Transcript Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma ASH Review 2012 Stephen Spurgeon ([email protected])

Chronic Lymphocytic Leukemia
and Mantle Cell Lymphoma
ASH Review 2012
Stephen Spurgeon ([email protected])
Disclosures
Speakers Bureau: GSK, Millenium,
Cephalon
CLL: Pertinent Topics
●
●
ASH treatment updates
●
James DF, et al. ASH 2011. Abstract 291.
●
Foa R, et al. ASH 2011. Abstract 294.
●
Badoux XC, et al. ASH 2011. Abstract 980.
FCR treatment expectations
●
●
Fink A, et al. ASH 2011. Abstract 977.
Rational therapeutic targets and novel agents
Rituximab + Lenalidomide for Patients
With Previously Untreated CLL: Phase II
●
Patients with previously untreated CLL (n = 69)
–
Patients younger than 65 yrs of age: n = 40
–
Patients 65 yrs of age or older: n = 29
●
Primary endpoint: CR in patients <65 yrs vs. > 65 yrs
●
Secondary endpoints
–
Safety, ORR, PFS
James DF, et al. ASH 2011. Abstract 291.
Rituximab + Lenalidomide in Previously
Untreated CLL: Study Design
●
Treatment protocol: 7 cycles
–
Cycle 1: lenalidomide on 21 of 35 days
–
Cycles 2-7: lenalidomide on 21 of 28 days
 Lenalidomide
– Day 1: Starting dose: 2.5
mg/day
 Rituximab
– 50 mg/m2 on Day 29 of C 1
– 325 mg/m2 on Day 31 of C 1
– Day 8: Escalated to 5 mg/day
– 375 mg/m2 on Day 33 of C 1
– Day 1 cycle 3: increase to 10
mg/day
– 375 mg/m2/wk x 4 for cycle 2
– 375 mg/m2 on Day 1 of C 3-7
 Tumor lysis syndrome prophylaxis with allopurinol 300 mg/day and oral hydration
 Thromboprophylaxis (aspirin 81 mg/day) added after 2 cases of pulmonary embolism
 Methylprednisolone for tumor flare reaction and growth factor support as needed
James DF, et al. ASH 2011. Abstract 291.
Rituximab + Lenalidomide for Patients With
Previously Untreated CLL: Efficacy
Outcome
Younger Than 65 Yrs
(n = 40)
65 Yrs or Older
(n = 29)
ORR, %
 CR
 CRi
 Nodular PR
 PR
95
20
0
20
55
78
7
4
0
68
PD
0
4
Median PFS, mos
 Median follow-up
19
18
20
17
●
●
ORR associated with higher median lenalidomide dose in younger
patients (P = .05)
Greater exposure to lenalidomide in younger patients vs older patients
James DF, et al. ASH 2011. Abstract 291.
Rituximab + Lenalidomide for Patients
With Previously Untreated CLL: Toxicity
AEs, %
Any toxicity
 Grade 1/2
 Grade 3/4
Nonhematologic
toxicity
 Grade 1/2
 Grade 3/4
Tumor flare reaction
 No
 Yes
Younger Than 65 Yrs
(n = 40)
65 Yrs or Older
(n = 29)
33
65
17
69
63
35
38
45
18
83*
41
59
*P = .05 vs older patients.
James DF, et al. ASH 2011. Abstract 291.
ML21445: Rituximab + Chlorambucil
Induction Therapy in Elderly Patients
●
Patients with previously untreated CLL (N = 97)
–
Ineligible for first-line R-FC
observation
Chlorambucil 8 mg/m2/day
Days 1-7
PR, CR
Rituximab
375 mg/m2 Day 1 of cycle 3
500 mg/m2 on Day 1 > C4
●
●
8 cycles (q 28 days)
Primary endpoint: ORR at end of induction
Foa R, et al. ASH 2011. Abstract 294.
R 375 mg/m2
8 wks for 12 doses
ML21445: Responses
Response Following
Induction, %
Patients
(ITT)
(N = 85)
ORR
 All patients
81.2
Response Following
Induction, %
 Binet stage A
86.0
CR/CRi
 Binet stage B
80.0
PR
60.0
 Binet stage C
79.0
PD
3.5
 60-64 yrs of age
84.0
 65-69 yrs of age
85.0
 70-74 yrs of age or older
75.0
 75 yrs of age
81.0
*By flow cytometry.
Foa R, et al. ASH 2011. Abstract 294.
Patients (ITT)
(N = 85)
19
ML21445: Efficacy
●
●
No correlation between treatment response and
standard prognostic factors
Pretreatment gene expression differed between
responders and nonresponders
–
Up-regulation of transcripts relevant to pro-proliferative and antiapoptotic
pathways, including Ras (K-Ras, N-Ras) and Rho
–
Up-regulation of genes related to protein metabolism
–
CD20 down-regulation detected by gene profiling (P = .018 vs
responders) but not by flow cytometry (P = .19 vs responders)
Foa R, et al. ASH 2011. Abstract 294.
ML21445: Toxicity
●
●
●
Chlorambucil dose reduction required in 7.8 % of
cycles
Grade 3/4 Hematologic AEs during induction:
–
Neutropenia: 19.6%
–
Thrombocytopenia: (1.0%)
–
Infections: (1.0%)
Grade 3/4 neutropenia during maintenance:
–
11.8% with rituximab vs 3.1% on observation
Foa R, et al. ASH 2011. Abstract 294.
Identifying High Risk for Progression in CLL
Patients Receiving FCR
●
CLL8 study: FC vs FCR as primary CLL therapy[1]
–
Median PFS: 57.9 mos FCR vs 32.9 mos FC (P < .0001)
–
OS dependent on length (< vs ≥ 2 yrs) of PFS (P < .001)
–
shortened PFS:
–
●
del(17p) + TP53 mutations
●
MRD,[2] IgVH unmutated status,[3] shorter PFS
Elevated β2-microglobulin or high WBC count not predictive
of short PFS
1.. Hallek M, et al. Lancet. 2010;376:1164-1174. 2. Boettcher S, et al. ASH 2008. Abstract 326. 3. Stilgenbauer S, et
al. ASH 2008. Abstract 781.
Identifying High Risk for Progression in
CLL Patients on FCR: Study Design
●
Subset analysis of GCLL CLL8[1] randomized phase III
trial (FC vs. FCR)
–
●
FCR-treated patients from CLL8 with short PFS and MRD at
final restaging (N = 143)
Definition of high risk for early progression
–
MRD levels > 10-2 or
–
MRD levels > 10-4 to < 10-2 plus either
●
del(17p), TP53 mutation, or IgVH unmutated status
Fink A, et al. ASH 2011. Abstract 977.
1.. Hallek M, et al. Lancet. 2010;376:1164-1174
Identifying High Risk for Progression in
CLL Patients Receiving FCR: PFS and OS
●
Survival outcomes significantly better in patients with
CLL and low risk
–
–
Median PFS in low-risk vs high-risk patients
●
69 vs 22 months
●
HR: 6.4 (95% CI: 3.97-10.347; P < .0001)
Median OS in low-risk vs high-risk patients
●
Not reached vs 57 mos
●
HR: 5.758 (95% CI: 2.799-11.844; P < .0001)
Fink A, et al. ASH 2011. Abstract 977.
Lenalidomide + Rituximab Combination
in Relapsed/Refractory CLL: Efficacy
Outcome
Patients (N = 59)
Clinical best response, %
 ORR
66
 CR*
12
 Nodular PR
12
 PR
42
36-mo OS, % (95% CI)
Median PFS, mos (95% CI)
*Minimal residual disease-negative CR.
Badoux XC, et al. ASH 2011. Abstract 980.
75 (64-87)
17.4 (11.9-23.0)
Lenalidomide + Rituximab Combination
Therapy in Relapsed/Refractory CLL
●
●
Patients with relapsed/refractory CLL (N = 59)
Treatment protocol: 28-day cycles
– Rituximab 375 mg/m2
●
●
●
–
–
●
Cycle 1: Days 1, 8, 15, 22
Cycle 2: no administration
Cycles 3-12: Day 1
Lenalidomide 10 mg/day starting Day 9
Allopurinol 300 mg orally Days 1-14 for tumor lysis
prophylaxis
Primary endpoint: ORR
– ITT analysis
– Assessed at end of cycles 3, 6, then Q 6 months
Badoux XC, et al. ASH 2011. Abstract 980.
Lenalidomide + Rituximab Combination in
Relapsed/Refractory CLL: Efficacy

Lenalidomide/rituximab responses not correlated with
disease biology
●
–
Rai stage, bulky disease, cytogenetics by FISH: correlation
insignificant
Fludarabine refractory patients do worse
●
Lower ORR (P < .05)
●
Shorter PFS (P = .019)
Badoux XC, et al. ASH 2011. Abstract 980.
Lenalidomide + Rituximab Combination
in Relapsed/Refractory CLL: Toxicity
Grade 3/4 AEs, n (%)
Patients (N = 59)
Neutropenia
43 (73)
Thrombocytopenia
20 (35)
Anemia
Any infection

Pneumonia/bronchitis
●
Frequent grade 1/2 AEs
–
Fatigue (37%)
9 (15)
–
Diarrhea (36%)
14 (24)
–
Tumor flare (27%)
6 (10)
–
Sensory neuropathy (24%)
–
Rash (22%)
Febrile neutropenia
6 (10)
Hypercalcemia*
1 (2)
Gastrointestinal
3 (5)
Tumor lysis
1 (2)
VTE
1 (2)
Pain
1 (2)
Weakness
1 (2)
Arrhythmia
1 (2)
Badoux XC, et al. ASH 2011. Abstract 980.
●
4 patients experienced secondary
malignancies on treatment
–
Myelodysplastic syndrome: n = 1
–
Squamous cell carcinoma: n = 1
–
Melanoma in situ: n = 1
–
Head/neck cancer recurrence: n = 1
Summary
●
●
●
●
Rituximab + lenalidomide active, well tolerated in both younger
and older patients (younger than 65 or 65 yrs or older) with
previously untreated CLL but produced higher ORR and CR in
the younger cohort
Rituximab + chlorambucil induction therapy active, well
tolerated in elderly patients with previously untreated CLL
In patients with CLL receiving FCR, cytogenetic analysis plus
MRD detection identifies patients at high risk of disease
progression
Lenalidomide + rituximab combination is active as salvage
therapy for patients with relapsed/refractory CLL and has a
manageable AE profile; response rates were lower among
patients with fludarabine-refractory disease
CLL is a Complex Disease
Diagram courtesy of Jan Burger
Therapeutic targeting of the BCR
Signaling Pathway
Stevenson et al. Blood. 2011.
Rationale for Targeting PI3K-δ in CLL
• PI3-kinase active in CLL
vs normal B-cells
• PI3K-δ inhibition in
CLL cells promotes
↑ Apoptosis
↓ Proliferation
↓ Chemokines
↓ Microenvironment
response
Herman S et al: Blood 2010
Lanutti B, et al: Blood 2011
Phase I Cal-101 (GS-1101)
Patient Demographics
Characteristics
N=55
Sex, males/females, %
82/18
Age, median[range], years
63 [37-82]
Bulky adenopathy (5 cm), %
82
Adverse genetics, % del(17p)
31
Relapsed/refractory disease, %
Prior therapies, median [range], n
29/71
5 [2-15]
Prior therapy type, %
Fludarabine
Rituximab
Alkylating agent
Alemtuzumab
100
98
87
33
CAL-101 (GS-1101) Response in CLL
Coutre S, et al: ASCO 2011
Patient B.C.
Diagnosed with CLL in 2002
70 year old man with relapsed bulky CLL
Since 2005:
8 treatment regimens
2010 progressive disease
Refractory CLL-pre treatment
Refractory CLL-after 1
cycle of CAL-101
GS-1101 Progression Free Survival
Coutre S, et al: ASCO 2011
GS-1101 Grade 3-4 Toxicity
Coutre S, et al: ASCO 2011
Where is GS-1101 Going in CLL?
●
Completion of phase I or II studies in untreated
and relapsed CLL
–
GS-1101 +combinations (Sharman et al. Abstract # 1787)
●
Registration studies in CLL
●
OHSU expects to have:
–
GS1101 (CAL-101) registration trial for
relapsed CLL
–
Novel combinations with other kinase
inhibitors
The Bruton’s Tyrosine Kinase (BTK) Inhibitor PCI-32765
Induces Durable Responses in Relapsed or Refractory
(R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic
Lymphoma (CLL/SLL): Follow-up of a Phase Ib/II Study
(abstract # 983)
SUSAN O'BRIEN, MD1, JAN A. BURGER, MD, PHD1, KRISTIE A.
BLUM, MD2, RICHARD R. FURMAN, MD3, STEVEN E. COUTRE, MD4,
JEFF SHARMAN, MD5, IAN W. FLINN, MD, PHD6, BARBARA GRANT,
MD7, NYLA A. HEEREMA, PHD2, AMY J. JOHNSON, PHD2, TASHEDA
NAVARRO8, ERIC HOLMGREN, PHD8, ERIC HEDRICK, MD8 AND
JOHN C. BYRD, MD2
1Department
of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 2Division of Hematology and The
Department of Pathology, The Ohio State University, Columbus, OH 3Department of Medicine, Division of Hematology-Oncology, Weill
Cornell Medical College, New York, NY 4Divisions of Hematology and Oncology and Stanford Cancer Center, Stanford University School
of Medicine, Stanford, CA 5US Oncology, Springfield, OR 6Sarah Cannon Research Institute, Nashville, TN 7Medicine, Vermont Cancer
Center, University of Vermont, Burlington, VT 8Pharmacyclics, Inc, Sunnyvale, CA
Relapsed/Refractory
PCYC-1102-CA
420 mg/d (n=27)
Dates enrolled: 5/20/10–9/27/10
Treatment Naïve ≥ 65 yrs
420 mg/d (n=26)
Dates enrolled: 6/2/10–4/5/11
PCYC-1102-CA
Total enrollment
117 patients
Relapsed/Refractory
840 mg/d (n=34)
Dates enrolled: 10/9/10–4/5/11
High-risk Relapsed/Refractory
420 mg/d (n=25)
Dates enrolled: 6/9/11–7/27/11
Treatment Naïve ≥ 65 yrs
840 mg/d (n=5)
Dates enrolled: 5/31/11–7/8/11
31
Patient Characteristics (cont.)
420 mg/d (N=27)
840 mg/d (N=34)
Total (N=61)
6/26 (23)
4 (15)
8 (30)
9 (33)
17 (50)
18 (53)
24 (71)
27 (79)
23/60 (38)
22 (36)
32 (52)
36 (59)
17/25 (68)
9 (33)
8 (30)
9/25 (36)
18/31 (58)
10 (29)
12 (35)
20/32 (63)
35/56 (63)
19 (31)
20 (33)
29/57 (51)
11 (41)
16 (59)
13/33 (39)
20/33 (61)
24/60 (40)
36/60 (60)
Refractory, # (%)
10 (37)
17 (50)
27 (44)
Bulky Disease, # (%) ≥ 5 cm
13 (48)
1 (4)
20 (59)
9 (26)
33 (54)
10 (16)
Cytopenia at baseline, # (%)
ANC < 1500/μL
HGB < 11g/dL
Platelets < 100,000/μL
HGB < 11g/dL or PLT < 100,00 μL
Prognostic Markers, # (%)
IgVH unmutated:
Del(17p):
Del(11q):
β2 Microglobulin > 3mg/L
ECOG Performance Status, #
(%)
0
1/2
≥ 10 cm
32
Best Response
CR
420 mg/d
(N=27)
1 (4)
840 mg/d
(N=34)
0 (0)
Total
(N=61)
1 (2)
PR
17 (63)
23 (68)
40 (66)
ORR*
67%
68%
67%
Nodal
6 (22)
8 (24)
14 (23)
SD
1 (4)
1 (3)
2 (3)
PD
1 (4)
0 (0)
1 (2)
NE
1 (4)
2 (6)
3 (5)
*Per IWCLL 2008 criteria
Splenomegaly before and after 2 months of
PCI-32765
Before PCI-32765
2 months of PCI-32765
Pattern of Response: Blood Lymphocytes
vs Lymph Nodes
Best Response by Risk Features
All Patients
n/N
41/60
ORR %
68
Hgb < 11 g/dL or PLT < 100K/μL at screening
35/60
58
Del 17p
12/18
67
Del 11q
14/20
70
IgVH unmutated
26/35
74
β2 Microglobulin > 3mg/L
19/29
66
≥ 70 years age
13/18
72
Refractory disease
17/26
65
Bulky disease ≥ 5 cm
24/33
73
Bulky disease ≥ 10 cm
7/10
70
Progression-free Survival
by 17p Del Status
Common AEs (All Grades)
Events occurring in > 15% of Patients (n=61)
Grade
1
Grade
2
Grade
3
Grade
4
Grade 3/4 Infectious and Hematologic
Toxicity
Grade 3/4 Hematology toxicity 1
420 mg/d
(n=27)
840 mg/d
(n=34)
Grade 3 Grade 4
Grade 3 Grade 4
Neutropenia
4%
4%
12%
9%
Anemia
7%
0%
9%
3%
Thrombocytopenia
0%
7%
9%
0%
Grade 3/4 Infectious toxicity
Patients with any Grade 3/4 (%, %)
420 mg/d
(n=27)
840 mg/d
(n=34)
5/2 (19%, 7%)
9/1 (26%, 3%)
1
Reported as AEs
Dasatinib in CLL
●
●
Inhibits SRC, LYN,
BTK
Results published on
15 relpased/refractory
patients
●
ORR 20%
●
Nodal response 66%
●
Can we do better?
Amrein et al. Clinical Cancer Research 2011
Dasatinib in CLL at OHSU
Can we predict who will respond to treatment?
●
Dasatinib Clinical Trial (NCT01441882)
–
Relapsed/refractory of if age > 70, Tx naive
–
Test patient CLL samples in the lab
–
Only enroll patients on trial if the drug first
demonstrates in vitro killing activity
–
Measure cell death signaling pathways
–
Examine signaling and gene expression in vivo
while receiving treatment
C-F: Response to treatment
C-F pretreatment scan
C-F after 6 months of dasatinib
Lymphocyte Count
CF Response to treatment
93 %
change
from
baseline
Summary: Targeting BCR signaling in CLL
●
●
●
●
●
Promising activity including in poor risk
patients
Most effective for nodal disease
Often results in lymphocytosis as CLL cells
are mobilized from the micro-environement
Well tolerated, oral agents
Studies to predict response and with novel
combinations are ongoing
Mantle Cell Lymphoma
●
Role of Rituximab
–
●
R-Cladribine Based Treatment
–
●
Kluin-Nelemans, et al. ASH 2011. Abstract 439
Spurgeon, et al. ASH 2011. Abstract 441
PCI 32765 in Mantle Cell Lymphoma
–
Wang, et al. ASH 2011. Abstract 442
MCL: Poor Prognosis and
Long–Term Outcome
18 months
Patients at risk
R-CHOP
58
45
28
15
5
CHOP
44
35
17
10
3
1
Progression-free survival after CHOP and R-CHOP
There were no significant differences between the two treatment arms (P=0.31)
Lenz G. et al. J Clin Oncol. 2005;23:1984-1992.
Percentage Surviving
Possible Improved Survival in Elderly
Patients Receiving Rituximab
Griffiths, R, et. al. Blood 2011 Nov 3;118(18):4808-16
R-Maintenance
●
SAKK[1]
–
●
GLSG[2]
–
●
 NO BENEFIT after R induction
PFS BENEFIT after R-FCM induction
Modified R-HyperCVAD[3]
–
–
–
2 years of R-Maintenance
PFS = 37 months
Median OS = 70 months
1. Ghielmini M, et al. J Clin Oncol. 2005, 2. Forstpointner, R, et al. Blood 2006) , 3. (Kenkre, V, et al. Leuk Lymphoma 2011)
R-CHOP vs R-FC followed by maintenance with
Rituximab vs. Interferon-alfa in elderly patients
with Mantle cell lymphoma
Hanneke C. Kluin-Nelemans
for the European MCL Network
University Medical Center Groningen
The Netherlands
First RCT for MCL Elderly
8 countries, n = 560 (Jan 2004-Oct 2010)
Newly diagnosed, >60-65 yr; performance 0-2, Stages
II-IV, central PA review
8 x R-CHOP
IFN-a maintenance
(3 x 3 M IU/week)
or Peg-IFN
(1mg/kg week)
PR, CR
6 x R-FC
Rituximab
maintenance
(all 2 months)
MCL Elderly: Baseline Characteristics 1st
randomization
Parameter
Age median (range)
% male
Stage IV
% pos. BM
B-Symptoms
Performance 0-1
Elevated LDH
MIPI low risk
MIPI intermediate risk
MIPI high risk
n
R-CHOP (%)
70 (61-87)
68
83
76
38
92
R-FC (%)
70 (60-85)
72
81
75
38
93
44
7
43
50
43
9
39
52
280
280
MCL Elderly: Overall survival
R-CHOP
R-FC
MCL elderly study
toxicity R-CHOP vs R-FC
100
80
60
40
100 20
90100
0
90
80 80
70 70
60 60
50 50
40 40
30 30
20 20
10 10
0 0
Hb
p=0.016
WBC
p=0.005
Lympho
p=0.011
Neutrophils
Platelets
p=0.25
p<0.001
R-CHOP Grade 3-4
R-CHOP Grade 1-2
R-FC Grade 3-4
R-FC Grade 1-2
Mucositis
Cardiac
Neuropathy
Alopecia
Infections
Febrile
Mucositis
Cardiac Pulm
Pulm
Neuropathy
Alopecia
Infections
Febrile
function
neutropenia
functionfunction
function
neutropenia
p=0.063
p=0.063p=0.70
p=0.70 p>0.99
p>0.99 p<0.001
p<0.001p<0.001
p<0.001p=0.004
p=0.004p=0.085
p=0.085
R-CHOP
Grade
R-CHOP
Grade
R-CHOP
Grade
3-43-4R-CHOP
Grade
1-21-2
R-FC
Grade
R-FC
Grade
R-FC
Grade
3-43-4
R-FC
Grade
1-21-2
MCL Elderly study
Remission duration maintenance
Intention-to-treat analysis
Rituximab
IFN
22-10-2011
MCL Elderly study
Remission duration related to induction
R-CHOP
R-FC
p=0.18 for interaction of induction and maintenance
22-10-2011
MCL Elderly: overall survival
related to induction regimen
After R-CHOP
After R-FC
p=0.0223 for interaction of induction and maintenance
22-10-2011
Toxicity of IFN and Rituximab
90
80
70
60
50
40
30
20
10
0
Hb
100
90 p=0.94
80
70
60
50
40
30
20
10
0
Depression
p=0.16
WBC
p=0.002
Lympho
p=0.054
IFN Grade 3-4
R Grade 3-4
Fatigue
p<0.001
IFN Grade 3-4
R Grade 3-4
Neutro
Platelets
p=0.20
p=0.001
IFN Grade 1-2
R Grade 1-2
Infections
p=0.022
IFN Grade 1-2
R Grade 1-2
R-cladribine based Therapies for MCL
Median PFS 37.5 months
Median OS 85 months
Spurgeon et. al, Leukemia & Lymphoma, 2011
R-cladribine based Therapies for MCL
Spurgeon et. al, Leukemia & Lymphoma, 2011
Phase I/II Study of Vorinostat (SAHA), Cladribine
(2-CdA), and Rituximab Shows Significant Activity
in Previously Untreated Mantle Cell Lymphoma
Stephen E. Spurgeon,MD1, David F. Claxton, MD2,
W. Christopher Ehmann, MD2, Samir S. Parekh, MD,3 Violetta
Leshchenko, PhD3, Motomi Mori, PhD2, Sara Shimko, BA,2
August Stewart, BA,2 Elliot M. Epner, MD PhD2
1. Knight Cancer Institute at Oregon Health & Science University, Portland, OR
2. Penn State Hershey Cancer Institute, Hershey, PA
3. Albert Einstein College of Medicine, Bronx, NY
Study Rationale
●
Cladribine has cytotoxic and epigenetic properties
●
Vorinostat (SAHA):
–
inhibits class I and II histone de-acetylases (HDAC)
–
has shown clinical activity in B-cell lymphomas1
–
●
increases tumor suppressor gene expression when combined
with a hypomethylating agent2-4
Cladribine and HDAC inhibition are synergistic as
evidenced by increased in vitro apoptosis in primary
CLL cells.5
1.
2.
3.
4.
5.
Human Pathology 2007;38(12):1849-1857
J Clin Oncol. 2011 Mar 20;29(9):1198203.
Cancer Sci. 2010 (1):196-200
Blood. 2010 Aug 19;116(7):1025-34
Br J Haematol. 2009 Jan;144(1):41-52.
Inclusion Criteria
●
Treatment Population
–
Phase I: relapsed CD20+ NHL, CLL
–
Phase II: Two cohorts
● Relapsed CD20+ NHL, CLL
● Previously untreated MCL
Primary Study Objectives
Phase I
● Safety and toxicity
Phase II
● Response rates
● Tolerability and toxicity
Secondary Objectives
●
Progression free survival
●
Overall survival
●
DNA methylation, histone deacetylation, and
changes in target gene expression
●
●
Phase I
Phase II dosing
–
No MTD reached
–
Responses were seen in MCL and SLL
Phase II vorinostat dose 400 mg/day, days 1-14
cycle > 1 Rituximab once per cycle
Phase II: Response in Relapsed Cohort (n =17)
Population
Total
MCL
10
MZL
3
2 (66%)
1 CR, 1
PR
FL
1
1 PR (100%)
Relapsed CLL
3
0
NHL Response by Modified Cheson Criteria
CLL Response by IWCLL Criteria
ITT Overall
Response (%)
2 (20%)
2 CR
Phase II: Previously Untreated Mantle Cell Cohort ( n=21)
Median Age (range)
Characteristic
64 ( 42-87)
Number of Patients (%)
Age > 60
Stage IV
Blastic Histology
MIPI*
low
intermediate
high
14 (70%)
20 (95%)
4 (19%)
B2 M > 3.0 g/dl
11 (52%)
11 (52%)
4 (19%)
6 (29%)
* Mantle Cell International Prognostic Index
Phase II: Clinical Response in Previously Untreated
MCL Cohort (n =20)
Response (%) Complete
Remission (%)
Partial
Remission (%)
20 (100%)
5 ( 25%)
15 (75%)
Phase II Toxicity:
Most Prevalent Adverse Events
Event
Frequency (158 treatment cycles)
Hematologic
Gr. 3
Gr. 4
50 (32%)
(11%)
32 (20%)
8 (5%)
17
6 (4%)
3 (2%)
0
0
Neutropenia
Thrombocytopenia
Anemia
8 (5%)
0
Non Hematologic
Fatigue
Infection
Grade 5 Pulmonary Hemorrhage
1 (1%)
Study currently enrolling patients at OHSU
* Off study
Months
Summary: Mantle Cell Lymphoma
●
●
•
•
Induction therapy with R-CHOP vs R-FC favors
R-CHOP: more overall responses, less toxicity
Rituximab maintenance doubles the remission
duration in patients responding upon initial therapy
Vorinostat , cladribine , and rituximab is safe
and effective regimen for lymphoid malignancies
•
All previously untreated MCL patients responded
•
75% CR
PCI-32765 active and well tolerated in relapsed
MCL
Reference/Backup Slides
Tumor Microenvironment
●
●
CLL cells
–
Migrate to stromal cell layer which is protective
–
Secrete CCL3 and CCL4 which attracts T cells
Lymph Nodes
–
●
CD40L engaged with CD40 on T-cells
More sensitive to chemotherapy if removed from
protective niche
Nurse-like cells
●
Marrow stromal cells
and nurse like cells
–
Secrete CXCL 12 and
CXCL 13
–
Attract CLL cells (via
chemokine receptors
CXCR4 and CXCR5)
* Nishio M et al. Blood 106:1012-20, 2005
¶ Burkle A et al. Blood 110:3316-25, 2007
† Burger JA et al. Blood 96, 2655-63, 2000
‡ Deaglio S et al. Blood 105(8):3042-50, 2005
●
●
●
Distinct differences between
node and peripheral blood
Increased expression of
CCL3 and CCL4 in lymph
nodes
Increased expression of
MYC
Y Herishanu et al., Blood. 2011 Jan 13;117(2):563-74
JA Burger et al. Blood. 113(13):3050-8, 2009
CCL3 and CCL4 levels affect prognosis
Sivina M et al, Blood 117:1662-9, 2011
A Phase 1 Study of the Selective
Phosphatidylinositol 3-Kinase-Delta (PI3K)
Inhibitor, GS-1101 (CAL-101), in Combination with
Rituximab and/or Bendamustine in Patients with
Relapsed or Refractory
Chronic Lymphocytic Leukemia (CLL)
Jeff Sharman1, Sven de Vos2, John P. Leonard3, Richard R. Furman3, Steven E. Coutre4, Ian W. Flinn5,
Marshall T. Schreeder6, Jacqueline Barrientos7, Nina D. Wagner-Johnston8, Thomas E. Boyd9, Nathan Fowler10,
Leanne M. Holes11, Harriet (Sissy) Peterman11, Brian J. Lannutti11, Dave M. Johnson11, Thomas M. Jahn11,
Langdon L. Miller11
1US Oncology Research and Willamette Valley Cancer Institute and Research Center, Springfield, OR; 2University of California Los Angeles, Los Angeles,
CA; 3Weill Cornell Medical College, New York, NY; 4Stanford University Cancer Center, Stanford, CA; 5Sarah Cannon Research Institute and Tennessee
Oncology, PLLC, Nashville, TN; 6Clearview Cancer Institute, Huntsville, AL; 7Long Island Jewish Medical Center, New Hyde Park, NY; 8Washington
University, St. Louis, MO; 9US Oncology Research and Yakima Valley Memorial Hospital, Yakima, WA; 10University of Texas, MD Anderson Cancer and
Research Center, Houston, TX; 11Gilead Sciences, Inc., Seattle, WA
Reference: Sharman, ASH 2011, #1787
In Previously Treated CLL, GS-1101 (CAL-101) Has Been
Evaluated as Monotherapy and in Combination Therapy
Phase 1b
Monotherapy
Study
Phase 1b
Combination Study
GS-1101
GS-1101
GS-1101
GS-1101
GS-1101
50 to 350 mg
BID
100 or 150 mg
BID
150 mg
BID
100 or 150 mg
BID
150 mg
BID
Rituximab
Fludarabine
Bendamustine
+
375 mg/m2 weekly
C1 and C2
+
40 mg/m2 P.O.
Days 1 – 5
C1 – C6
+
+
Rituximab
375 mg/m2 D1
C1 – C6
70 or 90 mg/m2
Days 1 and 2
C1 – C6
+
Bendamustine
70 or 90 mg/m2
Days 1 and 2
C1 – C6
Designs:
Phase 1-2 dose-ranging trials
Endpoints: Recommended dosing regimen, safety, antitumor activity
Follow-up: After 48 weeks, patients who continue to benefit can continue GS-1101
single-agent therapy on an extension study
ITT Responsea Rate 95% CI
GS-1101 Combination Therapies Substantially
Increased Overall Response Rate
G Mono
(N=55)
G+R
(N=19)
100
80
84%
n=46
84%
n=16
84%
n=16
LNR
OR
60
G+F
(N=7)
G+B
(N=14)
71%
n=5
71%
n=5
LNR
OR
79%
n=11
79%
n=11
G+R+B
(N=14)
86%
n=12
86%
n=12
LNR
OR
40
20
24%
n=13
0
a
b
Decrease by 50% in the nodal SPD
Response by IWCLL criteria [Hallek 2008]
LNR
OR
Both GS-1101 Monotherapy and Combination
Therapy were Associated with Durable Tumor
Control
GS-1101 Mono
G+R (N=19)
G+F (N=7)
% Progression-free
(N=55)
G+B (N=14)
G+R+B (N=14)
100
75
50
25
0
BL
2
4
6
8
10
12 BL
2
4
6
8
10
12 BL
2
4
6
8
Cycles (4 weeks)
GS-1101 monotherapy:
Median PFS >12 months
GS-1101 combination therapy:
Median PFS not yet reached
10
12
Adverse Event Profiles Have Been Generally Consistent
with the Known Safety Profiles of Each Agent
Grade 3 Adverse Events
(Regardless of Cause)
% (n)
Mono
Combination
GS-1101
(N=63)
GS-1101 +
R
(N=19)
GS-1101
+B
(N=20)
GS-1101
+ BR
(N=13)
All
Comb.
(N=52)
Anemia
10% (6)
5% (1)
10% (2)
̶
6% (3)
Neutropenia
11% (7)
32% (6)
25% (5)
23% (3)
27% (14)
Febrile neutropenia
2% (1)
̶
10% (2)
̶
4% (2)
Thrombocytopenia
8% (5)
5% (1)
15% (3)
8% (1)
10% (5)
ALT/AST elevated
22% (14)
21% (4)
30% (6)*
̶
19% (10)*
Cardiac arrest
̶
5% (1)
̶
̶
2% (1)
Colitis
̶
5% (1)
̶
̶
2% (1)
Fatigue
6% (4)
5% (1)
10% (2)
̶
6% (3)
Pneumonia/Pneumonitis
13% (8)
11% (2)
35% (7)
̶
17% (9)
Rash
3% (2)
5% (1)
10% (2)
8% (1)
8% (4)
̶
̶
5% (1)
̶
2% (1)
Sepsis
* Only 1 pt experienced repeated ALT/AST elevations upon GS-1101 re-exposure