GMMG- German Speaking Myeloma Multicenter Group Hartmut Goldschmidt

Transcription

1 GMMG- German Speaking Myeloma Multicenter Group Hartmut Goldschmidt

2 - Academic Study Group - Founded in 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

3 Transplantation and Associated Trial Sites

4 Previous GMMG First Line Trials HD1 Trial: Tandem-Transplantation (Phase II, n=151) HD2 Trial: Single- versus Double-Transplantation (Phase III, n=480) HD3 Trial: Tandem-Transplantation (Germany) plus/minus Thalidomide (Phase III, GMMG n=550, HOVON n=500) HO65/HD4 Trial: VAD vs. PAD, Transplantation, maintenance Thalidomide vs. Bortezomib (Phase III, GMMG n=399, HOVON=434)

5 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

6 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: , 2012), was one of the most-cited articles published in 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,

7 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/ Transplantation Sites 78 associated sites n= additional patients after amendment 07/2013

8 MM5-Trial symptomatic MM 1st line treatment 18-70a Randomization 3 x PAd A1 + B1 3 x VCD A2 + B2 1) 1) CAD + leukapheresis HDM + TPL 2. HDM + TPL (if no ncr/cr) Standard intensification according to local protocol (GMMG standard) 2 x Lenalidomide A1 B1 A2 B2 Lenalidomide for 2 years Lenalidomide if no CR Lenalidomide for 2 years Lenalidomide if no CR 1) High Risk Patients, optional in Phase II trial Flowsheet

9 Recruitment MM5 Trial First patient in: Last patient in (n=504): Amendment +100 pat.: Rekrutierung MM5 geplant registriert geplant: ca. 15 Pat./Monat (ab Monat 7) Last patient in (n=604): geplant: ca. 7 Pat./Monat (in den ersten 6 Monaten) 0 Juli 10 Januar 11 Juli 11 Januar 12 Juli 12 Januar 13 Juli 13 9

10 Primary Endpoints: MM5 Trial (1) Non-inferiority of VCD induction therapy compared to PAd (response rate VGPR or better) (2) Progression free survival (first results in 2017)

11 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 (Leukemia, submitted)

12 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 (Haematologica, submitted)

13 Number of collected stem cells* (CD 34+) 9,7 x 10 6 /kg in PAd vs. 9,3 x 10 6 /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

14 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 (Haematologica, submitted)

15 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

16 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 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

17 Relapsed Multiple Myeloma (1 st - 3 rd relapse) age 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) until progressive disease HD Mel 200mg/m² + autologous transplantation R-maintenance 3) 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

18 Primary and secondary endpoints Primary objective progression-free survival Secondary objectives overall survival response rates toxicity

19 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

20 Relapse -recruitment 185 patients Standard arm A Experimental arm B n = 91 pts. n = 94 pts.

21 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

22 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

23 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

24 HD6-Trial - proposal symptomatic MM 1st line treatment 18-70a N = 516 patients 3 years recruitment Randomization 4 x VRD A-I + A-II 4 x VRD + Elotuzumab 1) 1) Cy + G-CSF + leukapheresis HDM + TPL 2. HDM + TPL (if no ncr/cr) B-I + B-II GMMG standard intensificat ion A-I A-II B-I B-II 2 x VRD consolidation 2 x VRD + Elo. consolidation 2 x VRD consolidation 2 x VRD + Elo. consolidation Rev. MT Rev. MT + Elotuzumab Rev. MT Rev. MT + Elotuzumab 1) high risk patients, optional in phase II trial Flowsheet 06/2013 VRD= Velcade/Revlimid/Dexamethasone; Elo=Elotuzumab; Rev.MT= Revlimid maintenance

25 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 patients - extensive scientific program - Start: 04-05/2015

26 Sequence of GMMG trials 9. August 2004 Change in German Drug Law HD2 trial Recruitment 11/1998 2/2002 6/2004 EC Appr. HD4 HD4 trial Recruitment MM5 trial Recruitment 7/ /2013 Perspective HD6 BPV BIRMA HD1 trial Recruitment HD3 trial Recruitment 9/2001 9/2004 Relapse trial Recruitment ongoing Implementation of EU Clin. Trials Directive

27 Application of Clinical Trials Approval needed by: Competent authority (BfArM, PEI) Ethic committees =>large regulatory efforts

28 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

29 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)

30 GMMG Trials: Summary (1) nicht behandlungsbedürftig behandlungsbedürftig Erstbehandlung Rezidiv BPV Symptomatisches MM BIRMA Refraktär Myelomlast MGUS Smoldering Myeloma HD6 MM5 ReLApsE PERSPECTIVE Zeit

31 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

32

33

34

35 Substantial progress in therapeutic options Palliation Revlimid Bortezomib Thalidomide Steroids RTX MP s ALLO ASCT HDC VAD Steroids RTX MP s Thalidomide BP Mini-ALLO ASCT HDC VAD Steroids RTX MP 1990s BP Mini-ALLO ASCT HDC VAD Steroids RTX MP BP 2000s Cure? Chronic illness Pomalidomid PLD 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 NF-κB NPI1387 STAT3 WP1066 PKC Enzastaurin p38mapk SCIO469 Telomerase GRN 163L 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

36 Members of the GMMG Study Group at the Investigator Meeting 2012 in Heidelberg Thank you for your attention!