frankfurt 10. 11.märz 2017 glsg hämatologie im wandel · plus chop, cvp, or bendamustine†...

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??

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




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


ECWM - Trials 2017



Global, 59 centers


Relapse

ECWM-R2 Phase II;

Hovon, Greece


ECWM-1 (Phase III)



recruiting

TrialsFirst Line


BCR versus FCR

UK , 27 centers


ECWM-3 (Phase II)



60 centers

ECWM-R4


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


ECWM - Trials 2017



Global, 59 centers


Relapse

ECWM-R2 Phase II;

Hovon, Greece


ECWM-1 (Phase III)



recruiting

TrialsFirst Line


BCR versus FCR

UK , 27 centers


ECWM-3 (Phase II)



60 centers

ECWM-R4


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


ECWM - Trials 2017



Global, 59 centers


Relapse

ECWM-R2 Phase II;

Hovon, Greece


ECWM-1 (Phase III)



recruiting

TrialsFirst Line


BCR versus FCR

UK , 27 centers


ECWM-3 (Phase II)

DRC vs. B-DRC vs.



60 centers

ECWM-R4


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!)


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


Recruitment

finished Jan 2016

(150 patients in total)


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


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




Indolente B - NHL

aktive Zentren

Stand 3/2017

Register - Stand

• Seit Mai 2015

sequentielle Aktivierung aktuell 91 Zentren

256 Patienten Stand 28. Feb 2017

• Dokumentationsvergutung 100 € pro Fall

• Web-based Dokumentation OpenClinica geöffnet

MZL Registry GermanyWeb – based Documentation

OpenClinica:

Supported by

Deutsche Krebshilfe

GLSG Study Group

frankfurt 10. 11.märz 2017 glsg hämatologie im wandel · plus chop, cvp, or bendamustine†...

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