1. Nov 2008SPIRIT CML Trial Overview STI571 Prospective International RandomIsed Trial A phase III, prospective randomised comparison of imatinib (STI571, Glivec/Gleevec) 400mg daily versus imatinib 800mg daily versus imatinib plus PEGinterferon-alpha 2a (Pegasys) in patients with newly-diagnosed chronic-phase chronic myeloid leukaemia.

2. Nov 2008SPIRIT CML Trial Overview Contents Key Facts Study Summary Patient recruitment –Inclusion criteria –Consent Forms –Randomisation –Study Schedule AE’s and SAE’s PCR analysis Treatment arm details Further Information –Website –Forms eCRF system training

3. Nov 2008SPIRIT CML Trial Overview Key Facts NCRN Adopted study UK Multicentre study Versions running also in GE and FR - may combine data Looking for 2466 patients from UK Current situation –First patient recruited June 2005 –96 sites now with ethics approval –248 patients randomised Electronic Data Capture via internet Website: www.spirit-cml.org

4. Nov 2008SPIRIT CML Trial Overview Study Summary Randomised, Open label Newly Diagnosed CML (within 3 months) 2 treatment arms (822 patients on each) –Arm A: 400mg daily imatinib –Arm B: 800mg daily imatinib –Arm C: closed 21 Feb 2008 Arm C: 400mg daily imatinib plus up to 180  g weekly PEGinterferon  Primary end point is survival at 5 years Secondary endpoints include haematologic and cytogenetic responses

5. Nov 2008SPIRIT CML Trial Overview Patient recruitment –Inclusion criteria –Consent Forms –Randomisation –Study Schedule

6. Nov 2008SPIRIT CML Trial Overview Eligibility - Inclusion Criteria 1.≥ 18 years old. 2.ALL of the following should apply to patient: i.within 3 months of initial diagnosis of CML-Chronic Phase, ii.Received no CML treatment (but hydroxyurea and/or anagrelide OK), iii.Patient is Philadelphia chromosome positive, iv.Patient has a)< 15% blasts in peripheral blood and bone marrow; b)< 30% blasts plus promyelocytes in peripheral blood and bone marrow; c)< 20% basophils in peripheral blood; d)≥ 100 x 10 9 /L platelets; e)no extramedullary involvement (except hepatosplenomegaly). 3.Written voluntary informed consent.

7. Nov 2008SPIRIT CML Trial Overview Eligibility - Exclusion Criteria (1) 1.Patient is Ph-negative, BCR-ABL-positive. 2.Prior treatment for CML. 3.Prior chemotherapy (any type). 4.Prior haemopoietic stem cell transplant, either autograft or allograft. 5.ECOG Score ≥ 3. 6.Serum bilirubin, SGOT/AST, SGPT/ALT, or creatinine > 2.0 x IULN. 7.INR or PTT > 1.5 x IULN. 8.Uncontrolled medical disease. 9.Prior history of significant psychiatric illness, particularly depression.

8. Nov 2008SPIRIT CML Trial Overview Eligibility - Exclusion Criteria (2) 10.HIV-positive (HIV test not required). 11.Major surgery within 4 weeks of Study Day 1, or not recovered from prior major surgery. 12.Patient is: a. pregnant, b. breast feeding, c. without a negative pregnancy test, d. unwilling to use barrier contraceptive. 13.Another malignancy within the past five years. 14.History of non-compliance to medical regimens or potentially unreliable.

9. Nov 2008SPIRIT CML Trial Overview Informed Consent There are 3 consent forms 1.Participation in the SPIRIT Trial 2.Donation of material to CML Biobank 3.CML Patient Registry The patient only needs to agree to part (1) to be included in the trial. Remember: Patient Information Sheet and Informed Consent Forms should be printed on Hospital Headed Paper.

10. Nov 2008SPIRIT CML Trial Overview Randomisation 1.Fax to Trial Manager (0)191 376 0748. Signed informed consent form(s) Cytogenetics report 2.Create new patient in eCRF 3.Complete screening eCRF pages Open visit – visit date Eligibility criteria Demography Randomisation (save as complete) Randomisation – Patient Set-up Treatment arm allocation and subject number will then be displayed on screen.

11. Nov 2008SPIRIT CML Trial Overview Study Schedule (1) Year 1 Visit 1 – Screening Visit 2 – Day 28 (1 month) Visit 3 – Day 56 (2 months) Visit 4 – Day 84 (3 months) Visit 5 – 6 months Visit 6 – 9 months Visit 7 – 12 months Years 2 – 5 Visits 8 – 15 Visits every 6 months

12. Nov 2008SPIRIT CML Trial Overview Study Schedule (2) Visit Date – all visits Eligibility Demography (NHS number) Medical History CML Diagnosis Date PCR sample – every 3 months Bone marrow assessment – once a year Physical examination Extramedullary Involvement Liver & Spleen ECOG Score Quality of Life Questionnaire Labs (Haem/Biochem) Adverse Events Study medication Concomitant medications Screening only All visits

13. Nov 2008SPIRIT CML Trial Overview AE’s and SAE’s Protocol Section 9.3 - discusses Safety Reporting: An adverse event is defined as any undesirable sign, symptom, or medical condition occurring after starting study drug, whether considered study drug- related or not. Please ensure that all adverse events (whether related to study drug or not) are recorded in the patient’s electronic case report form (via the SPIRIT website). A serious adverse event is defined as an event that is: 1.fatal, or life-threatening 2.requires or prolongs hospitalization 3.significantly or permanently disabling 4.is a congenital anomaly 5.any other significant medical event SAE’s must be faxed to Trial Manager within 24 hours Fax SPIRIT SAE form to (0)191 376 0748.

14. Nov 2008SPIRIT CML Trial Overview PCR Samples PCR analysis - BCR-ABL (secondary endpoint). Hammersmith Hospital 20 mls peripheral blood - every 3 months. First PCR sample (visit 1) - PRIOR to imatinib treatment. Please label samples and package clearly as 'SPIRIT Trial’ and include Shipping Form. The samples should be sent via first class post on a Monday, Tuesday or Wednesday only (to avoid samples arriving at the weekend and degrading).

15. Nov 2008SPIRIT CML Trial Overview Treatment Arms Imatinib First 400mg daily imatinib in both treatment arms is supplied from usual NHS stock (as per non-trial patient) A SPIRIT Trial label must be applied Drug accountability still required – considered IMP A.400mg daily imatinib No additional supplies required B.800mg daily imatinib Total daily dose made up from 2 sources: –400mg daily supplied from NHS stock –400mg daily supplied from SPIRIT Trial stock Is usually taken as 400mg BD Imatinib trial stock supplied to hospital pharmacy directly from Novartis. If patient is randomisation to 800mg arm, trial manager will automatically order a re-supply of trial stock for pharmacy.

16. Nov 2008SPIRIT CML Trial Overview Treatment Arms (2) C.400mg daily imatinib plus up to 180  g weekly PEG interferon  **Protocol Amendment** PEG interferon (Pegasys) is started 6 weeks after the imatinib Pegasys is supplied in pre-filled syringes (180  g in 0.5ml) Pegasys is initiated at 90  g once every 4 weeks for 3 doses, then increased gradually. For 90  g dose - 0.25ml needs to be withdrawn from the pre-filled syringe to do this (discard remainder). Pegasys trial stock supplied to hospital pharmacy directly from Roche. If patient is randomisation to Arm C, the trial manager will automatically order a supply of trial stock for pharmacy. See pharmacy section on website

17. Nov 2008SPIRIT CML Trial Overview Where to get information Trial manager - Corinne Hedgley  01280 814 916  c.a.hedgley@ncl.ac.ukc.a.hedgley@ncl.ac.uk Website - www.spirit-cml.orgwww.spirit-cml.org  Pharmacy section (information for pharmacists, trial prescription, dispensing logs etc)  Study File section (details study file contents, site logs etc)  Document Centre (protocol, ethical approval and other documents)  Contact details (Trial Manager, Chief Investigator)  Newsletter (study updates)