GMMG Trials

GMMGGerman Speaking Myeloma
Multicenter Group
27.02.2015
Hartmut Goldschmidt
- Academic Study Group
- Founded in 1996
- Specialized in Multiple Myeloma
- Focus on Investigator Initiated Trials (IITs)
- About 40 Stem Cell Transplantation Centers
- About 100 NIO- Medical Offices/Hospitals without ASCT unit
(associated sites)
- Leading Group: 15 members
- Investigator Meetings twice per year
Transplantation and Associated Trial Sites
Previous GMMG First Line Trials
• HD1 Trial: Tandem-Transplantation 1996 – 1998 (Phase II, n=151)
• HD2 Trial: Single- versus Double-Transplantation (Phase III, n=480)
1998 – 2001
• HD3 Trial: Tandem-Transplantation (Germany) plus/minus
Thalidomide (Phase III, GMMG n=550, HOVON n=500) 2001 – 2004
• HO65/HD4 Trial: VAD vs. PAD, Transplantation, maintenance
Thalidomide vs. Bortezomib (Phase III, GMMG n=399,
HOVON=434) 2005-2008
Results I HD4
Standard für die Induktionstherapie war bislang VAD, so
dass der Ersatz der ohnehin nicht sehr wirksamen
Substanz Vincristin durch Bortezomib entsprechend dem
GMMG/HOVON-Protokoll als neuer Standard für die
Induktionstherapie anzusehen ist. Dies entspricht auch
der Bewertung der deutschen Studiengruppe GMMG.“
MDK Gutachten Prof. Heyll, August 2009
Results II HD4
December 19, 2014
Dear Dr. Sonneveld,
Please accept my sincere congratulations on being among JCO‘s top-cited authors!
According to data from Thomson Reuters provided to JCO, your article, „Bortezomib Induction and
Maintenance Treatment in Patients with Newly Diagnosed Multiple Myeloma: Results of the
Randomized Phase III HOVON-65/GMMG-HD4 Trial“ (J Clin Oncol 30: 2946-2955, 2012), was one
of the most-cited articles published in 2012. Since publication, your article has been cited 134
times. Please be sure to inform your co-authors of this exciting news. Thank you for choosing to be
a part of the JCO community and for helping to make JCO a leading journal in our field.
Our impact factor is one of the highest among oncology specialty journals. With a circulation of
approximately 26,000 readers, and with features such as the Rapid Review program for selected
papers, JCO attracts some of the most highly valued and prestigious clinical research in the world.
Your paper is included among the best of this group.
Thank you for your continued support of JCO.
Sincerely yours,
Ongoing First Line Trial
MM5 Trial
VCD vs. PAd, standard intensification
(high dose therapy and ASCT) consolidation/maintenance
with Lenalidomide, Maintenance 2a vs. until CR
•
•
•
•
•
Phase III, randomized, 4 treatment arms
Start 07/2010, last Patient in: 11/2013
31 Transplantation Sites
78 „associated sites“
n= 504 + 100 additional patients after amendment 07/2013
MM5-Trial
symptomatic MM
1st line treatment
18-70a
3 x PAd
A1 + B1
Randomization
3 x VCD
A2 + B2
1)
1)
CAD + leukapheresis
Standard
intensification
according to
local protocol
(GMMG
standard)
HDM + TPL
2. HDM + TPL (if no nCR/CR)
2 x Lenalidomide
A1
Lenalidomide
B1
Lenalidomide
if no CR
for 2 years
1) High Risk Patients, optional in Phase II trial
A2
Lenalidomide
B2
Lenalidomide
if no CR
for 2 years
Flowsheet 31.03.2011
Recruitment MM5 Trial
First patient in:
26.07.2010
Rekrutierung MM5
600
Last patient in (n=504):
500
11.10.2012
400
geplant
registriert
300
Amendment +100 pat.:
geplant: ca. 15 Pat./Monat (ab Monat 7)
200
12.07.2013
100
Last patient in (n=604):
geplant: ca. 7 Pat./Monat (in den ersten 6 Monaten)
14.11.2013
0
Juli 10
Januar 11
Juli 11
Januar 12
Juli 12
Januar 13
Juli 13
9
MM5 Trial
Primary Endpoints:
(1) Non-inferiority of VCD induction therapy
compared to PAd (response rate VGPR or
better)
(2) Progression free survival (first results in 2017)
Analysis of first primary endpoint 07/2013
Remission rates after induction:
VCD: 37% VGPR or better
vs.
PAd: 34.3 % VGPR or better
=> Non-inferiority of VCD vs. PAd regarding ≥VGPR
(p=<0.01)
Goldschmidt et al., ASH 2013 Abstract # 3369
Mai et al. 2015 (Leukemia, submitted)
Analysis of toxicity profile (PAd vs. VCD)
• Leukocyto/Neutropenia is increased in VCD compared to
PAd group
• Infection rates (AE and SAE) do not differ between VCD
and PAd
• Less thromboembolic events in VCD group (AE and SAE)
• Less neuropathy in VCD group (AE)
• Less deaths in VCD group
=> better toxicity profile in VCD
Merz et al., ASH 2014 Abstract 3475
Merz et al. 2015 (Haematologica, submitted)
Number of collected stem cells* (CD 34+)
• 9,7 x 106/kg in PAd vs. 9,3 x 106/kg in VCD
• Stem cell collection successful in 86,9% patients
in PAd vs. 88,4% in VCD
=> Stem cell collection is not hampered by
either PAd or VCD
* Preliminary data
Amendment 02/2012 (after inclusion of 314 patients)
→ subcutaneous administration of Bortezomib
Moreau et al., Lancet Oncol., 2011:
superior safety data (PNP ↓) and comparable response rates
Amendment 07/2013
→ additional 100 patients
Interim analysis 07/2014
Comparison of bortezomib application i.v.
versus s.c. in respect to toxicity (especially PNP)
Merz et al., ASH 2014 Abstract 3475
Merz et al. 2015 (Haematologica, submitted)
MM5 - Scientific Program (central diagnostics)
=> depth of remission?
=> risk assessment?
=> pathogenic mechanism?
•
•
•
•
•
sFLC (Freelite®), Heavy Chain Test (Hevylite)®
Interphase in situ Hybridization (iFISH), at least 14 probes
Gene Expression Profiling (GEP)
Multicolor Flow Cytometry
PCR-MRD approach => depth of remission
Current Relapse Trials
• PERSPECTIVE
Phase II, Pomalidomide in combination with low dose
Dexamethasone and i.v. Cyclophosphamid
n= 60, 10 trial sites, Start 06/2014, Recruitment
Febr. 2015 n=37
•
RELAPSE: Randomisierte, offene, multizentrische
Phase III Studie zum Vergleich von Lenalidomid
/Dexamethason versus Lenalidomid/Dexamethason mit
anschließender autologer Blutstammzelltransplantation
und Lenalidomid Erhaltungstherapie für Patienten mit
rezidiviertem Multiplen Myelom
n= 282, 18 trial sites, Start 12/2010,
Recruitment Febr 2015 n=185
Relapsed Multiple Myeloma (1st - 3rd relapse)
age 18-75 years
ReLApsE trial
282 patients
Randomization
3x Rd 1)
3x Rd 1)
Cyclophosphamide + G-CSF
stem cell collection 2)
Cylophosphamide + G-CSF
stem cell collection 2)
Rd 1)
HD Mel 200mg/m²
+ autologous transplantation
until progressive disease
R-maintenance3)
until progressive disease
for patients with progressive disease
HD Mel + Auto Tx recommended
(outside this trial)
1) Revlimid ® (Lenalidomide) 25mg p.o., day 1-21; Dexamethasone 40mg p.o., day 1, 8, 15, 22
2) stem cell mobilization only if no useable stem cells from earlier mobilization are available
3) Revlimid ® (Lenalidomide) - maintenance 10mg/day
R-Revlimid ® (Lenalidomide), d-Dexamethasone, HD Mel - high dose chemotherapy Melphalan, Auto Tx - autologous stem cell transplantation
Primary and secondary endpoints
Primary objective
• progression-free survival
Secondary objectives
• overall survival
• response rates
• toxicity
Relapse - trial sites
• 16 sites in
Germany
activated
Campus Benjamin Franklin Berlin Charité
Helios Klinikum Berlin-Buch
Med. Univ.-Klinik Bonn
Klinikum Bielefeld
Klinikum Chemnitz
Universitätsklinikum Düsseldorf
Universitätsklinikum Essen
Evang. KH Essen Werden
Universitätsklinikum Frankfurt/Main
Kath. Krankenhaus Hagen
Asklepios Klinik Hamburg Altona
Universitätsklinikum Heidelberg
Universitätsklinikum Köln
Universitätsmedizin Mannheim
Franziskuskrankenhaus Mönchengladbach
Universitätsklinikum Tübingen
Relapse -recruitment
185 patients
Standard arm A
Experimental arm B
n = 91 pts.
n = 94 pts.
GMMG BPV-Trial in NDMM
BPV Trial:
- First line therapy for patients not eligible for stem cell
transplantation: Bendamustine, Prednisone and Velcade
- Primary endpoint: therapeutic efficacy of BPV regimen:
overall response defined as partial response (PR) or
better
- 96 patients in 15 centers (mainly local established
hematologists)
- Phase IIB
Start: Nov 2014, Recruitment Febr 2015 n=3
BIRMA Trial in RRMM
- Refractory or relapsed myeloma patients with
mutation in BRAF-V600 gene
- Primary endpoint: therapeutic efficacy of
LGX818/MEK162 (both kinase inhibitors) to
reduce tumor burden
- Phase II, 15 patients
- Start: Summer 2015
=> new GMMG study generation with focus
on personalized therapy
GMMG HD 6 Trial
A randomized phase III trial on the effect
of Elotuzumab in VRD induction/
consolidation and Lenalidomide
Maintenance in patients with newly
diagnosed Myeloma
HD6-Trial proposal
symptomatic MM
1st line treatment
18-70a
A-I + A-II
4 x VRD
N = 516 patients
3 years recruitment
Randomization
4 x VRD + Elotuzumab
B-I + B-II
1)
1)
Cy + G-CSF + leukapheresis
GMMG
standard
intensificat
ion
HDM + TPL
2. HDM + TPL (if no nCR/CR)
A-I
2 x VRD
consolidation
Rev. MT
A-II
2 x VRD + Elo.
consolidation
Rev. MT
+ Elotuzumab
B-I
B-II
2 x VRD
consolidation
Rev. MT
1) high risk patients, optional in phase II trial
VRD= Velcade/Revlimid/Dexamethasone; Elo=Elotuzumab; Rev.MT= Revlimid maintenance
2 x VRD + Elo.
consolidation
Rev. MT
+ Elotuzumab
Flowsheet 06/2013
GMMG HD 6 Trial
- Four cycles induction therapy with VRD (Velcade,
Revlimid, Dexamethasone) vs. VRD + Elotuzumab
- Standard intensification (mobilization and stem cell
transplantation)
- Two cycles consolidation with VRD/VRD + Elotuzumab
- Primary endpoint: determination of the best of four
treatment strategies regarding progression-free survival
(PFS).
- Randomized phase III, four arms
- 516 patients
- extensive scientific program
- Start: 04-05/2015
Sequence of GMMG trials
9. August 2004
Change in
German Drug Law
1996
2000
HD2 trial
Recruitment
11/1998 – 2/2002
HD1 trial
Recruitment
1996-1998
2005
6/2004
EC Appr.
HD4
HD3 trial
Recruitment
9/2001 – 9/2004
HD4 trial
Recruitment
2005 – 2008
2010
MM5 trial
Recruitment
7/201011/2013
2015
Perspective
HD6
BPV
BIRMA
Relapse trial
Recruitment ongoing
Implementation of
EU Clin. Trials
Directive
Application of Clinical Trials
Approval needed by:
• Competent authority
(BfArM, PEI)
• Ethic committees
=>large regulatory efforts
Staff in GMMG Study Office
Head: Dr. med. U. Bertsch
+ 1,8 scientific project manager
+ 4,1 study nurses for IIT
+ 3,7 study nurses for company sponsored trials
+ 3 student assistants and 1 assistant by the hour
GMMG Quality Standard
Since 2005:
All GMMG trials are conducted according to the guidelines
of Good Clinical Practice (GCP)
=> contributes to protection of the rights, safety and wellbeing of trial subjects
=> assures high validity and quality of collected data
(quality control by onsite monitoring)
Since 2010:
electronic data capture systems (eCRF)
GMMG Trials: Summary (1)
behandlungsbedürftig
Erstbehandlung
nicht
behandlungsbedürftig
„Myelomlast“
BPV
MGUS
Smoldering
Myeloma
Rezidiv
Refraktär
Symptomatisches MM
HD6
BIRMA
PERSPECTIVE
ReLApsE
MM5
Zeit
GMMG Trials Summary (2)
• good recruitment rates due to a functional network
=> fast availability of data
• comprehensive quality assurance measures
=> high data quality and validity
• conduction according to GCP and German Drug Law
(AMG) => high patient‘s safety
• sophisticated scientific program
• standardized and innovative diagnostic procedures
• therapy standards and therapy recommendations based
on GMMG study results
Substantial progress in therapeutic options
Cure?
Chronic illness
Pomalidomid
PLD
Palliation
Revlimid
Bortezomib
Thalidomide
Carfilzomib Elotuzumab Panobinostat
Investigational treatments (2008)1
New targets
Agent
Hsp90
KOS 953
Proteasome
PR171, NPI0052
Aggresome
Tubacin
HDAC
LBH
Akt
Perifosine
XBP-1
XBP-1 peptide
Nitric oxide
JSK
Muc-1
NM3
MEK
AZD6244
Thalidomide
BP
BP
Mini-ALLO
ALLO
Mini-ALLO
ASCT
ASCT
ASCT
HDC
HDC
HDC
VAD
VAD
VAD
Steroids
NF-κB
NPI1387
Steroids
Steroids
Steroids
RTX
STAT3
WP1066
RTX
RTX
RTX
MP
PKC
Enzastaurin
MP
MP
MP
BP
p38MAPK
SCIO469
Telomerase
GRN 163L
1950–1960s
1970–1980s
1990s
2000s
Natural products
EGCG
ALLO, allogeneic SCT; BP, bisphosphonates; HDC, high-dose chemotherapy; MO, melphalan, prednisone; RTX, radiotherapy
1. Mitsiades C et al. Best Pract Res Clin Haematol 2007;20:79; Diagram adapted from Munshi D. Hematology 2008:297
Members of the GMMG Study Group at the
Investigator Meeting 2012 in Heidelberg
Thank you for your attention!