1. Setting up clinical trials in WM Prof. Dr. C. Buske EWMnetwork London 16.8.2014

2. Waldenström J Acta Medica Scandinaviva 1944 A rare disease with all implications!  No lobby  No major ‘economic’ interest of pharmaceutical companies  No deep knowledge about this disease in the community of physicians  No major interest to participate in clinical trials for physicians  Scattered activity in academia  Poor coordination of clinical trial activity  Nearly no major phase III trials performed until today Jan G. Waldenström, MD Waldenström Macroglobulinemia (WM) Our Challenges

3. Waldenström J Acta Medica Scandinaviva 1944 Working together  Forming networks  Speaking with one voice  Coordinating forces and resources  Patients on one side  We as physicians on the other side Jan G. Waldenström, MD Waldenström Macroglobulinemia (WM) How can we overcome all this?

4. Where to go now in Europe

5. Foundation of a New Consortium European Consortium for Waldenström’s Macroglobulinemia (ECWM)

6. Members - ECWM + Austrian Study Group (U. Jäger) + Czech Lymphoma Study Group (R. Hajek) + Polish Study Group (T. Robak) + Swiss Study Group (SAKK) + Association ALLG (Australian Study Group)

7. Pathology Panel - ECWM

8. http://www.ecwm.eu/

9. Our Goals: -- setting up clinical trials -- setting up national registries with the ultimate goal of a pan-European registry -- setting up biosampling with a European biobank for WM -- fostering translational research („from bench to bedside“) -- being represented in all major treatment guidelines  Making the disease more ‚public‘

10. Our Goals: Together with our patients and patient networks!

12. ECWM Meeting 8 th International Workshop on WM London August 14 th, 2014 Agenda: ECWM-1 trial (C. Buske) ECWM-R1 trial (M. Dimopoulos) Planned phase II trials -- Rituximab/Idelalisib (P. Morel, V. Leblond) -- Rituximab/Abt-199 (C. Buske) -- Rituximab/Oprozomib/Dexamethasone (S. Rassam) -- Ixazomib/Rituximab/Dexamethasone (M. Kersten) National Registries -- Sweden (E. Kimby/L. Brandefors) -- Czech Rep (R. Hajek) -- Germany (C. Buske) -- European WM Patient Record Study (C. Buske, M. Dimopoulos) Horizon 2020 (R. Garcia Sanz, R. Owen, C. Buske) Miscellaneous (all)

13. Clinical Trial Activity – ECWM - 1

14. Study Flow Registration Randomisation Standard Arm 6 x DRC Experimental Arm 6 x B - DRC Follow – up For response until progression For OS until death SD, PD Follow-up for survival SD, PD Follow-up for survival

15. Clinical Trial Activity – ECWM - 1

16. Clinical Trial Activity – ECWM - 1

17. Clinical Trial Activity – ECWM – 1 Ritux i.v. and s.c. will be provided by Roche

18. Bruton’s Tyrosine Kinase (BTK): A Critical Kinase for Lymphoma Cell Survival and Proliferation 18 Bruton’s tyrosine kinase (BTK) is an essential element of the BCR signaling pathway Inhibitors of BTK block BCR signaling and induce apoptosis PCI-32765 (ibrutinib) forms bond with cysteine-481 in BTK Highly potent BTK inhibition at IC 50 = 0.5 nM High degree of B-cell specificity Orally administered once daily dosing 3

19. A randomized phase III study of Ibrutinib p.o. versus extended Rituximab i.v. therapy in patients with previously treated WM ECWM-R1 ECWM-R1 Version 1.1 European Waldenström's Macroglobulinemia Consortium

20. Study design European/Australian phase III trial, multicenter, open label, and randomized Study population: Previously treated patients with WM who have received 1 to 3 prior lines of therapy EWMC-R1 Version 1.1

21. Objectives Primary study objective is Progression Free Survival (PFS) Secondary study objectives – Response rate (CR, VGPR, PR, MR) and (ORR) – Toxicity – best response – time to best response – time to first response – time to treatment failure – remission duration – cause specific survival & overall survival EWMC-R1 Version 1.1

22. Clinical Trial Activity – ECWM - R1 Filing for EMA planned!

23. ECWM-R1 / Relapse R R Rituximab plus oral Ibrutinib 420 mg qD continuously until evidence of progressive disease plus Ibrutinib Rituximb 375 mg/m 2 IV weekly for 4 consecutive weeks – week 1-4 and week 13-16 plus Placebo Crossover: Patients who are randomized in the rituximab arm and demonstrate progressive disease, will be allowed to receive ibrutinib 1:11:1

24. Guidelines

25. Treatment Algorithms – WM National Level DGHO

26. Treatment Algorithms - WM ESMO Guidelines Buske et al., 2014

27. Many thanks