Medical Research Council

AML 17 TRIAL: PATIENT INFORMATION SHEET 3 (Ref. ISRCTN55675535)

Acute Promyelocytic Leukaemia AIDA versus Chemo Free (ATRA and Arsenic).

Background:

You have already agreed to enter this trial. The diagnostic tests indicate you have a subtype of AML called Acute Promyelocytic Leukaemia (APL). This subtype does very well with the treatments that already exist and have and estimated chance of cure of over 80%. In this trial we wish to test whether we can actually reduce the intensity of the treatment needed while maintaining the good results. This sheet provides you with information on the treatments, which we want to compare.

What is the purpose of the trial?

We want to compare two treatment approaches to this AML sub-type. These are known as the AIDA schedule (the letters stand for the names of the chemotherapy drugs) and a chemotherapy free combination using a drug that is a bit like vitamin A called ATRA (this stands for all-trans-retinoic acid which is the proper name for this vitamin A like drug) and Arsenic Trioxide. They both produce very good results with more than an 80% chance of eradicating the disease, although not so many patients have been treated with the chemo-free approach.

What will happen?

APL is the sub group of AML that is most responsive to treatment. Recent large trials have produced similar good results with cure rates in the region of

Patient Information and Consent form 3, Version 5.1.: dated October 2011 1 of 7 80 to 90%. One of these trials was developed in Italy and combines the Vitamin A compound called all-trans-retinoic acid (ATRA) with a single chemotherapy drug to which this subgroup responds, called Idarubicin. This gives the schedule we call AIDA. More recently equivalent results have been produced in a smaller study which suggests that it may be possible to develop treatment which does not require any chemotherapy at all. This is the combination of ATRA with a drug called arsenic trioxide or Trisenox, which is licensed for the treatment of this disease when it relapses.

If you agree to enter this comparison you will be randomly allocated to receive either the AIDA treatment or the combination of ATRA and Arsenic Trioxide. In order to be eligible a number of lab tests and investigations including an ECG to ensure that this treatment is suitable for you

AIDA Treatment: In this treatment arm you will take ATRA by mouth for 60 days. On days 2, 4, 6 and 8 you will receive in infusion of the chemotherapy drug called Idarubicin into your vein. Your marrow and blood will be checked to make sure that you have responded after about four weeks.

You will then receive 3 more courses approximately 1 month apart This will be ATRA taken by mouth twice a day for 15 days together with infusions of Idarubicin or a similar drug given on days 1, 2, 3, and 4 of each treatment course. It is expected that the treatment will cause your marrow to stop working for a few days due to the Idarubicin treatment. At these times you may require transfusions of blood and platelets. Since your white cells will be low you are at risk of developing an infection which will need you to be in hospital in order to receive strong antibiotics. Other side effects are uncommon.

ATRA and Arsenic Treatment In this arm you will receive ATRA by mouth twice a day for 60 days. During the first week you will receive Arsenic Trioxide by a 2 hour infusion for 5 consecutive days and for 2 days in the following seven weeks making a total

Patient Information and Consent form 3, Version 5.1.: dated October 2011 2 of 7 of eight weeks of treatment. Your blood and bone marrow will be checked to ensure that you have responded.

You will then receive four further courses of treatment in each of which you will take ATRA by mouth twice a day for 14 day and arsenic trioxide intravenously for 5 days in the first week and on 2 days in the second to fourth weeks. In weeks 5 and 6 you will receive ATRA by mouth twice a day. There will be a four week gap between courses of ATO and there will be a 2 week gap between each ATRA course. If at diagnosis you have a raised white blood count, you will also be given an infusion of the drug called Mylotarg in your first course in order to get your blood count under control as quickly as possible. Mylotarg is an antibody which targets leukaemia cells with chemotherapy attached. If your white blood count is below 10, you will not need this.

Monitoring Disease Very sensitive tests can be done on the blood and marrow samples which will be taken to find out how your disease has responded which can predict if relapse is going to happen. This will allow intervention before the relapse occurs clinically. This test will be taken after each course of treatment and then at 3 monthly intervals for 3 years. In the attached consent form you will be asked if you will participate in the monitoring, which will involve more testing than would normally be done for other sorts of AML. Monitoring is considered especially important in this type of AML where we are testing the option of reducing the intensity of treatment. You are of course free to change your mind about participation in this aspect.

. Will the treatment have side-effects?

All chemotherapy can cause side effects. The Idarubicin treatment will stop your bone marrow making red cells, white cells and platelets. These will recover 2-4 weeks later but during that time you may need transfusions of red cells and platelets. You will also be at increased risk of developing an

Patient Information and Consent form 3, Version 5.1.: dated October 2011 3 of 7 infection, which would need prompt treatment with strong antibiotics. The ATRA can cause patients to accumulate extra fluid and sometimes to become breathless as a result. This can be treated promptly with steroids and usually resolves quickly. Some patients develop headaches requiring some pain killers or analgesia to be given. These effects may lead to a temporary or permanent stopping of ATRA treatment or a dose reduction if they are really troublesome.

Arsenic can also cause fluid retention which also may need treatment with steroids. It does not normally cause the bone marrow to stop producing cells, so transfusion, infection and antibiotic use is likely to be less. However, it can affect the electrical activity of the heart muscle, but this does not usually cause symptoms. Your medical team will check the ECG heart tracing from time to time to look out for this. If it is seen you may require some treatment of your blood chemistry, and or a slight delay in your treatment.

Since we know that both treatments result in good results we will be looking at other differences between treatments such as days in hospital, transfusion needs, days on antibiotics and how the treatment affects your day-to-day living. You will be asked to complete a questionnaire on at the start of treatment and on three more occasions later on to assess various aspect of your quality of life.

Will you benefit from the treatment?

Both of these treatment schedules have previously produced very good results. We do not know which is better. It is possible that you may not benefit from being on one or other of the treatments. The trial is carefully monitored by an independent panel of experts who will stop the trial if one treatment appears to be better. Patients will then receive the better treatment.

What are the alternatives?

Patient Information and Consent form 3, Version 5.1.: dated October 2011 4 of 7 In the present state of knowledge, the best treatment is the combination of ATRA and Idarubicin (AIDA) as described above. If you decide not to enter the trial, it is likely that your doctor will offer you treatment with AIDA chemotherapy.

Can I withdraw from the trial?

You may withdraw from the trial at any time. If you choose to do so, your doctor will discuss the best treatment available with you.

Contact for Further Information

Further information can be obtained from your local organiser (Principal Investigator) or the UK organiser (Chief Investigator) whose addresses are given below.

Chief Investigator: Prof Alan Burnett Department of Haematology University Hospital of Wales Cardiff CF14 4XW Tel: 029 2074 2375 e-mail: [email protected]

Patient Information and Consent form 3, Version 5.1.: dated October 2011 5 of 7 CONSENT FORM 3

Acute Myeloid Leukaemia 17 Trial (Trial Reference ISRCTN55675535)

Acute Promyelocytic leukaemia

(Please initial) 1. I have read the attached Information Sheet version 5.1 dated July 2011 ______

2. I have had an opportunity to discuss this study and ask questions

3. I have received satisfactory answers to all of your questions

4. I have received enough information about the study _

5. I have spoken with Dr./ Mr./ Ms.______

6. I understand that I am free to withdraw from the study:  at any time  without having to give reasons  without affecting my future medical care

7. I understand that sections of my medical records relating to my participation in the study may be inspected by responsible individuals from the trial Sponsor who is Cardiff University. All personal details will be treated as STRICTLY CONFIDENTIAL. The information will be used for medical research only and I will be identified only by trial number, initials and date of birth. I will not be identified in any way in analysis and reporting of the results.

Patient Information and Consent form 3, Version 5.1.: dated October 2011 6 of 7 I give permission for these individuals to have access to your records and to have my clinical details recorded in this way

8. I agree to participate in this study

9. I give permission to tell my GP about my participation in the study

Patient’s Signature:______

Name in block letters:______

Date______

Doctor’s Signature:______

Date______

Patient Representative’s Signature: (if appropriate)______

Relationship to patient: ______

Date______

Thank you for considering participating in this part of the trial.

Patient Information and Consent form 3, Version 5.1.: dated October 2011 7 of 7