Transcript Setting up clinical trials in WM
EWMnetwork London 16.8.2014
Setting up clinical trials in WM Prof. Dr. C. Buske
Waldenström Macroglobulinemia (WM) Our Challenges
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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 J Acta Medica Scandinaviva 1944
Waldenström Macroglobulinemia (WM) How can we overcome all this?
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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 J Acta Medica Scandinaviva 1944
Where to go now in Europe
Foundation of a New Consortium European Consortium for Waldenström’s Macroglobulinemia (ECWM)
Members ECWM
Involved study groups patients accrual
FIL Italian Intergroup (A. Tedeschi, Italy) FCGCLLWM Group (P. Morel, X. Leleu, V.LeBlond/France) + Austrian Study Group (U. Jäger) 15 / year + Czech Lymphoma Study Group (R. Hajek) 35 / year + Polish Study Group (T. Robak) GLSG/OSHO (C. Buske, M. Dreyling, W. Hiddemann, + Swiss Study Group (SAKK) M. Herold/Germany) 35 / year HOVON (P. Sonneveld , M.-J. Kersten, Netherlands) 15 / year Nordic Lymphoma Group (E. Kimby, Sweden) Greek Myeloma Study Group (M. Dimopoulos, Greece) ALLG (Australian Study Group) 10 / year Spanish Study Group (R. Garcia Sanz, Spain) BNLI (R. Owen, UK) Portuguese Lymphoma Study Group (M. Gomes da Silva) 15 / year 15 / year 5 / year
1.1
National Pathology Reference Centers Country
France / Belgium Italy Germany
Name of institution and address
Frédéric Charlotte Hôpital Pitié Salpêtrière 47 boulevard de l hôpital Paris 75013 France : +33 142 177 773
E-Mail:
Prof. Marco Paulli Sezione di Anatomia Patologica, Dipartimento di Medicina Molecolare, Università di Pavia Via Forlanini 14 - 27100 Pavia : +39 0382 503612
FAX
:+39 0382 525866
E-Mail:
Prof. Wolfram Klapper (coordinator) Institute of Pathology, Haematopathology Section and Lymph Node Registry, Universitätsklinikum Schleswig Holstein, Campus Kiel, Germany Michaelisstr. 11, 24105 Kiel : +49 431 597 3399
FAX
: + 49 431 597 4129
E-Mail: Fehler! Verweisquelle konnte nicht gefunden werden.
Prof. Alfred Feller Institute of Pathology, Universitätsklinikum Schleswig Holstein, Campus Lübeck, Lübeck, Germany Ratzeburger Allee 160, 23538 Lübeck : +49 451 500 2707
werden.
FAX
: + 49 451 500 3328
E-Mail: Fehler! Verweisquelle konnte nicht gefunden
Prof. Martin L. Hansmann Senckenberg Institute of Pathology, Goethe University, Frankfurt am Main, Germany Theodor-Stern-Kai 7 60590 Frankfurt : +49 69 6301 5364
FAX
: + 49 69 6301 3903
E-Mail:
[email protected] Prof. Peter Möller Institute of Pathology, University Hospital Ulm, Ulm, Germany Albert-Einstein-Allee 23, 89070 Ulm : +49 731 500 56321
FAX
: + 49 731 500 56384
E-Mail:
[email protected] Prof. Andreas Rosenwald Institute of Pathology, University Würzburg, Würzburg, Germany Josef-Schneider-Straße 2, 97080 Würzburg : +49 931 3181199
FAX
: + 49 931 3181224
Pathology Panel ECWM
Spain Nordic Group Greece The Netherlands Portugal United Kingdom Dr. Santiago Montes Moreno Adjunto Servicio de Anatomía Patológica. Hospital Universitario Marqués de Valdecilla. Avda. Valdecilla nº 25, 39008 SANTANDER, Spain : +34 94220 2520
E-Mail:
Prof. Dr. Birgitta Sander Department of Laboratory Medicine, Division of Pathology, F46 Karolinska Institutet and Karolinska University Hospital SE 141 86 Stockholm Sweden : +46 8 58580000, +46 8 58581044 (direct), +46 73 6994268 (mobile)
E-Mail:
Dr Theodora Papadaki, MD Department of Haemopathology, Evangelismos Hospital, 45-47 Ipsilantou Street, 10676, Athens Greece :+30 210 7201 744
FAX
: +30 210 7253 912
E-Mail:
Prof. S.T. Pals, Secretariaat Pathologie, H2-105 Academisch Medisch Centrum, Meibergdreef 9 1105 AZ Amsterdam + 31 205662827/ + 31 206979567
E-Mail:
Dr. José Cabeçadas Department of Pathology, Portuguese Institute of Oncology Rua Prof. Lima Basto 1099-023 Lisbon Portugal + 351 217229800 / + 351 217200400
E-Mail:
Prof. Dr. Richard Owen HMDS Laboratory, Level 3, Bexley Wing, St James's University Hospital, Leeds, Beckett Street, Leeds, UK. LS9 7TF :+44 113 206 7851
FAX
: +44 113 206 7883
E-Mail:
http://www.ecwm.eu/
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‘
Our Goals: Together with our patients and patient networks!
8 th ECWM Meeting International Workshop on WM London August 14 th , 2014
Agenda:
n n n n n n
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)
Clinical Trial Activity – ECWM - 1
Standard Arm 6 x DRC
Study Flow
Registration Randomisation Experimental Arm 6 x B - DRC
SD, PD Follow-up for survival SD, PD Follow-up for survival
Follow – up
For response until progression For OS until death
Clinical Trial Activity – ECWM - 1
Clinical Trial Activity – ECWM - 1
Clinical Trial Activity – ECWM – 1
Induction standard arm (Arm A): Cycle 1: Dexamethasone 20 mg p.o. Rituximab Day 1 375 mg/m 2 IV Day 1 100 mg/m 2 x 2 p.o. Day 1-5 Cyclophosphamide Cycle 2-6: Dexamethasone 20 mg p.o. Day 1
Rituximab
Cyclophosphamide Repeat day 29.
1400 mg absolute SC Day 1
100 mg/m 2 x 2 p.o. Day 1-5 Induction experimental arm (Arm B): Cycle 1: Bortezomib 1.6 mg/m 2 SC Day 1,8,15 Dexamethasone 20 mg p.o. Rituximab 375 mg/m 2 IV Cyclophosphamide 100 mg/m 2 x 2 p.o. Cycle 2-6: Bortezomib 1.6 mg/m 2 SC Day 1 Day 1 Day 1-5 Day 1,8,15 Dexamethasone 20 mg p.o. Day 1
Rituximab 1400 absolute SC mg
Cyclophosphamide 100 mg/m 2 x 2 p.o.
Day 1
Day 1-5 Repeat day 29.
Ritux i.v. and s.c. will be provided by Roche
Bruton’s Tyrosine Kinase (BTK): A Critical Kinase for Lymphoma Cell Survival and Proliferation
• 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 18 3
A randomized phase III study of Ibrutinib p.o.
versus extended Rituximab i.v. therapy in patients with previously treated WM ECWM-R1
European Waldenström's Macroglobulinemia Consortium ECWM-R1 Version 1.1
Study design
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European/Australian phase III trial, multicenter, open label, and randomized
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Study population: Previously treated patients with WM who have received 1 to 3 prior lines of therapy
EWMC-R1 Version 1.1
Objectives
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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
Clinical Trial Activity – ECWM - R1 Filing for EMA planned!
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ECWM-
R1
/ Relapse
1 : 1 Rituximb 375 mg/m 2 IV weekly for 4 consecutive weeks – week 1-4 and week 13-16 plus Placebo Rituximab plus oral Ibrutinib 420 mg qD continuously until evidence of progressive disease plus Ibrutinib Crossover: Patients who are randomized in the rituximab arm and demonstrate progressive disease, will be allowed to receive ibrutinib
Guidelines
Treatment Algorithms – WM National Level
DGHO
Treatment Algorithms - WM
ESMO Guidelines Buske et al., 2014