GLSG/OSHO Study Group
Supported by
Deutsche Krebshilfe
founded in 1985
Comparison of Two Consecutive Study
Generations of the GLSG
Overall Survival
Follicular Lymphomas
Questions 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
Antibody Therapy for B - Cell Lymphomas
CD22
CD25
slg
HLA-DR
CD20
CD19
B Cell
B-Cell
• Targeting agent
– Monoclonal antibody
CD37
– Engineered antibody
– Recombinant toxin
CD52 • Modifications
– None
– Conjugation
• Radioisotopes
• Drugs
• Toxins
Adapted from Press. Cancer J Sci Am. 1998;4(suppl 2):S19.
[email protected]
GA101
Type II
anti-CD20 mAb1
Glycoengineered
Fc region2
Increased
Direct Cell Death2
Increased
antibody-dependent
cellular cytotoxicity
(ADCC)2
1. Niederfellner G, et al. Blood 2011; 118:358–367. 2. Mössner E, et al. Blood 2010; 115:4393‒4402.
GALLIUM Phase III - Study Design
Previously untreated
indolent 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
CR/PR
Maintenance GA101
q2m × 2 years
Maintenance rituximab
q2m × 2 years
Experimental arm
GA101 1000 mg d1, d8, d15 cycle 1; d1 cycles 2–6/8 +
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 every
2 months for up to 2 years
Source: www.clinicaltrials.gov
GALLIUM Recruitment
GALLIUM Country Recruitment
8
GALLIUM: Patient Distribution
Strategy of GLSG/OSHO
in Follicular Lymphomas
Current Strategy/Studies:
Stage I/II:
Radio- Immunotherapy (MASAI)
Stage III/IV asymptomatic:
Watch and Wait – Recommendation, No Study
Stage III/IV symptomatic:
medically fit pts. – GALLIUM, RELEVANCE
medically non-fit pts. – G vs. GB
[email protected]
Follicular Lymphomas
Questions 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
Bachy E , and Salles G Clin Cancer Res 2014;20:5226-5239
Lenalidomide
Mechanism of Action
RELEVANCE : Phase 3 Study Design
(Rituximab and LEnalidomide Versus ANy ChEmotherapy, FL-001)
International, multi-centre, randomised study
CR, CRu, PR
R2
1st line
FL
n = 1000
R2 Maintenance
R
2 Years Rituximab Maintenance
R-Chemo
CR, CRu, PR
R2 Induction
R2 maintenance
Lenalidomide 20 mg d 2-22 for 6 Cycles
Ritux 4xCycle 1, 1x Cycles 2-6
2 Years of Rituximab
Maintenance
R-Chemo
R-CHOP (6x), R-CVP (8x), R-B (6x)
1 Year of Lenalidomide
Maintenance
PRIMA
3 Yrs. PFS: 74,9%
G. Salles, Lancet 2011
RELEVANCE
2 Yrs. PFS: 89%
N. Fowler, Lancet Oncology 2014
Follicular Lymphomas
Questions 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
R. M. Young & L. M. Staudt, Nature Reviews Drug Discovery 12, 229-243 2013)
R. M. Young & L. M. Staudt, Nature Reviews Drug Discovery 12, 229-243 2013)
R. M. Young & L. M. Staudt, Nature Reviews Drug Discovery 12, 229-243 2013)
Ibrutinib: First-in-class Inhibitor of Bruton’s
Tyrosine Kinase (BTK)
• 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
3/26/2015
23
23
Initial Phase 1 Study (PCYC-04753)
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
22
11
56%
5
Advani et al. ASCO 2010
24
3/26/2015
24
Durable BTK inhibition following an oral dose
Plasma Concentration of PCI-32765 vs. BTK Occupancy
Patients dosed at 2.5 mg/kg/day
100%
90%
Occupancy indicates
irreversible inhibition of
BTK
60
80%
50
70%
Plasma Conc
60%
40
50%
30
40%
Plasma concentration profile
reflects inhibition profile of
reversibly inhibited off targets
20
30%
20%
10
10%
0
0%
0
4
8
12
16
20
24
BTK Active-Site Occupancy
Plasma Concentration
(ng/mL)
70
28
Time Postdose (h)
3/26/2015
25
BTK Occupancy
Comparison of the Degree of BTK Occupancy by Ibrutinib at Each Dose-Level Cohort in the Study
*** P<0.001
3/26/2015
26
Percent of patients (%)
Efficacy in FL Patients
Median DOR:
Median PFS:
54.5%
≥
55.6%
≥
10.3 months
13.4 months
12.3 months
19.6 months
3/26/2015
27
SELENE Study Design
Population: relapsed/refractory iNHL (FL or MZL)
Stratification factors:
1. Background chemoimmunotherapy: BR or R-CHOP
2. Refractory vs relapsed disease
3. iNHL histology: FL vs. MZL
4. Prior lines of therapy (1 vs >1)
N ≈ 400 subjects
Primary endpoint:
• PFS
Secondary endpoints:
•
•
•
•
•
•
OS
CR
ORR (CR+PR) rate
DOR
PRO
Safety
R
A
N
D
O
M
I
Z
E
BR or R-CHOP x 6 cycles
+
Placebo*
1:1
BR or R-CHOP x 6 cycles
+
560mg Ibrutinib*
* continued until disease progression or
unacceptable toxicity
Janssen Research & Development
28
R. M. Young & L. M. Staudt, Nature Reviews Drug Discovery 12, 229-243 2013)
Janssen Research & Development
Single-Arm Study (N=125)
Accrual
Completed
October
2012
Idelalisib 150 mg BID
continuously
♦ 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
Therapy
maintained until
progression
Long Term follow-up
Study 101-09: Phase 2 Monotherapy in
Refractory iNHL
♦ Primary endpoint:
– Overall Response Rate (ORR)
♦ Secondary endpoints:
–
–
–
–
Duration of Response (DOR)
Progression Free Survival (PFS)
Safety
Quality of life
Salles G. et al., ICML 2013
Slide 30
Study 101-09: Prior Therapy Refractoriness
Characteristic
Rituximab
125/125 (100%)
Alkylating agent
124/125 (99%)
R-CHOP
46/60 (77%)
B-R
39/54 (72%)
R-CVP
27/36 (75%)
Bendamustine
45/81 (56%)
Refractory to ≥ 2 regimens
99 (79%)
Refractory to last regimen
93 (74%)
Slide 31
Study 101-09: ORR
Characteristic
N=125
Overall Response Rate, n (%)
70 (56)
Complete Response
12 (10)
Partial Response
58 (46)
Stable Disease
43 (34)
Progressive Disease
10 (8)
Not Evaluated
2 (2)
Time to response, months (N=67)
Median (Q1, Q3)
1.9 (1.8, 3.7)
A.K. Gopal ASH 2014
Slide 32
Study 101-09: PFS
[email protected]
A.K. Gopal ASH 2014
34
Follicular Lymphoma – First Line
ALTERNATIVE Studies
6 x GA 101 + Idelalisib
GA 101/ Idela.
Maintenance
6 x GA 101 + Ibrut
GA 101/ Ibrut.
Maintenance
Concept
Antibody– Partner:
GA 101
Study – Design:
6 Cycles Ibrutinib/Idelalisib plus GA 101
followed by 2 years maintenance
of Ibrutinib/Idelalisib plus GA 101
MRD Monitoring
Accompanying Research:
MRD
Molecular Risikfactors
NGS
Concept
Endpoint:
PFS at 1 Year
(MRD Negativity)
Patient Number:
Study Duration:
98
1 Year Recrutment
½ Year Induction
2 Years Maintenance
3 Years Follow-up
Follicular Lymphoma – First Line
ALTERNATIVE Studies
6 x GA 101 + CHOP /B
GA 101 Maintenance
R
6 x GA 101 + New Drugs
New Drug Maint.
Key Steps in Improving
Treatment for Follicular
Lymphoma
Cure ?
Chronic Disease ?
Today
Prolongation
of Life
since mid 1990ies
Palliation
of Symptomes
Antibodies
ASCT
until mid 1990ies
Cytostatic Drugs
Radiation
[email protected]
New Antibodies
New Drugs