glsg/osho study group - kompetenznetz- · pdf filefollicular lymphomas questions for the next...

Supported byDeutsche Krebshilfe
GLSG/OSHO Study Group
founded in 1985

Comparison of Two Consecutive Study Generations of the GLSG
Overall Survival

Follicular LymphomasQuestions for the Next Steps of Therapy
Best Chemotherapy to be combined with Rituximab Value of Radio-Immuno Therapy Value of Stem Cell Transplantation after R Chemo Improvement of Rituximab Application Improvement of Rituximab Maintenance New Antibodies New Agents

[email protected]
Adapted from Press. Cancer J Sci Am. 1998;4(suppl 2):S19.
CD22
HLA-DR
CD20
slg
CD19 B Cell
CD37
CD25
CD52
Antibody Therapy for B - Cell Lymphomas
Targeting agent Monoclonal antibody Engineered antibody Recombinant toxin
Modifications None Conjugation
Radioisotopes Drugs Toxins
B-Cell

1. Niederfellner G, et al. Blood 2011; 118:358367. 2. Mssner E, et al. Blood 2010; 115:43934402.
GA101
Type IIanti-CD20 mAb1
GlycoengineeredFc region2
IncreasedDirect Cell Death2
Increased antibody-dependent cellular cytotoxicity
(ADCC)2

GALLIUM Phase III - Study Design
Experimental arm GA101 1000 mg d1, d8, d15 cycle 1; d1 cycles 26/8 +CHOP q 21d / CVP q 21 d / Bendamustine 90 mg/m2 d1, d2 q28d
Control arm Rituximab 375 mg/m2 d1 cycles 1-6/8 +CHOP q 21d / CVP q 21 d / Bendamustine 90 mg/m2 d1, d2 q28d
Patient population 1200 fNHL and 200 MZL
Primary endpoint PFS of 1200 fNHL patients
Maintenance treatment Patients achieving CR or PR continue therapy every2 months for up to 2 years
Maintenance rituximab
q2m 2 years
Maintenance GA101
q2m 2 yearsCR/PR
Previously untreatedindolent NHL
(n=1400)
GA101 1000 mg x 6-8 cycles+
CHOP/CVP/Bendamustine x 6-8 cycles
Rituximab 375 mg/m2 x 6-8 cycles+
CHOP/CVP/Bendamustine x 6-8 cycles CR/PR
Source: www.clinicaltrials.gov

GALLIUM Recruitment

GALLIUM Country Recruitment
8

GALLIUM: Patient Distribution

Strategy of GLSG/OSHOin Follicular Lymphomas
Current Strategy/Studies:Stage I/II:
Radio- Immunotherapy (MASAI)Stage III/IV asymptomatic:
Watch and Wait Recommendation, No StudyStage III/IV symptomatic:
medically fit pts. GALLIUM, RELEVANCEmedically non-fit pts. G vs. GB
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Best Chemotherapy to be combined with Rituximab Value of Radio-Immuno therapy Value of Stem Cell Transplantation after R Chemo Improvement of Rituximab Application Improvement of Rituximab Maintenance New Antibodies New Agents

Bachy E , and Salles G Clin Cancer Res 2014;20:5226-5239

LenalidomideMechanism of Action

R1st line
FLn = 1000
R2 Maintenance
2 Years Rituximab Maintenance
R2
R-Chemo
CR, CRu, PR
CR, CRu, PR
R-ChemoR-CHOP (6x), R-CVP (8x), R-B (6x)
International, multi-centre, randomised study
R2 maintenance2 Years of Rituximab Maintenance1 Year of Lenalidomide Maintenance
R2 InductionLenalidomide 20 mg d 2-22 for 6 CyclesRitux 4xCycle 1, 1x Cycles 2-6
RELEVANCE : Phase 3 Study Design(Rituximab and LEnalidomide Versus ANy ChEmotherapy, FL-001)

N. Fowler, Lancet Oncology 2014
2 Yrs. PFS: 89%3 Yrs. PFS: 74,9%
G. Salles, Lancet 2011
PRIMA RELEVANCE

Best Chemotherapy to be combined with Rituximab Value of Radio-Immuno therapy Value of Stem Cell Transplantation after R Chemo Improvement of Rituximab Application Improvement of Rituximab Maintenance New Antibodies New Agents

R. M. Young & L. M. Staudt, Nature Reviews Drug Discovery 12, 229-243 2013)

Co-development by Janssen and Pharmacyclics
Oral, small-molecule inhibitor of BTK with once daily dosing; previously PCYC 32765
Forms a specific and covalent bond that causes highly potent BTK inhibition
Naming origins of ibrutinib (eye-BROO-ti-nib):
I: to indicate a modern breakthrough, ie: iPhone, iPad, etc.
Brut: this is a Bruton Tyrosine Kinase (BTK) inhibitor
tinib: all tyrosine kinase inhibitors end with the tinib suffix
>1400 patients treated to date with ibrutinib across multiple B-cell malignancies
Ibrutinib: First-in-class Inhibitor of Brutons Tyrosine Kinase (BTK)
233/26/2015 23

Initial Phase 1 Study (PCYC-04753)
24
N CR PR SD ORR %
CLL/SLL 16 1 10 2 85%
FL 16 1 3 5 31%MCL 9 3 4 1 78%DLBCL 7 2 1 29%
MZL/MLT 4 1 1 33%
WM 4 2 1 67%
TOTAL 56 5 22 11 56%
Advani et al. ASCO 2010
3/26/2015 24

0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0
10
20
30
40
50
60
70
0 4 8 12 16 20 24 28
BTK
Act
ive-
Site
Occ
upan
cy
Plas
ma
Con
cent
ratio
n(n
g/m
L)
Time Postdose (h)
Plasma Conc
Plasma concentration profile reflects inhibition profile of reversibly inhibited off targets
Occupancy indicates irreversible inhibition of BTK
Durable BTK inhibition following an oral dosePlasma Concentration of PCI-32765 vs. BTK Occupancy
Patients dosed at 2.5 mg/kg/day
3/26/2015 25

BTK Occupancy
*** P

Efficacy in FL Patients
54.5% 55.6%
Perc
ent o
f pat
ient
s (%
)
Median DOR:Median PFS:
10.3 months13.4 months
12.3 months19.6 months
3/26/2015 27

Janssen Research & Development
SELENE Study DesignPopulation: relapsed/refractory iNHL (FL or MZL)
Stratification factors:1. Background chemoimmunotherapy: BR or R-CHOP2. Refractory vs relapsed disease3. iNHL histology: FL vs. MZL4. Prior lines of therapy (1 vs >1)
RANDOMIZE
BR or R-CHOP x 6 cycles+
Placebo*
Primary endpoint: PFS
Secondary endpoints: OS CR ORR (CR+PR) rate DOR PRO Safety
BR or R-CHOP x 6 cycles+
560mg Ibrutinib*
1:1
* continued until disease progression or unacceptable toxicity
N 400 subjects
28

Janssen Research & DevelopmentR. M. Young & L. M. Staudt, Nature Reviews Drug Discovery 12, 229-243 2013)

Study 101-09: Phase 2 Monotherapy in Refractory iNHL
Idelalisib 150 mg BID continuously
Therapy maintained until
progression
Single-Arm Study (N=125)
Tumor assessments: Weeks 0, 8, 16, 24, 36, 48 Every 12 weeks thereafter Evaluated by Independent
Review Committee 2 radiologists with adjudication
if needed clinical review
Primary endpoint: Overall Response Rate (ORR)
Secondary endpoints: Duration of Response (DOR) Progression Free Survival (PFS) Safety Quality of life
Accrual Completed
October 2012
Long
Ter
m fo
llow
-up
Slide 30Salles G. et al., ICML 2013

Characteristic
Rituximab
Alkylating agent
R-CHOP
B-R
R-CVP
125/125 (100%)
124/125 (99%)
46/60 (77%)
39/54 (72%)
27/36 (75%)
Bendamustine 45/81 (56%)
Refractory to 2 regimens
Refractory to last regimen
99 (79%)
93 (74%)
Study 101-09: Prior Therapy Refractoriness
Slide 31

Characteristic N=125
Overall Response Rate, n (%)
Complete Response
Partial Response
Stable Disease
Progressive Disease
Not Evaluated
70 (56)
12 (10)
58 (46)
43 (34)
10 (8)
2 (2)
Time to response, months (N=67)
Median (Q1, Q3) 1.9 (1.8, 3.7)
Study 101-09: ORR
Slide 32A.K. Gopal ASH 2014

A.K. Gopal ASH 2014
Study 101-09: PFS
[email protected]
http://localhost:8091/ASH2014/abimages/Paper_74940_abstract_135454_0.pnghttp://localhost:8091/ASH2014/abimages/Paper_74940_abstract_135454_0.png

6 x GA 101 + Ibrut
6 x GA 101 + Idelalisib
GA 101/ Ibrut. Maintenance
GA 101/ Idela.Maintenance
Follicular Lymphoma First LineALTERNATIVE Studies

Concept
Antibody Partner:GA 101
Study Design:6 Cycles Ibrutinib/Idelalisib plus GA 101followed by 2 years maintenance of Ibrutinib/Idelalisib plus GA 101 MRD Monitoring
Accompanying Research:MRDMolecular RisikfactorsNGS

Concept
Endpoint: PFS at 1 Year(MRD Negativity)
Patient Number: 98Study Duration: 1 Year Recrutment
Year Induction2 Years Maintenance3 Years Follow-up

6 x GA 101 + New Drugs
6 x GA 101 + CHOP /B
R
New Drug Maint.
GA 101 Maintenance
Follicular Lymphoma First LineALTERNATIVE Studies

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Palliationof Symptomes
Prolongation of Life
Cure ?Chronic Disease ?
Key Steps in Improving Treatment for Follicular
Lymphoma
until mid 1990ies
Cytostatic DrugsRadiation
since mid 1990ies
AntibodiesASCT
Today
New AntibodiesNew Drugs
GLSG/OSHO Study GroupFoliennummer 2Follicular Lymphomas Questions for the Next Steps of TherapyFoliennummer 4GA101GALLIUM Phase III - Study DesignGALLIUM RecruitmentG

glsg/osho study group - kompetenznetz- · pdf filefollicular lymphomas questions for the next...

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