Patient Information SHEET                16.10.03

Immunotherapy with heat shock enhanced autologous tumour lysate, alpha-interferon and granulocyte macrophage colony stimulating factor in patients with malignant mesothelioma.

 Chief Investigator: Professor Bruce WS Robinson

 Associate Investigators: Dr Alex Powell, Clinical Professor Bill Musk,  Dr Michelle Murphy

Introduction

You are being invited to take part in a human research study that is investigating ways in which it is possible to induce, or stimulate, an immune response against mesothelioma. Before you make your decision, it is important for you to understand why the research is being done and what it would involve. Please take as much time as you need to read the following information carefully and discuss it with friends, relatives and your doctor if you wish. Ask us if there is anything that is not clear or if you would like more information.

 

What is the purpose of the study?

Unfortunately, despite the emergence of new types of treatment for mesothelioma there is no standard form of treatment proven to be effective in the majority of patients. At Sir Charles Gairdner Hospital we are investigating treatments which enhance the body’s own defences against cancer, such as mesothelioma. We are trying to improve the means by which the body’s defence cells communicate with each other so they can better attack the cancer. Cells ‘talk’ to each other by the use of very specific chemicals called cytokines. These are the same chemicals that cause the aches, pains, fever & tiredness associated with viral infections, such as “the flu”. Cytokines are produced in minute amounts in the human body and travel small distances from where they are produced to act on nearby cells.

The two cytokines we are investigating are granulocyte-macrophage colony stimulating factor (GM-CSF) and alpha-interferon (a IFN). A vaccine injection will be made from your tumour cells, which have been killed, combined with GM-CSF and aIFN. We hope that the cytokines will stimulate the body’s ‘guard’ cells that are responsible for taking up tumour cells and carrying them to the local lymph glands. This in turn will stimulate host T-cells or immune cells that spread around the body and attack and kill any cancer cells.

We will be looking at how the immune system responds to the vaccine, whether your cancer shrinks and whether your symptoms improve during and after the treatment.ave to take part?

It is your decision whether or not to participate in this study. If you decide to take part you can still withdraw at any time, without giving a reason. If you decide not to participate, or decide later to withdraw, it will not affect the standard of further care you would receive. If you do decide to take part you will be asked to sign a consent form. You will be given this information sheet to keep and you will receive a copy of your signed consent form.inical Trial?

If you decide to participate in the study, we will need to obtain a sample of your mesothelioma tissue. If you have a lump on your chest wall this can be removed under local anaesthetic or a light general anaesthetic. Otherwise you will need to undergo a surgical procedure, called a video-assisted thoracoscopy (VAT). This is performed by a specialist chest surgeon under a general anaesthetic, and involves a tube being inserted through the chest wall into the space between the lung and chest wall, to obtain a sample of tumour tissue. After the procedure you will return to the ward with a small plastic tube remaining in the chest wall for a further 24 hours. The utmost care will be taken to ensure that you are kept comfortable and pain-free. There is a small chance that the plastic tube may get infected; this would require intravenous antibiotics and a longer stay in hospital. Another potential complication is bleeding from the chest tube. In this case the tube may be left in for longer and a blood transfusion may be required. Without complications, you would remain in hospital for 3-4 days. You will be provided with a script for painkillers in case you experience any chest discomfort at home.

The vaccine

Mesothelioma tissue will be obtained from theatre and transported directly to the laboratory where the vaccine will be created under strict sterile conditions. The tissue will be minced then heated to 43° for 1 hour. This heating of the tumour is thought to increase the amounts of special proteins called heat shock proteins. These are thought to help boost the immune response. The sample will then be frozen and thawed multiple times to kill the cancer cells. They will then receive a dose of radiation to ensure that they are dead. Every effort will be made to ensure the tumour cells are rendered inactive (ie dead) prior to injection.

Therapy will begin within 2 weeks of surgery. To receive the vaccine, you will need to attend the University Department of Medicine, 4^th floor, G block, Sir Charles Gairdner Hospital once a fortnight for 12 weeks. Following this the visits will be at monthly intervals. Each visit will take approximately 15-30 minutes.

If you respond to the vaccine you will be offered further vaccinations (if there was enough of your tumour tissue initially to manufacture extra doses of vaccine). This will require ongoing fortnightly visits until the vaccine supply runs out, or there is evidence of tumour progression.

You will receive an injection of the vaccine (made up of inactive tumour cells), GM-CSF and aIFN under the skin over the shoulder. As mentioned above, the tumour vaccine plus GM-CSF and aIFN will be taken up by ‘guard’ cells and transported to the local lymph nodes to hopefully stimulate an immune response.

You will then receive similar daily injections of both GM-CSF and aIFN for the next 4 days. Your spouse or a friend can administer this at home, or your local doctor can give them to you. Appropriate teaching of how to give the injections will be provided.

Assessing response

The aims of the study are to see how effective this method is for inducing an anti-cancer immune response, how well the vaccine is tolerated and what effect the vaccine has on your tumour. To answer these questions, the following tests will be performed:

 1.      DTH skin tests: this involves an injection of dead tumour cells under the skin of the forearm.     

      If the body’s immune system ‘recognises’ and responds to the tumour, a red lump will form within 72 hours. These skin tests will be performed once a month during the clinic visit, and you will need to return to clinic 2 days later to have the result read.

 2.      Blood tests: will be done monthly to monitor for any potential adverse effects from the vaccine on the blood cells, liver or kidneys. We will also assess the anti-cancer immune response to the vaccine.

 3.      CT scan of the chest: will be done after surgery and at the end of the vaccination period. In those patients who respond to the vaccine and decide to have further vaccinations after the initial 12-week period, CT scans will be performed every 8 weeks to assess ongoing tumour response.

 4.      Lung function: this will be assessed at every visit. It involves blowing into a spirometer.

 Possible side effects

You may experience mild pain at the injection site, which may become swollen and red. You may also experience fever, chills, headaches, fatigue and muscle aches. These symptoms are unlikely at the doses we will use, but if they do occur paracetamol can be taken for symptomatic relief.

There is no standard form of treatment proven to be effective in the majority of patients with malignant mesothelioma. Some (20-30%) patients temporarily respond to chemotherapy, but the disease is usually progressive and ultimately fatal. If you agree to participate in the trial, this will not affect your ability to have chemotherapy in the future.

You may develop an immune response to the mesothelioma that could cause tumour shrinkage in the short term, and possibly improve your symptoms and  life expectancy.

However, it is possible that this study will not result in any direct benefit to you. By finding out the best way to stimulate the body’s anti-cancer immune response we may be able to understand the optimal source of cancer proteins for future therapy, and the best way to administer these proteins.

What are the possible risks from participation?   

Whilst we will make every effort to avoid the possibility of an adverse event, there can be no guarantee that one will not occur. Possible adverse effects of the surgery and vaccine injections have been outlined above. There is a remote possibility that the cytokine therapy may cause severe side effects, but this is unlikely at the doses we will be using.

GM-CSF may increase the white cells in your blood, but we will monitor this and stop the GM-CSF if necessary. In our last trial of a similar vaccine (inactivated tumour cells + GM-CSF) in patients with mesothelioma, the therapy was very well tolerated.

 aIFN is used in the treatment of diseases such as hepatitis B, hepatitis C, melanoma, kidney cancer and some types of leukaemia and lymphoma (cancers of the blood and lymph glands). In these conditions much higher doses are used than in this study. Adverse reactions to aIFN are dose related, and we do not expect any serious side effects at the doses we will be using in the study. However, possible side effects include flu-like symptoms (fever, chills, fatigue, headache, muscle aches), nausea, loss of appetite, low blood pressure, dizziness, sleepiness and thyroid problems. Rare, but serious, side effects include depression, liver, heart, bone marrow and lung problems. These are more common at high doses of aIFN and in people who have pre-existing problems with these organs. Blood tests will be done throughout the study to monitor for problems with the blood, liver or kidneys.

GM-CSF and aIFN are not recommended for use in pregnancy or if breastfeeding. Therefore, females of childbearing potential should practice an adequate form of birth control such as the oral contraceptive pill, a barrier method or complete abstinence during the study.  Likewise, males should avoid fathering children during the study.

·   GM-CSF and aIFN are not registered in Australia for treatment of mesothelioma and their use in this setting would be considered experimental. 

There is a theoretical possibility of re-introducing live tumour cells into the body, though this is extremely unlikely. Every possible effort will be made to ensure the tumour cells are rendered inactive prior to injection. In our last trial there was no growth of tumour at injection sites, and other researchers have used similar methods of killing tumour cells with success.

In the event of a research related adverse event or injury, the investigators will provide or arrange all necessary treatment and care. If compensation is required as a result of a research related injury Sir Charles Gairdner Hospital will provide this.t if new information becomes available?

Sometimes information about a new therapy becomes available as a study progresses. If this information is important to your decision to continue in the study, your doctor will tell you about it. If you then want to continue in the trial, you may be asked to sign a revised consent form.

What happens at the end of the study?

After the study is completed you will continue to be followed-up monthly in the clinic. You will also be under the care of your local doctor &/or referring specialist. You will be informed of the outcome of the study when it is completed.

 

Sometimes a trial needs to be stopped early because of safety concerns or for other reasons. If this occurs, the reasons will be explained to you and other treatments will be organised for your condition.Who will see my study records?

The trial records will be kept within the University Department of Medicine during the study and in a locked archive for at least 15 years from the time the study is closed.  Authorised representatives of the sponsor, the investigating doctor, the Hospital Human Research Ethics Committee and medicines regulatory bodies will be able to see study records. Your family doctor will be told that you have decided to take part in this study. Otherwise, your records obtained while you are in this study as well as related health records would remain strictly confidential at all times.

Personal data will be collected and processed but only for research purposes in connection with this study. The study data will be analysed here and at other sites, but will not leave this site in a form that could allow you to be identified. The result of the research will be made available to other doctors through medical journals or meetings, but you will not be identifiable in these communications. By taking part in this study you agree not to restrict the use of any data even if you withdraw. Your rights under any applicable data protection laws are not affected

By signing this form you give permission for the release of your medical records, x-ray results, laboratory and pathology specimens to the researchers for the evaluation of your disease and treatment. You have the option of allowing us to freely use any of your tumour vaccine that is not required for your treatment for future unspecified research (see the consent form titled: Consent for blood/tissue taking and cell line/tissue banking for clinical research). Reimbursement

There will be no cost to you for participating in this study and you will not be paid for your involvement.

Sponsorship of the study

This study is funded by the Health Department of Western Australia. Funds are expended in gaining the services of the doctors, nurses and other staff who conduct the study and in paying for the tests, procedures and other services that trial participants receive.

Ethical Approval of the Study

This study will be carried out in a manner conforming to the principles set out by the "National Statement on Ethical Conduct in Research involving Humans" and according to the Good Clinical Practice Guidelines and the International Conference of Harmonisation. The Sir Charles Gairdner Hospital Human Research Ethics Committee has reviewed and approved the study.

Further information and contacts during the study

If at any time you have any questions or concerns about the study, your safety or your rights, please contact your doctor, the other members of his/her team, or the study staff:

Chief Investigator: Professor Bruce Robinson      Phone: 08 93462098

Co-Investigator: Dr Alex Powell                           Phone: 08 93462098

Research Coordinator: Dr Michelle Murphy                     Phone: 08 93463259

If you want to discuss the study with someone who is not directly involved (eg. the information you have received, the conduct of the study, your rights as a participant, or a complaint you have), you can contact the Human Research Ethics Committee Secretariat on ph: (08) 9346 2999.

Advising Your Family Doctor about your Participation in the Study

Please provide your family doctor’s details below, we will keep him/her informed of your participation in the study as well as any other study relevant information.

 

GP's name:­­­­­­­­­­­­­­­­­

Telephone no.:

Address: