1. CML SPIRIT 3 Steve O’Brien Northern Institute for Cancer Research Newcastle University Medical School Newcastle, March 2013

2. www.spirit-cml.org Imatinib vs Dasatinib Thank you!

3. Acknowledgements

4. Randomised open label study 3 treatment arms Arm A: 400mg daily imatinib Arm B: 800mg daily imatinib Arm C: 400mg daily imatinib plus 180mg weekly PEGinterferon  Primary endpoint To compare overall survival in the three arms at 5 years N=259 SPIRIT 1 study design Chronic phase CML Within 3 months of diagnosis Arm A: Imatinib 400 Arm B: Imatinib 800 Arm C: Imatinib 400 + IFN R

5. Imatinib: SPIRIT 1 and trials like it 10 year survival >85% More imatinib isn’t any better Adding interferon… – Seems better (France) – Not so sure (Germany) – No difference in survival UK doesn’t like interferon

6. SPIRIT in France: IFN stays the distance Preudhomme al., New England Journal of Medicine, 2010 REPONSE % (CI 95 %) Imatinib 400 mg (N = 159) Imatinib 600 mg (N = 160) Imatinib + Cytarabine (N = 158) Imatinib + Peg-IFN (N = 159) P (P ajusted on Sokal score ) CHR 89 (83-93) 95 (90-98 ) 91 (87-96) ns CCR at 6 months at 12 months 50 (42-58 ) 58 (50-66 ) 69 (61-76) 65 (57-72) 59 (51-67) 70 (62-77) 57 (49-65) 66 (58-73) 0,0069 (0,0050) ns At 12 months MMR SMR 38 (30-46) 14 ( 9-21 ) 49 (41-57 ) 17 ( 11-24 ) 46 (38-54 ) 15 ( 10-22 ) 57 ( 49-65 ) 30 ( 23-37 ) 0,0063 (0,0048) 0,0014 (0,0011) At 24 months MMR SMR 43 ( 35-50) 21 (15-28) 53 (45-60) 26 (20-34) 54 (46-62) 26 (19-34 ) 64 (56-71) 38 (30-46 ) 0,0063 (0,0032) 0,0014 (0,0066) At 24 months Undetectable transcript 9 (5-14) 8 (4-13) 16 (12-24 ) 0,0132 (0,0134)

8. SPIRIT 2: Study Design Chronic phase CML within 3 months of diagnosis Chronic phase CML within 3 months of diagnosis Arm A Imatinib 400 Arm A Imatinib 400 Arm B Dasatinib 100 Arm B Dasatinib 100 Randomised open label study Primary endpoint: 5 year EFS Secondary: cyto, molec response, tox

9. 810 of 810 patients recruited! 246 since last year 172 sites currently participating 136 sites have recruited 41 more than last year not quite…

10. So where are we now? Most CML patients are fine – There are more and more… Not much difference between TKIs? – Apart from cost and perhaps side effects – Use wisely/selectively – Imatinib off patent 2016 We really need to figure out how to reduce and/or stop treatment for a lot more patients

11. CML in 2013 (cost) Greatest benefit Greatest benefit Side effects QoL Side effects QoL Efficacy

12. SPIRIT 3 A Phase III Randomized Trial to Evaluate the Most Effective Way to Use Imatinib, Nilotinib, and Ponatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia UK National Cancer Research Institute CML Working Group Prof Stephen O’Brien, Newcastle University

13. Stage 1 Compare first line intervention Randomised Stage 2 Identify partial responders early Switch Stage 3 Identify ‘best’ responders later Reduce/stop Primary endpoint: MR 3 (MMR) at 3 years Secondary: sustained MR 3 CMR on reduced dose/stop (no more bone marrows!) EFS, PFS, OS Health Economics, QoL SPIRIT 3 Newly diagnosed

14. Stage 1 Compare first line intervention Randomised Stage 1: up front randomisation Nilotinib R R Imatinib 1000 patients

15. BCR-ABL (IS) n 5Y-OS ≤1% 21897% 1-10% 28394% >10% 19187% Overall Survival (OS) BCR-ABL (IS) at 3 months ≤1% vs. 1-10% vs. >10% n.s. 0.012 p-value ≤1% 1-10% >10% Hanfstein et al. Leukemia. 2012 Mar 26. doi: 10.1038/leu.2012.85. [Epub ahead of print]

16. Stage 2: nilotinib/ponatinib? for >10% @ 3 months Imatinib >10% PCR ~25% patients Imatinib >10% PCR ~25% patients Nilotinib >10% PCR ~10% patients Nilotinib >10% PCR ~10% patients Stay in SPIRIT 3 Switch to ponatinib Stay in SPIRIT 3 Switch to ponatinib

17. A B Nilotinib Ponatinib Nilotinib Imatinib Ponatinib Comparison

18. Primary objective To determine whether, in terms of major molecular response (MMR, MR3) at three years, first-line treatment with imatinib is non inferior to first-line treatment with nilotinib when patients on either treatment who are not responding optimally at 3 and 12 months are ‘rescued’ with ponatinib.

19. Primary endpoint Rate of MR 3 at 3 years in groups A & B Is group A non-inferior to group B?

20. Stage 3 Identify ‘best’ responders later Reduce/stop How much is enough? Minimum of 3 years: Halve dose if MMR for 1 year Minimum of 4 years: Stop if remain in MMR Primary endpoint: MR 3 (MMR) at 3 years Secondary: sustained MR 3 CMR on reduced dose/stop (no bone marrows) EFS, PFS, OS Health Economics, QoL (DESTINY pilot)

21. Stage 1 Compare first line intervention Randomised Stage 2 Identify partial responders early Switch Stage 3 Identify ‘best’ responders later Reduce/stop SPIRIT 3 2013

22. Patients’ views What do you think about SPIRIT 3? Home care Keeping you informed

26. SPIRIT 3 arrangements Design: NCRI CML Working Group Sponsor: Newcastle Hospitals NHS Trust Funder: Ariad NCRI badged, CTAAC approved 2012 Trial management: Newcastle CTU Governance: TMG, TSC, DMEC Drug supply: – Imatinib & nilotinib – NHS, home delivery, VAT – Ponatinib – free of charge for 10 years, home delivery

27. SPIRIT 3 practicalities No more marrows – Unless you want/need to PCR essential, especially 3 months and stage 3 Check BP regularly, CV risk Home delivery, no hospital pharmacy stock – Pharmacy clinical check Biobanking material – Blood and mouthwash More direct patient & investigator involvement – Web, apps, meetings

28. SPIRIT 3 translational research UK wide collaboration – Newcastle, Liverpool, Glasgow, Edinburgh, Imperial, Kings Comprehensive biobanking – Leukaemia, ‘normal’ tissue Factors predicting response, outcome, ability to reduce/stop Stem cell biology, NGS (WGS, ES), PCR, TKD mutations, PK

29. Home care

31. Stage 1 Compare first line intervention Randomised Stage 2 Identify partial responders early Switch Stage 3 Identify ‘best’ responders later Reduce/stop Primary endpoint: MR 3 (MMR) at 3 years Secondary: sustained MR 3 CMR on reduced dose/stop (no more bone marrows!) EFS, PFS, OS Health Economics, QoL SPIRIT 3 Newly diagnosed

32. Questions?Questions? Thanks for listening

33. CML SPIRIT 3 Steve O’Brien Northern Institute for Cancer Research Newcastle University Medical School Newcastle, March 2013