frankfurt 10. 11.märz 2017 glsg hämatologie im wandel · plus chop, cvp, or bendamustine†...
TRANSCRIPT
Hämatologie im Wandel
Indolente Lymphome –
Behandlungsstrategien und Studien der GLSG
C. Buske
CCC Ulm
Klinik für Innere Medizin III
Universitätsklinikum Ulm
Frankfurt 10. – 11.März 2017GLSG
1. Follikuläres Lymphom (fortgeschrittene Lymphome)
2. Morbus Waldenström
3. Marginalzonenlymphom
Indolente B - NHL
Buske et al., 2017
Therapeutischer Algorithmus – Leitlinien der DGHO
Wie können wir neue
Standards setzen……?
Besserer Antikörper?
„Practice Changing“!
Plenary Session - ASH
Obinutuzumab-based induction and maintenance
prolongs progression-free survival (PFS) in patients
with previously untreated follicular lymphoma: primary
results of the randomized Phase III GALLIUM study
Robert Marcus,1 Andrew Davies,2 Kiyoshi Ando,3 Wolfram Klapper,4 Stephen Opat,5 Carolyn Owen,6
Elizabeth Phillips,7 Randeep Sangha,8 Rudolf Schlag,9 John F Seymour,10 William Townsend,7
Marek Trněný,11Michael Wenger,12 Günter Fingerle-Rowson,13 Kaspar Rufibach,13
Tom Moore,13 Michael Herold,14 Wolfgang Hiddemann15
1Kings College Hospital, London, United Kingdom; 2Cancer Research UK Centre, University of Southampton, Southampton, United Kingdom; 3Tokai University School of Medicine, Isehara,
Kanagawa, Japan; 4University of Kiel, Kiel, Germany; 5Monash Health and Monash University, Melbourne, Australia; 6Foothills Medical Centre and Tom Baker Cancer Centre, Calgary, AB,
Canada; 7Cancer Research UK and UCL Cancer Trials Centre, London, United Kingdom; 8Cross Cancer Institute, Edmonton, AB, Canada; 9Gemeinschaftspraxis Dr. Rudolf Schlag/Dr. Björn
Schöttker, Würzburg, Germany; 10Peter MacCallum Cancer Centre, Melbourne, Australia; 11Charles University, Prague, Czech Republic; 12Genentech Inc, South San Francisco, CA, USA; 13F. Hoffmann-La Roche Ltd, Basel, Switzerland; 14HELIOS-Klinikum, Erfurt, Germany; 15Ludwig-Maximilians-University, Munich, Germany
8
Study design
International, open-label, randomized Phase III study
*FL and MZL pts were randomized separately; stratification factors: chemotherapy, FLIPI (FL) or IPI (MZL) risk group, geographic region; †CHOP q3w × 6 cycles, CVP q3w × 8 cycles,
bendamustine q4w × 6 cycles; choice by site (FL) or by pt (MZL); ‡Pts with SD at EOI were followed for PD for up to 2 years; §Confirmatory endpoint
Primary endpoint Secondary and other endpoints
• PFS (INV-assessed in FL) • PFS (IRC-assessed)§
• OS, EFS, DFS, DoR, TTNT
• CR/ORR at EOI (+/− FDG-PET)
• Safety
Previously untreated
CD20-positive iNHL
• Age ≥18 years
• FL (grade 1–3a) or
splenic/nodal/extranodal MZL
• Stage III/IV or stage II bulky
disease (≥7cm) requiring
treatment
• ECOG PS 0–2
• Target FL enrolment: 1200
G-chemo
G 1000mg IV on D1, D8, D15 of C1
and D1 of C2–8 (q3w) or C2–6 (q4w)
plus CHOP, CVP, or bendamustine†
R-chemo
R 375mg/m2 IV on D1 of C1–8 (q3w)
or C1–6 (q4w) plus CHOP, CVP,
or bendamustine†
G
G 1000mg IV
q2mo for 2 years or until PD
R
R 375mg/m2 IV
q2mo for 2 years or until PD
Induction Maintenance
Randomized
1:1*
CR or
PR‡
at EOI
visit
-- Idelalisib (Rezidiv)
-- ABT-199??
-- Ibrutinib??
-- Idelalisib (Rezidiv)
-- ABT-199??
-- Ibrutinib??
Ibrutinib Plus Rituximab in Treatment-Naïve Patients with Follicular Lymphoma: Results from a Multicenter, Phase 2
Study
Nathan H. Fowler, MD1, Loretta Nastoupil, MD1, Sven De Vos, MD, PhD2, Mark Knapp, MD3, Ian W. Flinn, MD, PhD4, Robert Chen, MD5, Ranjana H. Advani, MD6,
Sumeet Bhatia, MD7, Peter Martin, MD8, Raul Mena, MD9, Samuel Suzuki, MS, MBA10, Darrin M. Beaupre, MD, PhD10, Jutta K. Neuenburg, MD, PhD10, M. Lia Palomba, MD11
1University of Texas MD Anderson Cancer Center, Houston, TX; 2David Geffen School of Medicine at UCLA, Los Angeles, CA; 3Mid Ohio Oncology/Hematology, Inc., Columbus, OH; 4Sarah Cannon Research Institute, Nashville, TN; 5City
of Hope National Medical Center, Duarte, CA; 6Stanford University School of Medicine, Stanford, CA; 7Community Health Network, Indianapolis, IN; 8Weill Cornell Medical College, New York, NY; 9Providence Saint Joseph Medical Center/Disney
Family Cancer Center, Burbank, CA; 10Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA; 11Memorial Sloan Kettering Cancer Center, New York, NY
ASH 2015, PCYC-1125, Fowler et al. Abstract 470.
Study Schema
until disease
progression or
unacceptable
toxicity
Data from Arm 1 presentedArm 1: Main Study (N=60)
rituximab 375 mg/m2
IV q week × 4
Imaging every 12 weeks for 72 weeks, then every 24 weeks
12 weeks 24 weeks 36 weeks
Arm 2: Exploratory Arm (N=20)
2 monthlead-in
Imaging at 8 weeks, then every 12 weeks for 68 weeks (6x), and then every 24 weeks
20 weeks 32 weeks
until disease
progression or
unacceptable
toxicity
rituximab 375 mg/m2
IV q week × 4
8 weeks
ibrutinib 560 mg PO continuously
ibrutinib 560 mg PO continuously
4
ALTERNATIVEA prospective multicenter Phase 2 Study of the Chemotherapy-free
Combination of the Bruton's Tyrosine Kinase Inhibitor, PCI-32765 (Ibrutinib)
in Combination with Obinutuzumab (GA 101) in Patients with
Previously Untreated Follicular Lymphoma (FL) and a High Tumor Burden
+
Studiendesign / Flowchart
1st line
FL
n = 1000
Re. FLMZL
n = 400
Ibrutinib
Obinutuzumab ( cycle 1 : on days 01, 08, 15 cycles 2–18 : only on day 01 )
Efficacy Evaluation
MRD
Start Maintenanceintervals 3w = 21d 3w 3w 3w 3w 3w 3w
weeks 00 03 06 09 12 15 18 21 ...26
months 00
Start Observation
intervals 2mo = 60d 2mo 2mo 2mo 2mo 2mo 2mo 2mo 2mo 2mo 2mo 2mo 6mo
weeks (approx.) 34,5 43 51,5 60 68,5 77 85,5 94 102,5 111 119,5 128
months 09
6mo 6mo …
months (simple maintenance) …
months (extended maintenance) …42 48 54 60
30
03
6mo = 180d
42 66 (min.) - 78 (max.)36 48
6mo = 180d
06 12 18 24 30
EoI06…………………
EoS
EoEM42
66 (min.) - 78 (max.)
36
EoM
5w = 35d
and all 6 months (until progession or end of study)
560 mg ibrutinib daily (for 30 months or until progression)
MAINTENANCE THERAPY
INDUCTION THERAPY
EXTENDED MAINTENANCE THERAPYonly for patients
remaining MRD positive (at EoM)
560 mg ibrutinib daily (for 12 additional months or until progression)560 mg ibrutinib daily (for 30 months or until progression)
OBSERVATION(until end of study, but for a minimum of 2 years)
C3 C4 C5 C6C2C1
C7 C8 C9 C10 C11 C12 C13 C14 C15 C16 C17 C18
Rekrutierung (Stand 3. März. 2017)
-- Idelalisib (Rezidiv)
-- ABT-199??
-- Ibrutinib??
Abstract no.: 617
Phase 2 Study of Venetoclax plus Rituximab or
Randomized Venetoclax plus Bendamustine +
Rituximab (BR) versus BR in Patients with
Relapsed/ Refractory Follicular Lymphoma:
CONTRALTO Study- Interim Data
Pier Luigi Zinzani1, Max S. Topp2, Sam L.S. Yuen3, Chiara Rusconi4, Isabelle Fleury5,
Barbara Pro6, Giuseppe Gritti7, Michael Crump8, Wanling Hsu9, Elizabeth Punnoose9,
James Hilger9, Mehrdad Mobasher9, Wolfgang Hiddemann10
1. Institute of Hematology “L. e A. Seragnoli”, University of Bologna, Bologna, Italy; 2. Medizinische Klinik und Poliklinik II,
Universitatsklinikum Wurzburg, Germany; 3. Department of Haematology, Calvary Mater Newcastle, NSW Australia; 4.
Division of Hematology, Niguarda Hospital, Milan, Italy; 5. Department of Hematology, Maisonneuve-Rosemont Hospital
and University of Montreal, Montreal, Canada; 6. Robert H. Lurie Comprehensive Cancer Center Chicago, Il, USA; 7.
Ospedale Papa Giovanni XXIII, Hematology and BMT Unit, Bergamo, Italy; 8. Princess Margaret Cancer Centre,
University of Toronto, Toronto, Canada; 9. Genentech, Inc., South San Francisco, CA, USA; 10. Department of Internal
Medicine III, Klinikum der Universitat Munchen, Munich, Germany
American Society of Hematology
San Diego, CA, December 5, 2016Download this presentation: http://tago.ca/ZINZ
CONTRALTO Phase 2 Study Design
VEN + R and randomized VEN + BR vs BR alone in patients
with R/R FL, Grade 1–3a
Chemotherapy Free(N = 50)
ARM A
VEN+R
Chemotherapy Containing(N = 100)
R 1:1a
ARM C
BR
Key inclusion criteria
Age ≥18 yrs
Confirmed R/R FL (Gr 1–3a)
Treated with ≥1 line of prior therapy for FL
Adequate marrow, coagulation, renal, and hepatic function
No history of bendamustine-refractory disease
No CNS lymphoma
Primary Endpoint
PET-CR rate by IRC at end of induction (Cheson 2014)
Secondary Endpoints
CR rate (PET and CT) by investigator at end of induction and 1 year
ORR
PFS
Safety
Chemo vs. No ChemoInvestigator’s Discretion
a Stratified: DOR to prior tx (≤12m vs. >12m) Disease burden (high vs. low)
ARM B
VEN+BR
Safety run-in (N=9)
600 mg VEN+BR
12.4mb 6.3mb 6.2mb
b median months on study so far (ongoing)
Download this presentation: http://tago.ca/ZINZ
0 2 4 6 8 10 12 14 16 18 20
Dosing Schedule by Arm and Time on Study (Ongoing)
Months
Blue circles represent the median, and the lines are for the associated range
*R administered on Days 1, 8, 15 and 22.
28-day cycles
Rituxumab D1 of period indicated
Bendamustine D1 + D2 of period indicated
Venetoclax Daily over period indicated 800 mg daily
375 mg/m2
Arm A: VEN + R
Arm B: VEN + BR
Arm C: BR
VEN 800 mg (daily)
VEN 800 mg (daily)
*
TLS mitigation on day 1
• hydration
• allopurinol or rasburicase
• mandatory hospitalization for pts with
bulk and high ALC
BR end
(Arm B+C)
VEN end (Arm A+B)
R end (Arm A)
90 mg/m2
ALTERNATIVE Trial II?
6 x GA 101 + ABT-199GA 101/ ABT-199
Maintenance
Unser Ziel:
Für ältere Lymphom-
patienten
Lebensqualität zu
erhalten!
Trial Flow
1. Follikuläres Lymphom (fortgeschrittene Lymphome)
2. Morbus Waldenström
3. Marginalzonenlymphom
Indolente B - NHL
European Consortium for Waldenström‘s Macroglobulinemia
ECWM - Trials 2017
ECWM-R1 (Phase III, iNNOVATE):
Rituximab + Placebo vs Rituximab plus Ibrutinib
Global, 59 centers
Activation in Europe Dec 2014
Relapse
ECWM-R2 Phase II;
Hovon, Greece
Ixazomib/Rituximab/Dexa
ECWM-1 (Phase III)
DRC versus Bortezomib-DRC
European, over 60 centers
recruiting
TrialsFirst Line
R2W (ECWM-2)(Phase II)
BCR versus FCR
UK , 27 centers
Finished recruitment
ECWM-3 (Phase II)
DRC vs. B-DRC vs.
B-Rituximab/Ibrutinib
Germany, France, Greece
60 centers
ECWM-R4
Phase II GA101/CD38 mAb
ECWM-R3
Phase II; France
Idelalisib/GA101
European Consortium for Waldenström‘s Macroglobulinemia
ECWM - Trials 2017
ECWM-R1 (Phase III, iNNOVATE):
Rituximab + Placebo vs Rituximab plus Ibrutinib
Global, 59 centers
Activation in Europe Dec 2014
Relapse
ECWM-R2 Phase II;
Hovon, Greece
Ixazomib/Rituximab/Dexa
ECWM-1 (Phase III)
DRC versus Bortezomib-DRC
European, over 60 centers
recruiting
TrialsFirst Line
R2W (ECWM-2)(Phase II)
BCR versus FCR
UK , 27 centers
Finished recruitment
ECWM-3 (Phase II)
B-Rituximab/Ibrutinib
Germany, France, Greece
60 centers
ECWM-R4
Phase II GA101/CD38 mAb
ECWM-R3
Phase II; France
Idelalisib/GA101
ECWM-1first line WM
Registration
Randomisation
Standard Arm
6 x DRC
Experimental Arm
6 x Bortezomib - DRC
Follow – upFor response until progression
For OS until death
SD, PD
Follow-up for survival SD, PD
Follow-up for survival
Study ECWM-1 - Status
• Study activated in: Germany, France, Greece,
Sweden, Czech Republic
• Patients included: 114 (März 2017)
• Activation pending in: Spain, Portugal
European Consortium for Waldenström‘s Macroglobulinemia
ECWM - Trials 2017
ECWM-R1 (Phase III, iNNOVATE):
Rituximab + Placebo vs Rituximab plus Ibrutinib
Global, 59 centers
Activation in Europe Dec 2014
Relapse
ECWM-R2 Phase II;
Hovon, Greece
Ixazomib/Rituximab/Dexa
ECWM-1 (Phase III)
DRC versus Bortezomib-DRC
European, over 60 centers
recruiting
TrialsFirst Line
R2W (ECWM-2)(Phase II)
BCR versus FCR
UK , 27 centers
Finished recruitment
ECWM-3 (Phase II)
B-Rituximab/Ibrutinib
Germany, France, Greece
60 centers
ECWM-R4
Phase II GA101/CD38 mAb
ECWM-R3
Phase II; France
Idelalisib/GA101
ECWM-3 June 2017first line WM – single arm phase II
Registration
Single arm phase II
R-Ibrutinib/Bortezomib
53 pts
European Consortium for Waldenström‘s Macroglobulinemia
ECWM - Trials 2017
ECWM-R1 (Phase III, iNNOVATE):
Rituximab + Placebo vs Rituximab plus Ibrutinib
Global, 59 centers
Activation in Europe Dec 2014
Relapse
ECWM-R2 Phase II;
Hovon, Greece
Ixazomib/Rituximab/Dexa
ECWM-1 (Phase III)
DRC versus Bortezomib-DRC
European, over 60 centers
recruiting
TrialsFirst Line
R2W (ECWM-2)(Phase II)
BCR versus FCR
UK , 27 centers
Finished recruitment
ECWM-3 (Phase II)
DRC vs. B-DRC vs.
B-Rituximab/Ibrutinib
Germany, France, Greece
60 centers
ECWM-R4
Phase II GA101/CD38 mAb
ECWM-R3
Phase II; France
Idelalisib/GA101
ECWM-R1 / Relapse – first line
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
Rituximab refractory: oral Ibrutinib 420 mg qD
continuously until evidence of progressive disease
(observational arm only, max 35 pts!)
ECWM-R1 / Relapse – first line
R Rituximab 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
Rituximab refractory: oral Ibrutinib 420 mg
qD continuously until evidence of progressive
disease
(observational arm only, max 35 pts!)
Recruitment
finished Jan 2016
(150 patients in total)
ECWM-R1 / Relapse – first line
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
1:1
Rituximab refractory: oral Ibrutinib 420 mg qD
continuously until evidence of progressive disease
(observational arm only, max 35 pts!)
13%19%
58%
13%
71%90%
0%
20%
40%
60%
80%
100%
SD MR PR VGPR Major Response
(≥PR)
Overall Response
(≥MR)
Best Response All (N=31)
VGPR 4
PR 18
MR 6
ORR, n (%) 28 (90)
MRR, n (%) 22 (71)
Dimopoulos et al., Lancet Oncology, 2016
1. Follikuläres Lymphom (fortgeschrittene Lymphome)
2. Morbus Waldenström
3. Marginalzonenlymphom
Indolente B - NHL
aktive Zentren
Stand 3/2017
Register - Stand
• Seit Mai 2015
sequentielle Aktivierung aktuell 91 Zentren
256 Patienten Stand 28. Feb 2017
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