subject to some minor amendments.

Item 3: Chairman's Actions

A number of Chairman's actions had been taken since the last meeting, none of which gave rise to any discussion.

Item 4: Any other business

There was a brief discussion of conflicts of interests for researchers involved in clinical trials.

Item 5: Press cuttings

A number of press cuttings were provided in the meeting papers.

Next meeting: Wednesday, 22 June in Skipton House

GTAC Secretariat
June 2005

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