Setting up clinical trials in WM

Prof. Dr. C. Buske

EWMnetworkLondon16.8.2014

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

Waldenström J Acta Medica Scandinaviva 1944

• Working together Forming networksSpeaking with one voiceCoordinating forces and resources

Patients on one sideWe as physicians on the other side

Jan G. Waldenström, MD

Waldenström Macroglobulinemia (WM)How can we overcome all this?

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) 15 / year

FCGCLLWM Group (P. Morel, X. Leleu, V.LeBlond/France) 35 / year

GLSG/OSHO (C. Buske, M. Dreyling, W. Hiddemann,

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) 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

+ Austrian Study Group (U. Jäger)

+ Czech Lymphoma Study Group (R. Hajek)

+ Polish Study Group (T. Robak)

+ Swiss Study Group (SAKK)

+ AssociationALLG (Australian Study Group)

Pathology Panel - ECWM  

1.1 National Pathology Reference Centers

Country Name of institution and address

France / Belgium

Frédéric Charlotte Hôpital Pitié Salpêtrière 47 boulevard de l hôpital Paris 75013 France : +33 142 177 773 E-Mail: frederic.charlotte@psl.aphp.fr

Italy 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

Germany 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 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

Spain 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

Nordic Group 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

Greece 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

The Netherlands 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

Portugal 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

United Kingdom 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 Arm6 x DRC

Experimental Arm

6 x B - DRC

Follow – upFor response until progression

For OS until death

SD, PDFollow-up for survival SD, PD

Follow-up for survival

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. Day 1

Rituximab 375 mg/m2 IV Day 1

Cyclophosphamide 100 mg/m2 x 2 p.o. Day 1-5

Cycle 2-6:

Dexamethasone 20 mg p.o. Day 1

Rituximab 1400 mg absolute SC

Day 1

Cyclophosphamide 100 mg/m2 x 2 p.o. Day 1-5

Repeat day 29.

Repeat day 29.

Induction experimental arm (Arm B):

Cycle 1:

Bortezomib 1.6 mg/m2 SC Day 1,8,15

Dexamethasone 20 mg p.o. Day 1

Rituximab 375 mg/m2 IV Day 1

Cyclophosphamide 100 mg/m2 x 2 p.o. Day 1-5

Cycle 2-6:

Bortezomib 1.6 mg/m2 SC Day 1,8,15

Dexamethasone 20 mg p.o. Day 1

Rituximab 1400 mg absolute SC

Day 1

Cyclophosphamide 100 mg/m2 x 2 p.o. Day 1-5

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

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 IC50 = 0.5 nM

• High degree of B-cell specificity

• Orally administered once daily dosing

3

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

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

RRituximab plus oral Ibrutinib 420 mg qD continuously until evidence of progressive disease plus Ibrutinib

Rituximb 375 mg/m2 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

1:1

Guidelines

Treatment Algorithms – WMNational Level

DGHO

Treatment Algorithms - WM

ESMO Guidelines

Buske et al., 2014

Many thanks