EWMnetwork
London
16.8.2014
Setting up clinical trials in WM
Prof. Dr. C. Buske
Waldenström Macroglobulinemia (WM)
Our Challenges
• 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?
• 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
+ Austrian Study Group (U. Jäger)
15 / year
+ Czech Lymphoma Study Group (R. Hajek)
FCGCLLWM Group (P. Morel, X. Leleu, V.LeBlond/France)
35 / year
+ Polish Study Group (T. Robak)
FIL Italian Intergroup (A. Tedeschi, Italy)
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)
10 / year+
Greek Myeloma Study Group (M. Dimopoulos, Greece)
Association
ALLG
(Australian Study Group)
10 / year
Spanish Study Group (R. Garcia Sanz, Spain)
15 / year
BNLI (R. Owen, UK)
15 / year
Portuguese Lymphoma Study Group (M. Gomes da Silva)
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: frederic.charlotte@psl.aphp.fr
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: m.paulli@smatteo.pv.it
Prof. Wolfram Klapper (coordinator)
Institute of Pathology, Haematopathology Section and
Lymph Node Registry, Universitätsklinikum SchleswigHolstein, 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 SchleswigHolstein, Campus Lübeck, Lübeck, Germany
Ratzeburger Allee 160, 23538 Lübeck
: +49 451 500 2707
FAX: + 49 451 500 3328
E-Mail: Fehler! Verweisquelle konnte nicht gefunden
werden.
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: Jacqueline.Liebezeit@kgu.de
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: peter.moeller@uniklinik-ulm.de
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: smontes@humv.es
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: brigitta.sander@ki.se
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: sseh@evaggelismos-hosp.gr
Prof. S.T. Pals,
Secretariaat Pathologie, H2-105
Academisch Medisch Centrum,
Meibergdreef 9
1105 AZ Amsterdam
 + 31 205662827/ + 31 206979567
E-Mail: s.t.pals@amc.uva.nl
Dr. José Cabeçadas
Department of Pathology,
Portuguese Institute of Oncology
Rua Prof. Lima Basto 1099-023 Lisbon
Portugal
 + 351 217229800 / + 351 217200400
E-Mail: jcabecadas@ipolisboa.min-saude.pt
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: rogerowen@nhs.net
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!
ECWM Meeting
8th International Workshop on WM
London August 14th, 2014
Agenda:
n ECWM-1 trial (C. Buske)
n ECWM-R1 trial (M. Dimopoulos)
n 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)
n National Registries
-- Sweden (E. Kimby/L. Brandefors)
-- Czech Rep (R. Hajek)
-- Germany (C. Buske)
-- European WM Patient Record Study (C. Buske, M. Dimopoulos)
n Horizon 2020 (R. Garcia Sanz, R. Owen, C. Buske)
n Miscellaneous (all)
Clinical Trial Activity –
ECWM - 1
Study Flow
Registration
Randomisation
Standard Arm
6 x DRC
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):
Induction experimental arm (Arm B):
Cycle 1:
Cycle 1:
Dexamethasone
20 mg p.o.
Day 1
Bortezomib
1.6 mg/m2 SC
Day 1,8,15
Rituximab
375 mg/m2 IV
Day 1
Dexamethasone
20 mg p.o.
Day 1
Cyclophosphamide
100 mg/m2 x 2 p.o.
Day 1-5
Rituximab
375 mg/m2 IV
Day 1
Cyclophosphamide
100 mg/m2 x 2 p.o.
Day 1-5
Cycle 2-6:
Dexamethasone
Rituximab
Cyclophosphamide
20 mg p.o.
Day 1
1400 mg absolute
SC
2
100 mg/m x 2 p.o.
Cycle 2-6:
Bortezomib
1.6 mg/m2 SC
Day 1,8,15
Dexamethasone
20 mg p.o.
Day 1
Rituximab
1400
absolute SC
Day 1
Day 1-5
Repeat day 29.
Cyclophosphamide
Repeat day 29.
Ritux i.v. and s.c. will be
provided by Roche
mg
100 mg/m2 x 2 p.o.
Day 1
Day 1-5
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 IC50 = 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
• 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
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
Clinical Trial Activity –
ECWM - R1
Filing for EMA planned!
ECWM-R1 / Relapse
Rituximb 375 mg/m2 IV weekly for 4 consecutive weeks –
week 1-4 and week 13-16 plus Placebo
R
1
:
1
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
Many thanks