Indolente B – Zellymphome: Beginn einer neuen Ära in der Therapie?

DGIM Wiesbaden 2014
KML – Symposium
Indolente B – Zellymphome:
Beginn einer neuen Ära in der Therapie?
C. Buske
CCC Ulm
Klinik für Innere Medizin III
Universitätsklinikum Ulm
Indolente B – Zellymphome:
Beginn einer neuen Ära in der Therapie?
JA!
Trends: weg von der klassischen Chemotherapie
Trends: weg von der ‘i.v.’ – Therapie’
s.c. !
Orale Therapie!
Indolente B - NHL
Zwei Bespiele!
1. Follikuläres Lymphom (fortgeschrittene Lymphome)
2. Morbus Waldenström
Therapeutischer Algorithmus – follikuläres Lymphom
- Wie können wir uns verbessern? Diagnose  Diagnostischer Work-up (CT etc.)
Watch & Wait
Neue Substanzen !
s.c./orale Applikation!
Entwicklung von Krankheitssymptomen
Induction
Start der Therapie
Neue Substanzen !
s.c./orale Applikation!
Maintenance
Rituximab
Immunochemotherapy
Wie können wir uns weiter
verbessern……?
Besserer Antikörper?
GA101 Mechanisms of Action
Increased direct cell death
Type II vs. Type I antibody
Enhanced ADCC
Glycoengineering for increased
affinity to FcγRIIIa
Effector
cell
B cell
Lower CDC activity
GA101
Complement
CD20
FcγRIIIa
Type II vs. Type I antibody
Phase III Trial in Previously untreated
follicular/indolent NHL (Gallium)
R
A
N
D
O
M
I
Z
E
D
R-CHOP or
R-CVP
R-Bendamustine
G-CHOP or
G-CVP or
CR
PR
Rituximab
maintenance*
CR
PR
GA101
maintenance
G - Bendamustine
2
*375mg/m every 2 months for 2
years or until relapse
Wie können wir uns weiter
verbessern……?
Lenalidomid?
Study Design
Months
1
2
3
4
5
7
6
8
9
10
11
Lenalidomide 20mg Days 1-21 Cycles 1-6*
Lenalidomide 20mg Days 1-21 Cycles 7-12*
Rituximab 375mg/M2 Day 1 of Cycles 1-6
Rituximab 375mg/M2 Day 1 of Cycles 7-12
R= RESTAGING
R
R
If clinical benefit, can
proceed to 12 cycles
•Phase II, single institution
12
R
*SLL patients: Dose escalation of
lenalidomide starting with cycle 1: (10mg,
15mg, 20mg)
•Planned Enrollment - UNTREATED
•N= 50 Follicular lymphoma (grade I/II)
•N=30 Small lymphocytic lymphoma
•N=30 Marginal zone lymphoma
•Groups analyzed independently for response and toxicity
R
Follicular Lymphoma Response:
Tumor Burden, Molecular Response
BY GELF CRITERIA N=46
GELF (+) HIGH TUMOR BURDEN N=22 (48%)
GELF (-) HIGH TUMOR BURDEN N=24 (52%)
SD
PR
CR/Cru
ORR
SD
PR
CR/Cru
ORR
0
1 (5%)
21(95%)
100%
1(4%)
4(17%)
19 (79%)
96%
BY BULK OF DISEASE N=46
BULKY N=13 (28%)
NON-BULKY N=33 (72%)
SD
PR
CR/CRu
ORR
SD
PR
CR/CRu
ORR
0
1(8%)
12(92%)
100%
1(3%)
4 (12%)
28 (85%)
97%
MOLECULAR RESPONSE N=44 (eval)
PCR POSITIVE
PRETREATMENT
17(41%)
POST CYCLE 3
5(11%)
POST CYCLE 6
2(5%)
•Bone marrow and peripheral blood for major or minor breakpoint
1. Brice P, et al. JCO 1997: 15:1110–1117.
PCR NEGATIVE
26(59%)
39(89%)
42(95%)
RELEVANCE Study Design
(Rituximab and LEnalidomide versus Any ChEmotherapy)
1st line
FL
N=1000
R2
R2 Maintenance
R + Chemo
Rituximab Maint.
R
• R+Chemo:
•Investigator’s choice of R-CHOP, R-CVP, BR
• R2: Lenalidomide 20mg for 6 cycles, then 10mg for 12 cycles if CR/Cru
Rituximab 375 mg/m2 day 1,8,15,22 cycle 1, day 1 cycle 2-6
The New World……………..
PI3Kδ and BTK Inhibition Impacts Multiple Critical
Pathways in iNHL
Mature Response Data from a Phase 2 Study of
PI3K-Delta Inhibitor Idelalisib in Patients with
Double (Rituximab and Alkylating Agent)Refractory Indolent B-Cell Non-Hodgkin
Lymphoma (iNHL)
A Gopal,1 B Kahl,2 S de Vos,3 N Wagner-Johnston,4 S Schuster,5 K Blum,6 W Jurczak,7 I Flinn,8 C Flowers,9 P Martin,10 A Viardot,11
A Goy,12 A Davies,13 PL Zinzani,14 M Dreyling,15 L Holes,16 D Li,16 R Dansey,16 Wayne Godfrey,16 and G Salles17
1University
of Washington School of Medicine, Seattle, WA, USA; 2University of Wisconsin Carbone Cancer Center, Madison, WI, USA; 3David Geffen School of Medicine at UCLA, Los Angeles, Los Angeles, CA,
USA;
University School of Medicine, St. Louis, MO, USA; 5Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA; 6Ohio State University Wexner Medical Center,
Columbus, OH, USA; 7Jagiellonian University, Krakow, Poland; 8Sarah Cannon Research Institute, Nashville, TN, USA; 9Winship Cancer Institute of Emory University, Atlanta, GA, USA; 10Weill Cornell Medical
College, New York, NY, USA; 11University Hospital of Ulm, Ulm, Germany; 12Hackensack University Medical Center, Hackensack, NJ, USA; 13University of Southampton, Southampton, United Kingdom; 14University
of Bologna, Bologna, Italy; 15University Hospital Grosshadern, LMU Munich, Germany; 16Clinical Research Oncology,
Gilead Sciences, Seattle, WA, USA; 17Hospices Civils de Lyon, University Claude Bernard, Pierre Benite, France
4Washington
American Society of Hematology
December 8, 2013
New Orleans, LA
Oral No 85.
Study 101-09: Key Eligibility Criteria
 Previously treated iNHL: (FL, SLL, MZL, LPL/WM)
 Refractory to BOTH rituximab and an alkylating agent:
– Defined as less than PR on therapy, or progression within 6
months of completion of therapy
– Refractoriness documented radiologically
– Median number previous regimens 4 (2-12)
– 58 % FL patients
– 65 % Bendamustine
Single-Arm Study (N=125)
Enrolled
April 2011 to
October 2012
Idelalisib 150 mg BID
 Primary endpoint:
– Overall Response Rate (ORR)
 Secondary endpoints:
– Duration of Response (DOR)
– Progression Free Survival (PFS)
– Overall Survival (OS)
– Safety
– Quality of life
Therapy maintained
until progression
Long Term follow-up
Phase 2 Idelalisib Monotherapy in Refractory iNHL
(Study 101-09)
Study 101-09: Overall Response Rate (ORR)
Characteristic
Overall Response Rate, n (%)
95% CI
N=125
71 (57%)
(48%, 66%)
Complete Response
7 (6%)
Partial Response
63 (50%)
Minor Response1
1 (1%)
Stable Disease
42 (34%)
Progressive Disease
10 (8%)
Not Evaluated
2 (2%)
Time to response, months (N=71)
Median (Q1, Q3)
1-LPL/WM
patients
1.9 (1.8, 3.7)
Study 101-09: Forest Plot of ORR
ORR (95% CI)
Overall (N=125)
0.57 (0.48, 0.66)
Age <65 years (N=69)
>=65 years (N=56)
0.57 (0.44, 0.68)
0.57 (0.43, 0.70)
M ale (N=80)
Fem ale (N=45)
0.55 (0.44, 0.66)
0.60 (0.44, 0.74)
FL
SLL
M ZL
LPL/W M
(N=72)
(N=28)
(N=15)
(N=10)
0.54 (0.42, 0.66)
0.61 (0.41, 0.79)
0.47 (0.21, 0.73)
0.80 (0.44, 0.98)
Bulky disease: No (LD <7 cm ) (N=92)
Yes (LD >=7 cm ) (N=33)
0.57 (0.46, 0.67)
0.58 (0.39, 0.75)
# Prior therapy: <4 (N=52)
>=4 (N=73)
0.50 (0.36, 0.64)
0.62 (0.50, 0.73)
Prior bendam ustine: No (N=44)
Yes (N=81)
0.57 (0.41, 0.72)
0.57 (0.45, 0.68)
Refractory to bendam ustine: No (N=20)
Yes (N=61)
0.50 (0.27, 0.73)
0.59 (0.46, 0.71)
Refractory to last therapy: No (N=13)
Yes (N=112)
0.69 (0.39, 0.91)
0.55 (0.46, 0.65)
0.0
Dotted line: Null hypothesis <20% Response rate
0.2
0.4
0.6
ORR
0.8
1.0
Study 101-09 Waterfall Plot Lymph Node Response
SPD of Measured Lymph Nodes,
Best % Change from Baseline
+50
•90% had improvement in lymphadenopathy
•57% had ≥50% decrease from baseline
+25
0
-25
-50 a
-75
-100
aCriterion
Individual Patients (N=125)
for lymphadenopathy response [Cheson 2007]
b 3 subjects no post baseline evaluation:
□ 2 subjects NE
■ 1 subject PD by Lymph Node biopsy
% Continued Response
Study 101-09: Duration Of Response (DOR)
Median DOR = 12.5 months
100
32 % of pts still on treatment!
75
50
25
0
0
(71)
3
(54)
6
(34)
9
(17)
12
(9 )
15
(0 )
18
(0 )
Time from Response, Months
(N, Patients at Risk)
Analysis includes subjects who achieved a CR or PR (or MR for WM subjects) according to IRC assessments
Study 101-09: Adverse Events > 10%
AE
Diarrhea
Fatigue
Nausea
Cough
Pyrexia
Dyspnea
Decreased appetite
Abdominal pain
Vomiting
URI
Decreased weight
Rash
Asthenia
Night Sweats
Pneumonia
+ neutropenia Grade > 3 : 27%
Any Grade
N, %
54 (43%)
37 (30%)
37 (30%)
36 (29%)
35 (28%)
22 (18%)
22 (18%)
20 (16%)
19 (15%)
18 (14%)
17 (13%)
16 (13%)
14 (11%)
14 (11%)
14 (11%)
Grade ≥ 3
N, %
16 (13%)
2 (2%)
2 (2%)
None
2 (2%)
4 (3%)
1 (1%)
3 (2%)
3 (2%)
None
None
2 (2%)
3 (2%)
None
9 (7%)
The Bruton’s Tyrosine Kinase (BTK) Inhibitor
Ibrutinib (PCI-32765) is Active and Tolerated in
Relapsed Follicular Lymphoma (FL)
Nathan Fowler MD1, Ranjana Advani MD2,
Jeff Sharman MD3, Sonali M. Smith MD4,
Jesse McGreivy MD5, Lori Kunkel MD5,
Vina Troung5, Cathy Zhou5, Thomas Boyd MD6
1Dept.
of Lymphoma/Myeloma, UT MD Anderson Cancer Center, Houston, TX
2Dept. of Medicine/Oncology, Stanford University, Stanford, CA
3Willamette Valley Center Institute (US Oncology Research), Springfield, OR
4Hematology/Oncology, University of Chicago Hospitals, Chicago, IL
5Pharmacyclics, Inc., Sunnyvale, CA
6North Star Lodge Cancer Center (US Oncology Research), Yakima, WA
2
Study Design
• Dose Escalation Study in recurrent B-NHL
• Cohorts: n ≥ 6 patients
• Escalate to maximum tolerated dose (MTD) or 3 dose levels above
complete active site occupancy
• Tumor assessment performed every 2 cycles
• Dosing
• 1.25, 2.5, 5.0, 8.3, 12.5 mg/kg/d po (Cycle = 28 days +
7 days rest)
• 2 continuous dosing cohorts (Cycle = 35 days)
• 8.3 mg/kg/d po
• 560 mg/day po (fixed dose)
4
Adverse Events >10%
(includes both related and unrelated AEs)
Hematologic AEs
Neutropenia
1 1 13%
Anemia
1 1 13%
Grade 1
Grade 2
Grade 3
All grades
0
Non-Hematologic AEs
20
40
60
80
100
> Grade 1
Upper Respiratory tract infection
Vomiting
1
1
Headache
2
Myalgia
2
Cough
2
Fatigue
Grade 2
13%
13%
Grade 3
13%
13%
25%
4
0
All Grade 4 AEs
13%
2
20
40
60
80
Percent of patients (%)
100
•One hypokalemia (unrelated)
•One MDS 29 days after last ibrutinib dose in a heavily pretreated subject with pre-existing anemia
10
Efficacy in FL Patients
(Evaluable population with ≥ 1 response assessment, n=15)
CR
PR
Percent of patients (%)
100
80
60
55%
40
27.3%
25%
20
25%
27.3%
56%
22.2%
33.3%
0
1.25 mg/kg/day
(n=4)
Median DOR:
Median PFS:
NE
NE
≥ 2.5 mg/kg/day
(n=11)
10.3 months
13.4 months
≥ 5.0 mg/kg/day
(n=9)
12.3 months
19.6 months
15
Follicular lymphoma
GLSG Studies 2014
medically non-fit
R-CHOP/B vs.
G-CHOP/B
R vs G maintenance
R-CHOP vs. R2
Ritux maintenance
(+/- lenalidomide)
GA101
vs
G-Bendamustine
Planned:
GA101 plus Ibrutinib
Phase II Trial
Relapse
R-Benda Temsirolimus
(BeRT)
R- Lenalidomide
+/- Benda
R-maintenance
Indolente B - NHL
1. Follikuläres Lymphom (fortgeschrittene Lymphome)
2. Morbus Waldenström
Problem
-- oft ältere Patienten
-- Therapien teilweise toxisch
-- kaum prospektiv randomisierte Daten
De-eskalieren der
Behandlung?
DRC
Chemotherapie vermeiden
(Bortezomib/Rituximab)
DRC +/- Bortezomib
Dexamethason:
Cyclophosphamide:
Rituximab:
20 mg p.o. day 1
100 mg/m2 x 2 p.o. day 1-5
1400 mg s.c. day 1
+/- Bortezomib:
1,6 mg s.c. day 1,8,15
Every 28 days for 6 courses
NO IV THERAY ANYMORE
ECWM-1: Study Flow
Registration
Randomisation
Standard Arm
6 x DRC
Experimental Arm
6 x B - DRC
SD, PD
Follow-up for survival
SD, PD
Follow-up for survival
Follow – up
For response until progression
For OS until death
Phase II Study of the
Bruton’s Tyrosine Kinase (Btk) Inhibitor
Ibrutinib in Waldenstrom’s
Macroglobulinemia
Steven P. Treon
Dana‐Farber Cancer Institute
SCHEMA FOR MULTICENTER PHASE II STUDY OF IBRUTINIB IN
RELAPSED/REFRACTORY WM
N=35, expanded to
63.
Screening
Informed Consent and Registration
Ibrutinib
420 mg po daily
Progressive Disease or
Unacceptable Toxicity
Stop Ibrutinib
Event Monitoring
Stable Disease or Response
Continue x 26 four week cycles
Event Monitoring
OPENED MAY 2012
36
DFCI, MSKCC, STANFORD
Study PCYC‐1118E: Efficacy
• N = 63
• Median of 9 cycles; range 1-18 cycles
• Response assessment per investigator using the
3rd WM response criteria
• Data cut off 8 Nov. 2013
• Study ongoing, data subject to change
Best response to ibrutinib
100
90
VGPR; 9,5
80
70
60
%
ORR,
83%
Major RR,
64%
PR; 54
50
40
30
20
MR; 19
16
10
2
0
ORR
PD
SD
SD
MR
PR
PD
VGPR
A randomized phase III study of Rituximab/Ibrutinib p.o.
versus Rituximab/Placebo
in patients with previously treated WM
ECWM‐R1
Sponsor: Pharmacyclics
in collaboration with The European Waldenström's Macroglobulinemia Consortium and the ALLG Study Design / Treatment R
1
:
1
Rituximab (weekly for 4 consecutive weeks x 2)
plus Ibrutinib (420 mg qD continuously until evidence of progressive disease)
Rituximab (weekly for 4 consecutive weeks x 2)
plus Placebo
Crossover: Patients who are randomized in the rituximab arm and demonstrate progressive disease, will be allowed to receive ibrutinib
GLSG Study Group